Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[F:3][C:4]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[N:14]2)=[CH:9][CH:8]=1)([F:6])[CH3:5].[NH4+].[Cl-]>CCO.O.[Fe]>[F:6][C:4]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]2)=[CH:9][CH:8]=1)([F:3])[CH3:5]
Reactant: CC(F)(F)c1ccc(Cn2ccc([N+](=O)[O-])n2)o1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Temperature: 75 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-3-nitro-1H-pyrazole (208 mg, 0.81 mmol), iron powder (137 mg, 2.43 mmol) and NH4Cl (218 mg, 4.04 mmol) in a mixture of EtOH (4.0 mL) and water (2.0 mL) was stirred at 75° C. for 45 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (20 mL) was added followed by 1M NaOH (20 mL). The aq. layer was extracted with CH2Cl2 (2×20 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 deep orange oil. LC-MS-conditions 02: tR=0.73 min; [M+H]+=228.13
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:18][C:19](OCC)=[O:20])=[CH:11][CH:10]=1.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:26]1[CH2:25][O:24][C:17]([CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)([CH2:18][CH2:19][OH:20])[O:27]1
Reactant: CCOC(=O)CC1(CCc2ccc(OC)cc2)OCCO1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(CCC2(CCO)OCCO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 2 l. 3-necked r.b. flask equipped with mechanical stirrer, reflux condenser, and heating mantle was added 18 g. (0.474 mole) of LiAlH4 and 500 ml. of dry tetrahydrofuran at such a rate as to control vigorous reflux of reaction solution. 97 g. (0.33 mole) of ethyl 5-(4-methoxyphenyl)-3,3-ethylenedioxypentanoate in 100 ml. of dry tetrahydrofuran and added dropwise over a period of 40 minutes. The reaction mixture was stirred at room temperature for 30 minutes and refluxed for 2 hrs. Excess LiAlH4 was carefully decomposed with saturated Na2SO4 solution. The inorganic solid was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo leaving 84.6 g. of crude ketal alcohol.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH2:33](I)[CH:34]=[CH2:35].[Cl-].[NH4+]>C(OCC)(=O)C.CCCCCC.O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:35][CH:34]=[CH2:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCI
Reactant: O=C(Cc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccccc1
Reaction time: 0.42 h

Procedure:
Combine (S)-4-benzyl-3-phenylacetyl-2-oxazolidinone (14.13 g, 47.9 mmol) and tetrahydrofuran (150 mL). Cool in a dry-ice/acetone bath. Add dropwise a solution of sodium hexamethyldisilazide (52.6 mL, 1.0 M in tetrahydrofuran, 52.6 mmol). After 25 minutes, add allyl iodide (13.12 mL, 143.5 mmol) and then replace the bath with a dry-ice/carbon tetrachloride bath. After 1 hour, quench the reaction by the addition of a saturated aqueous ammonium chloride solution, extract with diethyl ether, and separate the layers. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 15% ethyl acetate/hexane. Combine the product containing fractions, evaporate, and recrytallize from chloroform/hexane to give (S)-4-benzyl-3-(2-phenylpent-4-enoyl)-2-oxazolidinone: Rf =0.40 (silica gel, 15% ethyl acetate/hexane).
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]=[CH:6][C:7]1[CH:35]=[CH:34][C:10]([CH2:11][NH:12][C:13](=[O:33])C2C=CC(N3CCN(CC4C=NC=CC=4)CC3)=CC=2)=[CH:9][CH:8]=1)=[O:4].COC(=O)C=CC1C=CC(CNC([O:51][CH2:52][C:53]2[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=2)=O)=CC=1>>[N:55]1[CH:56]=[CH:57][CH:58]=[C:53]([CH2:52][O:51][C:13](=[O:33])[NH:12][CH2:11][C:10]2[CH:9]=[CH:8][C:7]([CH:6]=[CH:5][C:3](=[O:4])[NH:2][OH:1])=[CH:35][CH:34]=2)[CH:54]=1
Reactant: O=C(C=Cc1ccc(CNC(=O)c2ccc(N3CCN(Cc4cccnc4)CC3)cc2)cc1)NO
Reactant: COC(=O)C=Cc1ccc(CNC(=O)OCc2cccnc2)cc1
Product: O=C(C=Cc1ccc(CNC(=O)OCc2cccnc2)cc1)NO
Yield: 39 %

Procedure:
The titled compound was prepared as described in the process (1-3) using the compound from the process (8-2).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=O)=O)=[C:23]([F:31])[CH:22]=1.O>C1COCC1>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[C:23]([F:31])[CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc(Br)ccc1S
Temperature: 20 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
Triphenylphosphine was added portionwise to a solution of 4-bromo-2-fluorobenzenesulfonyl chloride (8.44 g) in THF (30 ml) at 0° C. After 15 min water was added and the colourless solution was stirred at 20° C. for 18 h. The solvent was removed in vacuo, the residues dissolved in DCM and extracted with 2M sodium hydroxide (twice). The aqueous layers were washed with DCM, combined, acidified (4M HCl) and extracted with ethyl acetate (thrice). These organic extracts were dried (MgSO4) and evaporated to give the sub-title compound (5.89 g).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:12]=[N:11][C:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([N:24]4[CH2:28][N:27]=[C:26]([CH:29]([F:31])[F:30])[O:25]4)=[CH:19][C:18]=3[CH3:32])=[CH:9][CH:8]=2)OCC[O:3]1.C(O)(=O)C.Cl.C(=O)(O)[O-].[Na+]>O>[C:2]([C:7]1[N:12]=[N:11][C:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:18]([CH3:32])=[CH:19][C:20]([N:24]3[CH2:28][N:27]=[C:26]([CH:29]([F:30])[F:31])[O:25]3)=[CH:21][C:22]=2[CH3:23])=[CH:9][CH:8]=1)(=[O:3])[CH3:1]
Reactant: Cc1cc(N2CN=C(C(F)F)O2)cc(C)c1OCCCc1ccc(C2(C)OCCO2)nn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1ccc(CCCOc2c(C)cc(N3CN=C(C(F)F)O3)cc2C)nn1
Yield: 75.8 %

Procedure:
A mixture of 0.24 g (0.538 mmol) of 6-(2-methyl-1,3-dioxolan-2-yl)-3-[3-[2,6-dimethyl-4-(5-difluoromethyl-1,2,4-oxadiazol-2-yl)-phenoxy]-propyl]-pyridazine from example 8d, 20 mL of acetic acid, 5 mL of water, and 5 mL of 2M HCl solution was heated to reflux for 24 hr. The reaction mixture was added to a freshly prepared sodium bicarbonate solution, the aqueous layer was extracted with ethyl acetate (4×50 mL), and the combined organic layer was washed with water (50 mL) and brine (100 mL), dried and concentrated in vacuo. The residue was purified by chromatography on MPLC eluting with 30% ethyl acetate/hexane followed by recrystallization from ethyl acetate/hexane to afford 165 mg (76%) of 6-acetyl-3-[3-[2,6-dimethyl-4-(5-difluoromethyl-1,2,4-oxadiazol-2-yl)-phenoxy]-propyl]-pyridazine (Formula I; R1, R2 =3,5-dimethyl, R3 -6-acetyl, R4 =hydrogen, R5 =5-difluoromethyl-1,2,4-oxadiazolyl, Y=1,3-propylene), m.p. 95°-96° C.
Reaction SMILES: [CH2:1]([N:4]([CH3:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[O:19])=[C:14](F)[CH:13]=1)[CH:2]=[CH2:3].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([N:4]([CH3:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[O:19])=[C:14]([NH:36][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)[CH:13]=1)[CH:2]=[CH2:3]
Reactant: COc1ccc(CN)cc1
Reactant: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(NCc2ccc(OC)cc2)c1

Procedure:
17.55 g of [4-[6-(allyl-methyl-amino)-hexyloxy]-2-fluoro-phenyl]-(4-bromo-phenyl)-methanone are boiled under reflux with 50.7 ml of 4-methoxybenzylamine and 6.5 g of potassium carbonate in 600 ml of toluene for 23 hrs. After filtration, evaporation and purification over silica gel with methylene chloride/methanol (2.5% to 10%) there are obtained 17.43 g of [4-[6-(allyl-methyl-amino)-hexyloxy]-2-[(4-methoxy-benzyl)amino]-phenyl]-(4-bromo-phenyl)-methanone. A solution of this material in 200 ml of trifluoroacetic acid is stirred at room temperature for 45 hrs., evaporated and converted into the free base with methylene chloride/saturated sodium bicarbonate solution. After purification over silica gel with methylene chloride/methanol (9:1) there are obtained 13.23 g of [2-amino-4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl]-(4-bromo-phenyl)-methanone, m.p. of the fumarate 78° C.(decomposition).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[C:28](Cl)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][O:32][C@H:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@H:34]1[NH2:42].C(N(CC)CC)C.C(O)CCC>>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[N:25]=[CH:26][N:27]=[C:28]([NH:42][C@@H:34]3[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:41][C@@H:33]3[O:32][CH3:31])[CH:29]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1N
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(Cl)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Yield: 78.9 %

Procedure:
A mixture of 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine (260.0 mg, 0.0005494 mol), (1R,2S)-2-methoxyindan-1-amine (0.359 g, 0.00220 mol) and triethylamine (115 μL, 0.000824 mol) in 1-butanol (0.97 mL, 0.011 mol) was subjected to microwave irradiation (300 watts, 200° C.) for 30 minutes. The resulting dark brown mixture was filtered and concentrated. The residue was purified by flash chromatography (0 to 15% EtOAc/hexanes) to give 0.26 g (79%) of the title compound. LC/MS: Rt=3.42 min, ES+ 600 (AA standard).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:27].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+].[ClH:83]>C(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.O.C1(C)C=CC=CC=1>[ClH:83].[ClH:83].[ClH:83].[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:27]
Reactant: Brc1ccccn1
Reactant: Cn1c(=O)ccc2cc(OCCCCCNCCc3cccnc3)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c(=O)ccc2cc(OCCCCCN(CCc3cccnc3)c3ccccn3)ccc21
Temperature: 80 °C

Procedure:
1-methyl-6-[5-(2-pyridin-3-ylethylamino)pentyloxy]-1H-quinolin-2-one (182 mg), 2-bromopyridine (0.060 ml), palladium acetate (II) (11.2 mg), xantphos (32 mg), and sodium t-butoxide (68 mg) were added to toluene (2 ml). The mixture was heated at 80° C. for 10 hours under nitrogen atmosphere. The reaction liquid was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution (0.58 ml) was added to a ethanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and diethyl ether were added to the residue. The precipitated insoluble matter was separated, washed with diethyl ether, and dried to give the title compound (72 mg) as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([CH3:12])[CH2:8][CH:7]2[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1C=CC=CC=1>[CH2:24]([O:23][C:21]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([CH3:12])[CH2:8][CH:7]2[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CN1Cc2c(N)cccc2C(c2ccc(Cl)cc2)C1
Solvent: c1ccccc1
Product: CCOC(=O)Nc1cccc2c1CN(C)CC2c1ccc(Cl)cc1
Yield: 45 %

Procedure:
A solution of 13.1 g (0.047 mole) of 8-amino-4-p-chloro-phenyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline and 300 ml of anhydrous benzene is admixed with a solution of 6.8 g (0.0625 mole, 6 ml) of ethyl chloroformate and 60 ml of anhydrous benzene. The reaction mixture is refluxed for 2.5 hours and the benzene is distilled off in vacuo. The residue is dissolved in 10 ml of water, made alkaline with 10 ml of a concentrated ammonium hydroxide solution and extracted three times with 100 ml of chloroform each. The chloroform extracts are united, dried over anhydrous sodium sulfate, evaporated and the residue is recrystallized twice from ethanol. Thus 7.3 g of the title compound are obtained in the form of white crystals, yield 45.6%, Mp.: 155° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:26]=[CH:25][C:7]2[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=[O:23])[NH:17]4)=[CH:9][O:10][C:6]=2[CH:5]=1)[CH3:2].[CH2:27](OC(C1C2C=CC(O)=CC=2OC=1)=O)[CH3:28].BrCC1CC1>>[CH:2]1([CH2:1][O:3][C:4]2[CH:26]=[CH:25][C:7]3[C:8]([CH2:11][O:12][C:13]4[CH:21]=[CH:20][CH:19]=[C:18]5[C:14]=4[CH:15]=[C:16]([C:22]([OH:24])=[O:23])[NH:17]5)=[CH:9][O:10][C:6]=3[CH:5]=2)[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1coc2cc(O)ccc12
Reactant: CCOc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Agent: BrCC1CC1
Product: O=C(O)c1cc2c(OCc3coc4cc(OCC5CC5)ccc34)cccc2[nH]1

Procedure:
4-(6-cyclopropylmethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (30b) is synthesized analogous to 30a from 6-Hydroxy-benzofuran-3-carboxylic acid ethyl ester (26) and bromomethyl cyclopropane.
Reaction SMILES: C([N:5]([C:15](=[O:24])[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1)[NH:6][C:7](=O)[C:8]1C=CC=C[CH:9]=1)(C)(C)C.[H-].[Na+].C(Br)C#C>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([NH:6][NH:5][C:15](=[O:24])[C:16]1[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:8]#[CH:9]
Reactant: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccccc2)C(C)(C)C)c1
Agent: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCNNC(=O)c1cc(C)cc(C)c1
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a stirred suspension of N'-t-butyl-N-benzoyl-N'-(3,5-dimethylbenzoyl)hydrazine (1.5 g) in dimethylformamide (DMF) (20 ml) was added sodium hydride (200 mg of 60% oil dispersion) portionwise. After 15 min., propargyl bromide (0.6 g) was added to the reaction mixture dropwise and the reaction stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (5×20 ml). The organic layer was then dried over magnesium sulfate and the solvent removed under vacuum to afford N-(2-propynyl)-N'-(3,5-dimethylbenzoyl)hydrazine as a yellow amorphous solid. The product, N-(2-propynyl)-N'-t-butyl-N-benzoyl-N'-(3,5-dimethylbenzoyl)hydrazine, was purified by column chromatography on silica gel (solvent system: methylene chloride) to afford a 70% yield as a white solid.
Reaction SMILES: [OH:1][C:2]1([C:30]([F:33])([F:32])[F:31])[C:14]2[CH:13]=[C:12]([CH3:15])[CH:11]=[C:10]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[CH:20]=3)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.FC(F)(F)C(O)=O>O1CCOCC1>[OH:1][C:2]1([C:30]([F:32])([F:33])[F:31])[C:14]2[CH:13]=[C:12]([CH3:15])[CH:11]=[C:10]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:20]=3)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: Cc1cc(-c2cnn(CCC(=O)OC(C)(C)C)c2)c2c(c1)C(O)(C(F)(F)F)c1ccccc1-2
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cnn(CCC(=O)O)c2)c2c(c1)C(O)(C(F)(F)F)c1ccccc1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
To a mixture of 1,4-dioxane (6.7 ml) and an optically active form (1.34 g) of t-butyl 3-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionate was added trifluoroacetic acid (6.7 ml), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure. Toluene was added to the obtained residue and the mixture was concentrated under reduced pressure. To the residue was added water (10 ml) and the mixture was extracted twice with ethyl acetate (10 ml). The combined organic layer was washed twice with water (10 ml) and once with saturated brine (10 ml), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the obtained filtrate was concentrated under reduced pressure. Toluene was added to the obtained residue and the mixture was concentrated under reduced pressure. n-Hexane (10 ml) was added to the concentrated residue, and the slurry was stirred and filtered. The obtained solid was washed with n-hexane, and dried under reduced pressure to give the title compound (1.12 g, 96%).
Reaction SMILES: [F:1][C:2]1([F:14])[O:7][C:6]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:5]=2[NH:4][C:3]1=[O:13].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>O>[F:14][C:2]1([F:1])[O:7][C:6]2[CH:8]=[C:9]([F:12])[C:10]([N+:20]([O-:22])=[O:21])=[CH:11][C:5]=2[NH:4][C:3]1=[O:13]
Reactant: O=C1Nc2ccc(F)cc2OC1(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1Nc2cc([N+](=O)[O-])c(F)cc2OC1(F)F
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (2.5 g, 12.31 mmol) was dissolved in sulfuric acid (40 ml, 750 mmol). The reaction mixture was cooled to 0-5° C. Slowly nitric acid (1.761 ml, 39.7 mmol) was added dropwise and the temperature was maintained between 0-5° C. The reaction mixture was stirred for 30 min at this temperature. Then the reaction mixture was added dropwise to vigorously stirred cold water. A solid was formed, which was extracted with dichloromethane. The combined extracts were dried over Na2SO4, and concentrated to yield 2.56 g of the title compound as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]2[C:9]([O:16]C)=[N:10][C:11]([O:14]C)=[N:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1>CO>[CH3:1][C:2]1[O:3][C:4]([C:8]2[C:9](=[O:16])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: COc1ncc(-c2oc(C)nc2C)c(OC)n1
Solvent: CO
Product: Cc1nc(C)c(-c2c[nH]c(=O)[nH]c2=O)o1
Yield: 92.7 %

Procedure:
To a solution of 5-(2,4-Dimethyl-oxazol-5-yl)-2,4-dimethoxy-pyrimidine (Prep61, 600 mg, 2.5 mmol) in MeOH (40 mL) 2N HClaq (10 mL) was added. After refluxing the mixture for 3 hours, the solvents were evaporated. The crude was triturated with acetone and filtered to give 480 mg of 5-(2,4-Dimethyl-oxazol-5-yl)-1H-pyrimidine-2,4-dione as a light brown powder (92% yield)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH2:18][CH3:19])[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[Na+].[I-].Cl[CH2:28][CH2:29][NH:30][C:31]([NH:33][C:34]1[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([CH3:41])[CH:35]=1)=[O:32]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:28][CH2:29][NH:30][C:31]([NH:33][C:34]3[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([CH3:41])[CH:35]=3)=[O:32])[CH2:14][CH2:13]2)[CH2:18][CH3:19])=[O:10])=[CH:4][CH:3]=1
Reactant: CCN(C(=O)Cc1ccc(Cl)cc1)C1CCNCC1
Reactant: Cc1cc(NC(=O)NCCCl)cc(C)n1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(=O)Cc1ccc(Cl)cc1)C1CCN(CCNC(=O)Nc2cc(C)nc(C)c2)CC1
Temperature: 50 °C
Reaction time: 648 h

Procedure:
A suspension of 2-(4-chloro-phenyl)-N-ethyl-N-piperidin-4-yl-acetamide (Example A10., 3.37 g, 12.0 mmol), NaHCO3 (5.4 g, 64 mmol), NaI (1.2 g, 8 mmol) and 1-(2-chloro-ethyl)-3-(2,6-dimethyl-pyridin-4-yl)-urea (Example D1, 1.82 g 8 mmol) in THF (40 mL) is stirred at 50° C. for 27 days. The mixture is quenched with Na2CO3 (150 mL) and extracted with CH2Cl2 (3×100 mL). The organic extracts are washed with sat. aq. Na2CO3 (70 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by MPLC to provide the title compound.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]([F:30])([F:29])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([O:26]CC)=[O:25])=[CH:20][CH:19]=3)[CH:15]=[CH:16][CH:17]=2)[N:6]=1.Cl>C1COCC1.CO.[Cl-].[Na+].O>[F:30][C:4]([F:3])([F:29])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=3)[CH:15]=[CH:16][CH:17]=2)[N:6]=1
Reactant: CCOC(=O)c1ccc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)cc1
Temperature: 45 °C

Procedure:
Lithium hydroxide (2 M, 0.374 mL, 0.749 mmol) was added to a solution of ethyl 3′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-4-carboxylate in THF (1.99 mL) and methanol (0.99 mL) at room temperature, and then the mixture was heated at 45° C. for 6 hours. The reaction mixture was cooled to room temperature, neutralized with 10% aqueous HCl, diluted with brine, extracted with ethyl acetate (2×), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes+0.1% AcOH) to afford 3′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-4-carboxylic acid as an off-white solid MS ESI calc'd. for C18H13F3N3O2 [M+H]+ 360, found 360. 1H NMR (500 MHz, CD3OD): δ 8.74 (s, 1H); 8.17 (s, 1H); 8.12 (d, J=7.9 Hz, 2H); 7.81-7.73 (m, 3H); 7.45 (t, J=7.9 Hz, 1H); 7.42-7.36 (m, 1H); 7.15 (d, J=4.5 Hz, 1H).