Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[NH2:25][CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:32][CH3:33]>>[CH2:32]([N:28]1[CH2:29][CH2:30][CH2:31][CH:27]1[CH2:26][NH:25][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:14][CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:33]
Reactant: CCN1CCCC1CN
Reactant: COc1cc(C(=O)O)cc(OC/C=C(\C)CCC=C(C)C)c1OC
Product: CCN1CCCC1CNC(=O)c1cc(OC)c(OC)c(OC/C=C(\C)CCC=C(C)C)c1
Yield: 58.3 %

Procedure:
In a manner identical to Example 15, 3,4-dimethoxy -5-geranyloxy benzoic acid (0.80 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.31 g), thereby yielding 0.62 g (58%) of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([OH:11])=O)=[O:5].[CH2:29]([O:33][NH2:34])[CH2:30][CH2:31][CH3:32]>>[CH2:29]([O:33][NH:34][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([CH3:15])=[C:6]([C:4](=[O:5])[C:3]2[CH:16]=[CH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])=[CH:19][C:2]=2[Cl:1])[CH:7]=1)[CH2:30][CH2:31][CH3:32]
Reactant: Cc1ccc(C(=O)O)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: CCCCON
Product: CCCCONC(=O)c1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1

Procedure:
Compound 424 (100 mg, 0.25 mmol) and O-butyl-hydroxylamine (63 mg, 0.50 mmol) were treated as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: graduated from 20/80 to 60/40) provided the title compound. 13C NMR (CDCl3) δ 195.4, 165.9, 159.3 (dd), 155.7 (dd), 148.3, 142.0, 139.8, 135.4, 133.8, 131.7, 129.5, 129.1, 128.6, 127.7, 124.6 (dd), 124.1 (dd), 116.2, 112.8, 111.7 (dd), 105.0 (dd), 76.9, 30.1, 20.4, 19.1, 13.8
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([Cl:12])[Cl:11])[C@H:3]1[C:14]([OH:16])=[O:15].[C:18]([C@@H:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[N:19]>>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([Cl:11])[Cl:12])[C@H:3]1[C:14]([O:16][C@H:20]([C:18]#[N:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1)=[O:15]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCC(Cl)Cl
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCC(Cl)Cl

Procedure:
Using the procedure of Step F of Example 9, 3 g of the product of Step B and 2.25 g of (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain after elution with 8-3 and 9-1 mixtures of cyclohexane-ethyl acetate 1.6 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2-dichloroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+54°±2° (c=1% in benzene).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([NH:24][C:25]3[S:26][C:27]([C:37](=[O:39])[NH2:38])=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=4)[N:29]=3)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:40](OCC)(OCC)OCC>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]3[N:21]=[CH:40][N:24]([C:25]4[S:26][C:27]([C:37](=[O:39])[NH2:38])=[C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=5)[N:29]=4)[C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(Nc3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2)CC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1

Procedure:
The crude 4-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazole-2-ylamino]-4-nitro-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester (VII.21) was dissolved in 4 mL of acetic acid and 0.14 mL (0.84 mmole) of triethyl orthoformate. The mixture was heated at 70 degrees for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate and saturated aqueous sodium carbonate solution. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-dichloromethane (gradient 50:50-100:0) to give 0.10 g of 4-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazole-2-yl]-3H-benzoimidazol-5-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (I.21a).
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][NH2:11].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27](O)=[O:28])=[C:18]([C:31]([O:33]C)=[O:32])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27]([NH:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([C:3]3[O:2][CH:6]=[CH:5][CH:4]=3)[CH:8]=2)=[O:28])=[C:18]([CH:17]=1)[C:31]([OH:33])=[O:32]
Reactant: NCc1cccc(-c2ccco2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Agent: Cl
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)NCc1cccc(-c2ccco2)c1

Procedure:
Using the same method as in Example 1 (ii), 3-(furan-2-yl)benzylamine hydrochloride was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(furan-2-yl)benzyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 84%). Note that 3-(furan-2-yl)benzylamine.hydrochloride was neutralized in DMA by adding an equivalent amount of triethylamine, and then used in the reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:30][N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[C:33](=[O:38])[CH2:32]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:30][N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[C:33](=[O:38])[CH2:32]3)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CN1CCN(N)CC1=O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(NC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)CC1=O

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 4-amino-1-methyl-piperazin-2-one trifluoroacetate (1:1) as starting materials; LC-MS (UV peak area/ESI) 94.7%, 443.1084 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][N:9]=1)=[O:7].[H-].[Na+].[CH3:22]I.O>CN(C)C=O>[CH3:22][N:5]([CH2:4][CH2:3][C:2]([F:19])([F:18])[F:1])[C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1)=[O:7]
Reactant: CI
Reactant: COC(=O)c1ccc(C(=O)NCCC(F)(F)F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCC(F)(F)F)C(=O)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
To a solution of methyl 6-[(3,3,3-trifluoropropyl)carbamoyl]nicotinate (2.4 g, 8.6 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% suspension in mineral oil) (1.3 g). The reaction mixture was stirred at ambient temperature for 1 h. Methyl iodide (3.42 g, 5.0 mL, 24.1 mmol) was added and the reaction mixture was stirred over night and then added water (20 mL). The reaction mixture was stirred for another 30 min and then extracted with ethyl acetate (2×50 mL). The aqueous layer was acidified with citric acid and the formed precipitate was filtered off and dried in vacuum oven to yield 1.12 g (47%) of the title compound; 1H NMR (400 MHz, CDCl3) δ ppm 9.26 (d, 1 H), 8.49 (d, 1 H), 7.78-7.91 (dd, 1 H), 3.80 (t, 1 H), 3.61-3.73 (m, 1 H), 3.16 (d, 3 H), 2.46-2.76 (m, 2 H); MS (ESI) m/z 277[M+H+].
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Na+].Cl[CH2:7][C:8]1[N:9]=[C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][C:12]=1[CH:13]1[CH2:15][CH2:14]1>CC(O)C>[CH:13]1([C:12]2[O:11][C:10]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[N:9][C:8]=2[CH2:7][O:3][CH:2]([CH3:4])[CH3:1])[CH2:15][CH2:14]1
Reactant: FC(F)(F)c1ccncc1-c1nc(CCl)c(C2CC2)o1
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)OCc1nc(-c2cnccc2C(F)(F)F)oc1C1CC1

Procedure:
A freshly prepared solution of sodium isopropoxide (20 mg of Na, 5 ml of 2-propanol) was added to a solution of 4-chloromethyl-5-cyclopropyl-2-(4-trifluoromethyl-3-pyridyl)-oxazole (200 mg) in 2-propanol (5 ml), and the mixture was heated under reflux for 10 hours. The reaction mixture was subsequently concentrated, mixed with water and extracted with dichloro-methane. The organic phase was washed with saturated sodium chloride solution, dried (MgSO4) and filtered through silica gel. Concentration of the organic phase gave the product in pure form as a pale yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]12.CN(C)C(=O)C.[N:28]1([CH2:33][C:34](Cl)=[O:35])[CH:32]=[N:31][N:30]=[N:29]1.C(=O)([O-])O.[Na+]>ClCCl>[N:28]1([CH2:33][C:34]([NH:1][C@@H:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]23)=[O:35])[CH:32]=[N:31][N:30]=[N:29]1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)Cn1cnnn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cn3cnnn3)[C@H]2SC1

Procedure:
In dichloromethane (10 ml) was suspended 7β-amino-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid (942 mg), followed by the addition of N,N-dimethylacetamide (1 ml). Then, under ice-cooling and stirring, a solution of (1H-tetrazol-1-yl)acetyl chloride (441 mg) in dichloromethane (3 ml) was added. The mixture was further stirred at room temperature for 30 minutes, after which it was poured in an aqueous solution of sodium hydrogen carbonate. The water layer, i.e. aqueous extract, was purified by column-chromatography on Sephadex LH-20. The fractions rich in the desired product were pooled, concentrated, made acidic with phosphoric acid and extracted with ethyl acetate. The extract was dried, concentrated and treated with ether. The procedure provided 7β-[2-(1H-tetrazol-1-yl)acetamido]-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1)([O-:7])=[O:6].[CH3:19]O>>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]([O:16][CH3:19])=[O:15])=[CH:17][CH:18]=1)([O-:7])=[O:6]
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Thionyl chloride (2.3 ml) was added dropwise under ice cooling to a solution of 5.0 g (25 mmol) of 4-nitrophenoxyacetic acid in 250 ml of methanol, followed by stirring at room temperature for 1 hour. After the solvent was distilled out under reduced pressure, the residue was dissolved in 50 ml of methylene chloride, followed by neutralization with an aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over sodium sulfate. The solvent was thereafter distilled out under reduced pressure, whereby 5.2 g of pale yellow powder were obtained (yield: 96%).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][O:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[OH:22])=[O:16].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30](O)[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]([O:22][C:21]1[CH:20]=[CH:19][S:18][C:17]=1[C:15]([O:14][CH3:13])=[O:16])[CH3:31]
Reactant: CC(O)c1ccccc1Cl
Reactant: COC(=O)c1sccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1sccc1OC(C)c1ccccc1Cl
Temperature: 25 °C
Yield: 50.6 %

Procedure:
DEAD (2.6 mL, 16.4 mmol, 1.3 Eq.) was added dropwise to a stirred solution of methyl-3-hydroxythiophene-2-carboxylate (2.0 g, 12.6 mmol, 1.0 Eq.), 1-(2-chlorophenyl)ethanol (2.57 g, 16.4 mmol, 1.3 Eq.) and triphenylphosphine (4.31 g, 16.4 mmol, 1.3 Eq.) in anhydrous THF (30 mL) at 0° C. under nitrogen. The reaction was allowed to warm to ambient temperature overnight. The crude reaction mixture was absorbed onto SiO2 and purified by column chromatography eluting with 0 to 10% EtOAc/petroleum ether to give the sub-title compound as a white solid (1.89 g, 6.37 mmol, 50%); 1H NMR (400 MHz, CDCl3) δ 1.72 (3H, d), 3.87 (3H, s), 5.78 (1H, quint), 6.65 (1H, d), 7.21-7.32 (3H, m), 7.38 (1H, dd), 7.55 (1H, dd).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@H:9]([CH:13]=[CH2:14])[O:8][C@:7]([C:19]#[C:20][CH:21]3[CH2:23][CH2:22]3)([C:15]([F:18])([F:17])[F:16])[C:6]=2[CH:24]=1.[N+](=[CH2:27])=[N-]>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@H:9]([CH:13]3[CH2:27][CH2:14]3)[O:8][C@:7]([C:19]#[C:20][CH:21]3[CH2:23][CH2:22]3)([C:15]([F:16])([F:17])[F:18])[C:6]=2[CH:24]=1
Reactant: C=C[C@@H]1O[C@](C#CC2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O[C@H]1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
To a solution of 71 mg of rel-(3S,5S)-7-chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one (from Example 41) in 7.5 mL of anhydrous ether was added first 4 mg of palladium (II) acetate and then a solution of approximately 1.23 mmol of diazomethane in 3.5 mL of ether. After stirring 30 min at room temperature, the reaction mixture was filtered through a pad of filter-aid and the filtrate was evaporated to dryness. The crude product was purified by column chromatography over silica gel (elution with methylene chloride) to give 65 mg of the title compound as a pure solid was recrystallized from ether-hexanes to afford 36 mg: mp 192-192.50; HRMS: Calcd. for C18H14NO2F3Cl (M-H)- : 368.0665. Found: 368.0657.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3](=O)[CH2:4][C:5]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)=O.Cl.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>C(O)C>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([C:5]3[N:32]([C:29]4[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:31][CH:30]=4)[N:33]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:4]=3)[S:8][C:9]=2[CH:15]=1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: COc1ccc2nc(C(=O)CC(=O)C(F)(F)F)sc2c1
Agent: Cl
Solvent: CCO
Product: COc1ccc2nc(-c3cc(C(F)(F)F)nn3-c3ccc(S(C)(=O)=O)cc3)sc2c1
Yield: 77.2 %

Procedure:
The mixture of 4,4,4-trifluoro-1-(6-methoxybenzothiazol-2-yl)butane-1,3-dione (300 mg, 1.0 mmol) and 4-methylsulfonyl-phenylhydrazine hydrochloride (260 mg, 1.1 mmol) was heated under reflux in ethanol (50 ml) for 3.5 hours, and then allowed to cool. The precipitated crystals were collected and subjected to recrystallization from ethanol and ethyl acetate-isooctane to afford 6-methoxy-2-[1-(4-methylsulfonylphenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]benzothiazole (350 mg, 77%). NMR(CDCl3) δ: 3.11 (3H, s), 3.89 (3H, s), 7.11 (1H, dd, J=2.3 Hz, 8.6 Hz), 7.20 (1H, s), 7.32 (1H, d, J=2.3 Hz), 7.75 (2H, d, J=8.6 Hz), 7.82 (1H, d, J=8.6 Hz), 8.04 (2H, d, J=8.6 Hz); mp 217-218° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4](Cl)[C:3]=1[CH3:13].C1(C)C=CC=CC=1.[OH-].[Na+].[CH3:23][O:24][CH2:25][CH2:26][OH:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([O:27][CH2:26][CH2:25][O:24][CH3:23])[C:3]=1[CH3:13]
Reactant: Cc1c(Cl)ccc(S(C)(=O)=O)c1Cl
Reactant: COCCO
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COCCOc1c(S(C)(=O)=O)ccc(Cl)c1C
Temperature: 25 °C
Yield: 81.2 %

Procedure:
1,3-Dichloro-2-methyl-4-(methylsulfonyl)benzene (13.1 g) and toluene (40 mL) were mixed, and 2-methoxyethanol (4.49 g) and sodium hydroxide (4.55 g) were added, followed by heating and refluxing for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. To the obtained residue, a mixed solvent of methanol (12 mL) and water (48 mL) was added, followed by stirring for a while. Then, the formed solid was collected by filtration, further washed with water and dried to obtain 1-chloro-3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzene (12.4 g) as slightly yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].[OH-].[Li+].C(OCC)(=O)C>CS(C)=O>[F:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([NH:1][C:2]2[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:19]=1
Reactant: CC(C)c1ccc(N)c(C#N)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)c1ccc(Nc2cc(F)ccc2[N+](=O)[O-])c(C#N)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
Heat a solution of 2-amino-5-isopropyl-benzonitrile (1.21 g, 7.55 mmol) with 2,4-difluoro-1-nitro-benzene (1.20 g, 7.55 mmol) and lithium hydroxide (0.54 g, 22.66 mmol) in DMSO (15 ml) to 70° C. for 18 hours. Cool the reaction to ambient temperature and then pour into approximately 200 ml of ice water and stir for one hour. The title compound precipitates and is colleted by filtration. Purify the solid via flash chromatography eluting with a 95% hexanes: 5% ethyl acetate mobile phase to obtain 0.372 g (1.24 mmol, 16% yield) of the title compound as an orange amorphous solid: Mass Spectrum (m/e): 298 (M−1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:13][CH:14]=1
Reactant: c1ccc(COc2ccc(CCNCCC(c3ccccc3)c3ccccc3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(CCNCCC(c2ccccc2)c2ccccc2)cc1
Reaction time: 70 h

Procedure:
The starting material is prepared as follows: The mixture of 7.5 g of N-[2-(4-benzyloxyphenyl)-ethyl]-3,3-diphenylpropylamine, 125 ml of ethanol and 0.25 g of 10% palladium on charcoal is shaken under 3 atmospheres of hydrogen for 20 hours. 4.5 g of fresh catalyst are added and hydrogenolysis continued at 3 atmospheres for 70 hours. The mixture is filtered and evaporated to afford the N-[2-(4-hydroxyphenyl)-ethyl]-3,3-diphenylpropylamine of sufficient purity.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[OH:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:34]3[CH2:33][CH2:32][N:31]([C:28]4[CH:27]=[CH:26][C:25]([OH:24])=[CH:30][CH:29]=4)[CH2:36][CH2:35]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: Oc1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Oc1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
DIPEA (12.15 mL, 69.78 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (10.35 g, 46.52 mmol) and 1-(4-hydroxyphenyl)piperazine (CAS 56621-48-8, 9.12 g, 51.17 mmol) in DMF (80 mL). The resulting solution was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, evaporated to dryness and the residue re-dissolved in DCM (250 mL). The solution was washed with water (200 mL), dried over MgSO4 and evaporated to afford crude product, which was triturated with diethyl ether. The resulting solid was collected by filtration and dried under vacuum to give 4-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]phenol (14.27 g, 84%) as a solid.
Reaction SMILES: [CH3:1][C:2]([OH:10])([CH3:9])[CH2:3][O:4][CH2:5][CH:6]1[CH2:8][O:7]1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:9])[O:10][CH:6]([CH2:8][OH:7])[CH2:5][O:4][CH2:3]1
Reactant: CC(C)(O)COCC1CO1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)COCC(CO)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.5 %

Procedure:
2-methyl-1-(oxiran-2-ylmethoxy)propan-2-ol (620 mg, 4.24 mmol) and 10-CSA (300 mg, 1.29 mmol) were dissolved in DCM (30 mL) and stirred at ambient temperature for 24 hr. Saturated NaHCO3 solution was added and the two layers were separated. The aqueous phase was extracted four times with DCM. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on a silica gel column (heptane:EtOAc 1:0 to 1:2) to give the desired product as a colorless oil (400 mg, 64%). Some starting material was recovered. 1H NMR (400 MHz, CDCl3) δ ppm 3.90-3.96 (1H, m), 3.76 (1H, dd, J=11.2, 2.8 Hz), 3.56 (1H, dd, J=11.6, 4.0 Hz), 3.46-3.50 (2H, m), 3.29 (1H, t, J=11.2 Hz), 3.24 (1H, dd, J=11.6, 1.2 Hz), 2.69 (1H, br s), 1.35 (3H, s), 1.13 (3H, s).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH:24]4[CH2:29][CH2:28][CH:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]4)[CH:19]=3)[CH:14]=2)[CH2:7]1)=[O:5])C.C(O)C.[OH-].[Na+].O.Cl>>[C:30]([C@H:27]1[CH2:28][CH2:29][C@H:24]([O:23][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:22]=[CH:21]3)[CH2:25][CH2:26]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)[C@H]1CCCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CN4CCC[C@H](C(=O)O)C4)ccc3c2)CC1
Reaction time: 18 h

Procedure:
(S)-1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-piperidine-3-carboxylic acid ethyl ester (151.23 mg, 0.33484 mmol) was dissolved in ethanol (5 mL, 80 mmol) then treated with 1 M sodium hydroxide in water (5 mL, 5 mmol). The mixture was stirred vigorously for 18 hours. pH was adjust to 3-4 with 3 N HCl and reaction was then extracted three times with ethyl acetate. Organics were combined then dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Diethyl ether was then added and a white precipitate formed which was removed via filtration to give the title compound as a white solid (21 mg, 13%). EDI-MS: 424.1 (M+H)+. 1H NMR (400 MHz, MeOD) δ=7.82 (s, 1H), 7.74-7.62 (m, 2H), 7.44 (d, J=2.3, 1H), 7.19 (d, J=2.3 Hz, 1H), 7.08 (d, J=2.5, 1H), 4.43-4.34 (m, 1H), 4.33-4.22 (m, 2H), 2.71 (br. s., 1H), 2.16 (d, J=2.0 Hz, 2H), 1.88-167 (m, 4H), 1.40-1.25 (m, 3H), 1.24-1.11 (m, 4H), 1.11-0.94 (m, 5H), 0.80 (s, 9H).