Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:4][NH:5]C(=O)OCC1C=CC=CC=1>[Pd].CO>[NH2:5][CH2:4][CH:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:2]([F:25])([F:1])[F:24]
Reactant: CC(C)(C)OC(=O)NC(CNC(=O)OCc1ccccc1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CN)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of benzyl tert-butyl (3,3,3-trifluoropropane-1,2-diyl)biscarbamate (160 g, 442 mmol) and palladium on carbon (10% w/w, 12 g) in methanol (1500 mL) was stirred at room temperature under a hydrogen atmosphere. After 16 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure, washed with hexane (500 mL), and dried in an oven under reduced pressure to afford tert-butyl (3-amino-1,1,1-trifluoropropan-2-yl)carbamate. MS ESI calc'd. for C8H16F3N2O2 [M+H]+ 229. found 229. 1H NMR (400 MHz, CDCl3) δ 5.30 (d, J=6.8 Hz, 1H), 4.23 (s, 1H), 3.10-2.98 (m, 2H), 1.63 (s, 2H), 1.46 (s, 9H).
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[C:12]2[N:11]=[CH:10][N:9]([CH2:13][CH2:14][CH3:15])[C:8]=2[C:7](=[O:16])[NH:6][C:5]1=[O:17].[K].N1C(=O)C2NC=NC=2NC1=O.Cl[CH2:31][CH2:32][CH2:33][C:34]([OH:37])([CH3:36])[CH3:35]>CO.CN(C)C=O>[OH:37][C:34]([CH3:36])([CH3:35])[CH2:33][CH2:32][CH2:31][N:6]1[C:7](=[O:16])[C:8]2[N:9]([CH2:13][CH2:14][CH3:15])[CH:10]=[N:11][C:12]=2[N:4]([CH3:3])[C:5]1=[O:17]
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(C)(O)CCCCl
Agent: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1cnc2c1c(=O)n(CCCC(C)(C)O)c(=O)n2C
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of 5.6 g (0.1 mol) of potassium hydroxide in 100 ml of methanol is added to a suspension of 20.8 g (0.1 mol) of 3-methyl-7-propylxanthine in 250 ml of methanol. On heating, a clear solution forms, and this is evaporated to dryness under reduced pressure. The potassium salt of the xanthine compound which remains is intensively dried under a high vacuum, 500 ml of dimethylformamide and 15.0 g (0.11 mol) of the tertiary alcohol from stage (a) are added and the mixture is stirred at 80° C. for 18 hours. The mixture is worked up analogously to Example 5b, whereupon 25.1 g of crude product (81.4% of theory) are obtained and can be purified by recrystallization from diisopropyl ether, with the addition of a little ethyl acetate, at the boiling point.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[CH:16]12[CH2:21][CH:20]1[CH2:19][NH:18][CH2:17]2>>[CH:16]12[CH2:21][CH:20]1[CH2:19][N:18]([C:13]([C:5]1[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[CH3:12])[C:2]([Cl:1])=[N:3][CH:4]=1)=[O:15])[CH2:17]2
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Reactant: C1NCC2CC12
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CC4CC4C3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and 3-azabicyclo[3.1.0]hexane by following the similar procedure as described for intermediate-11a.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:14][C:15]([O:17]CC)=[O:16])[C:3]1=[O:20].[Li+:21].[OH-].Cl>C1COCC1.O>[CH3:1][C@@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:14][C:15]([O-:17])=[O:16])[C:3]1=[O:20].[Li+:21]
Reactant: CCOC(=O)CN1C(=O)[C@H](C)OC[C@H]1c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1OC[C@@H](c2ccccc2)N(CC(=O)[O-])C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl [(2S,5R)-2-methyl-3-oxo-5-phenylmorpholin-4-yl]acetate from Step F (125 mg, 0.45 mmol) in THF (4 mL) and H2O (4 mL) was added 1 N aqueous LiOH (0.54 mL, 0.54 mmol) and the resulting mixture was stirred at ambient temperature for 18 h. The mixture was adjusted to pH 6 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=250 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16]S(C(C)(C)C)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[NH2:16][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH2:6][C:7]21[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[CH2:26][CH2:27]2
Reactant: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C1(N)c2cc(Br)ccc2CC12CCC(OC)CC2
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 47.6 %

Procedure:
To a solution of compound 6 (40 mg, 0.11 mmol) in DCM (3 mL) was added TiCl4 (0.22 mL, 0.22 mmol) and the mixture was stirred in microwave at 50° C. for 10 min. After the reaction, bis-trimehtlysilylcarbodiimide (62 mg, 0.33 mmol) was added and the mixture was stirred in microwave at 60° C. for 10 min. The reaction was quenched with ice water and extracted with CH2Cl2, the organic layer was washed with water, brine, dried and concentrated to give the product 7 (20 mg, 57%).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[CH2:9]([N:6]1[CH2:7][CH2:8][CH:4]([CH:1]([OH:3])[CH3:2])[CH2:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)C1CCN(Cc2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.6 %

Procedure:
To a 5° C. solution of 3-acetyl-1-benzylpyrrolidine (1 g, 4.9 mmol [L. E. Overman, J. Am. Chem. Soc. 1983, 105, 6622]) in methanol (10 mL) was added portionwise sodium borohydride (0.37 g, 9.8 mmol). After stirring at room temperature for 17 hours, the mixture was concentrated, diluted with ethyl acetate, washed with water, brine, dried with sodium sulfate and concentrated to afford the title compound (0.75 g). MSCI: m/z=206 (MH+).
Reaction SMILES: C[N:2](CC1C=CC=CC=1)[CH2:3][C:4]#C.O=[C:14]1O[C@H:19]([C@H:21]([CH2:23][OH:24])[OH:22])[C:17](O)=[C:15]1O>>[NH2:2][CH2:3][CH2:4][C:17]1[CH:15]=[CH:14][C:23]([OH:24])=[C:21]([OH:22])[CH:19]=1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: C#CCN(C)Cc1ccccc1
Product: NCCc1ccc(O)c(O)c1

Procedure:
Uptake reaction was performed using each well of a 96-well round-bottom plate and a 200 μl volume in total of a solution containing pargyline (final concentration: 10 μM) and ascorbic acid (final concentration: 0.2 mg/ml).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH2:26][CH2:27][C:28]([CH3:31])([OH:30])[CH3:29]>C(#N)C>[OH:30][C:28]([CH3:31])([CH3:29])[CH2:27][NH:26][CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: CC(C)(O)CN
Solvent: CC#N
Product: CC(C)(O)CNCC(=O)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 52.3 %

Procedure:
Prepared from 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 3 step A) (100 mg, 0.281 mmol) and 1-amino-2-methyl-propan-2-ol (126 mg, 1.405 mmol) in acetonitrile (1 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (60 mg, 52%), MS (ISP) m/e=409.3 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](Br)[C:6]([F:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[CH3:14][CH:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[CH3:16].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.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(OCC)(=O)C>[F:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:20]1[CH2:21][CH2:22][N:17]([CH:15]([CH3:16])[CH3:14])[CH2:18][CH2:19]1
Reactant: COc1cc(Br)c(F)cc1[N+](=O)[O-]
Reactant: CC(C)N1CCNCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(N2CCN(C(C)C)CC2)c(F)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
To 5-bromo-4-fluoro-2-nitrophenyl methyl ether (4.0 g, 16.0 mmol) in dioxane (150 mL) was added 1-(1-methylethyl)piperazine (4.1 g, 32.0 mmol), XANTPHOS (0.9 g, 1.6 mmol), and Cs2CO3 (10.4 g, 32.0 mmol). The mixture was bubbled with N2 for 15 min prior to the addition of Pd2(dba)3 (0.7 g, 0.8 mmol). The reaction was stirred at 100° C. for 18 h. Ethyl acetate (100 mL) was used to dilute the reaction mixture, followed by the addition of water (80 mL). After partitioning, extraction with Ethyl acetate (2×75 mL), drying (Na2SO4), filtration and concentration, silica gel chromatography afforded 1-[2-fluoro-5-(methyloxy)-4-nitrophenyl]-4-(1-methylethyl)piperazine as a yellow solid (3.3 g, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (d, J=6.6 Hz, 6 H), 2.54-2.61 (m, 4 H), 2.68 (dt, J=13.2, 6.6 Hz, 1 H), 3.24-3.31 (m, 4 H), 3.91 (s, 3 H), 6.64 (d, J=7.7 Hz, 1 H), 7.82 (d, J=13.6 Hz, 1 H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[C:9]([CH3:18])([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:10][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)([CH3:18])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)=[CH:3][CH:4]=1)=[O:19]
Reactant: CN1CCN(C(C)(C)C(=O)c2ccc(F)cc2)CC1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(C(=O)C(C)(C)N3CCN(C)CC3)cc2)CC1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
13.2 g (0.05 mol) of 1-(4-fluorophenyl)-2-methyl-2-(4-methylpiperazino)-propan-1-one and 6.5 g (0.065 mol) of 1-methylpiperazine are dissolved in 20 ml of dimethyl sulfoxide, and the solution is heated to about 115° C. together with 6.9 g (0.05 mol) of potassium carbonate. After 15 hours of stirring at about 115° C. the suspension is cooled down and is poured at about 60° C. onto ice. The crystals are filtered off and are recrystallised twice from ethyl acetate. Melting point 133°-136° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:4][CH2:3]1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Br:22][C:20]1[CH:21]=[C:16]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:13][N:12]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: CN1CCN(c2ccc(N)nc2)CC1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Temperature: 120 °C
Yield: 27.8 %

Procedure:
To 5-(4-Methyl-piperazin-1-yl)-pyridin-2-ylamine (1.06 g, 5.53 mmol), 3,5-Dibromo-1-methyl-1H-pyridin-2-one (1.23 g, 4.61 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (400 mg, 0.691 mmol), and cesium carbonate (4.50 g, 13.8 mmol) was added 45 mL 1,4-dioxane and tris(dibenzylidineacetone)dipalladium(0) (422 mg, 0.461 mmol). This was heated in a a 120° C. oil bath for 6 hours under argon. This was partitioned between ethylacetate and dilute aqueous sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution with 2 to 5% methanol/dichloromethane) to yield 5-Bromo-1-methyl-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-1H-pyridin-2-one (484 mg, 1.28 mmol). MS (ESI) 380.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([C:20]([OH:22])=O)[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].P(Cl)(Cl)(Cl)(Cl)[Cl:24]>C1C=CC=CC=1>[CH2:1]([C:8]1[CH:9]=[C:10]([C:20]([Cl:24])=[O:22])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCCCCCc1ccc(-c2ccccc2)c(C(=O)O)c1
Solvent: c1ccccc1
Product: CCCCCCCc1ccc(-c2ccccc2)c(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.29 g of 4-heptylbiphenylcarboxylic acid was added to 10 ml of benzene, and 2.36 g of PCl5 was added little by little under stirring at room temperature, followed by 4 hours of heat-refluxing. Thereafter, the solvent was distilled off to obtain 4-heptylbiphenylcarboxylic acid chloride.
Reaction SMILES: C(=N/[OH:9])\C1C=CC=CC=1.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH3:26])([CH3:25])[C:20]([O:22]CC)=O)[C:14]=1[C:27]#[C:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C=O)C.O1CCOCC1>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:14]=1[C:27]([OH:9])=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:20](=[O:22])[C:19]2([CH3:25])[CH3:26]
Reactant: O/N=C/c1ccccc1
Reactant: CCOC(=O)C#Cc1c(Cl)cccc1C(C)(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(O)c2c(Cl)cccc2C(C)(C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
A solution of (E)-benzaldehyde oxime (234 mg, 1.93 mmol) in dry DMF (9 mL) was added to a suspension of NaH (46 mg, 1.93 mmol) in dioxane (9 mL) at room temperature. The mixture was stirred for 30 minutes and then cooled to 0° C. A solution of ethyl 3-(2-chloro-6-(1-ethoxy-2-methyl-1-oxopropan-2-yl)phenyl)propiolate (520 mg, 1.61 mmol) in dry DMF (9 mL) was added, and the mixture was stirred at 0° C. for 3 hours and then at room temperature for 1 hour. The mixture was quenched with water and then washed with EtOAc (2×). The aqueous layer was made acidic with 10% HCl and then extracted with EtOAc (2×). The extracts were dried over anhydrous MgSO4 and concentrated under vacuum. The residue was purified by flash chromatography to give 210 mg of ethyl 5-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate as a colorless oil. MS m/e=295 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:23])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[NH4+].[Cl-]>CN(C=O)C>[CH2:30]([O:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:23])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: C[C@]12CC[C@@H]3c4cc([N+](=O)[O-])c(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H]3c4cc([N+](=O)[O-])c(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.1 %

Procedure:
To a solution of 3-hydroxy-2-nitroestra-1,3,5(10)-trien-17-one (76b, 1.58 g, 5.0 mmol) in DMF (20 mL) were added potassium carbonate (1.38 g, 10 mmol) and benzyl bromide (0.9 mL, 7.5 mmol) and stirred for 19 h at room temperature. To the reaction mixture was added saturated aqueous NH4Cl at 0° C. and extracted with CHCl3. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was washed with Et2O to afford 2.01 g of 79 (99% yield) mp: 234-235° C.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([OH:14])(C)C.FC(F)(F)C(O)=O.C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C(O)=O>O.CO.CS(C)=O.C1C=CC=CC=1.N1C=CC=CC=1>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:1]([C:10]([CH:5]([CH3:6])[CH3:4])=[O:14])([CH3:8])[CH3:2]
Reactant: CC(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1C2CC3CC1CC(C2)C3
Agent: O=C(O)C(=O)O
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)C(=O)C(C)C
Reaction time: 8 h

Procedure:
Adamantane-1-isopropyl alcohol (50 gm.), 20.6 ml. pyridine, 10.3 ml. trifluoroacetic acid, 387 ml. benzene, and 387 ml. dimethylsulfoxide were added to a reaction flask and 159 gm. dicyclohexylcarbodiimide was added over 5 minutes. The mixture was stirred overnight, a solution of 70 gm. oxalic acid in 650 ml. methanol added, and the reaction mixture left 1 day at room temperature. The solution was mixed with 4 liters of water, stirred several hours, filtered and the ether separated, washed, dried and concentrated. The ether residue was taken up in a small amount of ether, filtered to remove solid, concentrated and distilled to give 37 gm. b0.025 64°-73°.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Al].[CH2:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]1[O:14][CH2:13]1>C1C(O)=CC=C(S(O)(=O)=O)C=1>[CH3:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:9][CH2:13][CH:12]([OH:14])[CH2:11][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCO
Reactant: CCCCCCCCOCC1CO1
Agent: O=S(=O)(O)c1ccc(O)cc1
Agent: [Al]
Product: CCCCCCCCOCC(O)COCCCCCCCC
Temperature: 95 °C
Yield: 80.7 %

Procedure:
Octyl alcohol (11.7 g; 0.09 mol), aluminum triisopropxide (0.36 g; 1.77 mmol) and p-phenolsulfonic acid (0.94 g; 5.40 mmol) were placed in a 100-ml four-necked flask and heated up to 95° C. while stirring them under nitrogen. Octyl glycidyl ether (17.1 g; 0.09 mol) was then added dropwise over 10 minutes, and the resultant mixture was stirred for 3 hours as it was. After completion of the reaction, the reaction mixture was washed with a 4N aqueous solution (40 ml) of sodium hydroxide and additionally twice with water (40 ml) and then purified by vacuum distillation to obtain 23.0 g of 1,3-dioctyl glyceryl ether (9,13-dioxa-11-heneicosanol) as a colorless transparent oil (yield: 81%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[C:29]3[C:30](=[O:35])[CH2:31][CH2:32][CH2:33][CH2:34][C:28]=3[N:27]=[C:26]2[CH:36]([CH3:38])[CH3:37])=[CH:20][CH:19]=1.[NH4+].[Cl-]>C1COCC1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]2[C:29]3[C:30]([CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3])([OH:35])[CH2:31][CH2:32][CH2:33][CH2:34][C:28]=3[N:27]=[C:26]2[CH:36]([CH3:38])[CH3:37])=[CH:22][CH:23]=1
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(=O)CCCC2
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCCCc2nc(C(C)C)n(Cc3ccc(Cl)cc3)c21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Ethyl acetate (1.08 mL) in 2-methylTHF (1 ml) was added dropwise to a stirred solution of LiHMDS, 1M in THF (11.1 mL) cooled to −78° C. under nitrogen atm. The mixture was stirred at −78° C. under nitrogen for 30 mins. Then Intermediate 3 (700 mg) in 2-methylTHF (5 ml) was added dropwise. The RM was stirred at −78° C. under nitrogen for 4 hours. An excess of sat NH4Cl aq. sol. was added and the resulting suspension was warmed up to room temp and extracted with EtOAc (100 ml). The phases were separated and the aqueous layer was again extracted with EtOAc (50 ml), the phases were separated. The organics were combined, dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica (100 g) using a dichloromethane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (670 mg) LC/MS MH+ 405, Rt 0.89 min (2 minute run).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[CH:11][C:10]=12)=[O:5])C.O[Li].O.Cl>C1COCC1.CO.O>[F:18][C:15]([F:16])([F:17])[C:14]1[N:9]2[N:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]2[CH:11]=[C:12]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=2)[CH:13]=1
Reactant: CCOC(=O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cc12
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cc12
Temperature: 23 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
To a solution of 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (example C.22 step 7) (1.21 g, 3.0 mmol) in THF (15 mL), MeOH (1.8 mL) and H2O (4.8 mL) was added LiOH.H2O (0.3.8 g, 9.0 mmol) and the reaction mixture was stirred at 23° C. for 18 h. Poured into ice water, adjusted with 1 N HCl to pH 2–3, filtered the precipitate off, washed with H2O and dried at HV to give the title compound as an off-white solid (1.08 g, 96%). MS (ISN) 373 [(M−H)−]; mp>250° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:15](=O)[CH3:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12].[CH3:18][C:19]([S@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>>[CH3:18][C:19]([S@:22]([NH:24][CH:15]([C:4]1[CH:5]=[N:6][C:7]([O:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:2]([CH3:1])[CH:3]=1)[CH3:16])=[O:23])([CH3:21])[CH3:20]
Reactant: CC(=O)c1cnc(OCCC(F)(F)F)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCCC(F)(F)F
Yield: 65 %

Procedure:
The title compound is prepared in 65% yield (1.50 g, colorless oil) from 1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone (1.63 g, 6.59 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][N:5]=1)(=[O:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19](B(O)O)[CH:20]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]([C:17]2[CH:16]=[C:15]([Cl:14])[CH:20]=[CH:19][C:18]=2[CH3:24])[N:5]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(Cl)cc1B(O)O
Reactant: CCOC(=O)c1cc(C(C)=O)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(C)=O)nn1-c1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.8 %

Procedure:
A mixture of ethyl 3-acetyl-1H-pyrazole-5-carboxylate (364 mg, 2.0 mmol), (5-chloro-2-methylphenyl)boronic acid (680 mg, 4.0 mmol), copper(II) acetate (571 mg, 3.0 mmol) and pyridine (0.32 mL, 4 mmol) in DCM (10 mL) was stirred at r.t. under an air atmosphere for 48 h. After removal of the insolubles by filtration, the filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography (hexane/AcOEt, 90/10) to obtain ethyl 3-acetyl-1-(5-chloro-2-methylphenyl)-1H-pyrazole-5-carboxylate as a white solid (269 mg, 43%),