Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C([O-])(O)=O.[Na+].Cl[CH2:18][C:19](Cl)=[O:20]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:19](=[O:20])[CH2:18][O:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1COc2cc([N+](=O)[O-])ccc2N1
Yield: 91.3 %

Procedure:
This compound was prepared by General Method 1 from 2-amino-5-nitrophenol (6.0 g, 39 mmol), NaHCO3 (7.8 g, 93 mmol), and chloroacetyl chloride (3.58 mL, 45 mmol) to afford 6.91 g (91%) of 7-nitro-2H-1,4-benzoxazin-3(4H)-one. Data for 7-nitro-2H-1,4-benzoxazin-3(4H)-one: Rf 0.44 (11.5:1 CH2Cl2:MeOH); 1H NMR (400 MHz, DMSO-d6) δ 11.3 (br s, 1H), 7.90 (dd, 1H, J=8.7, 2.6), 7.76 (d, 1H, J=2.5), 7.06 (d, 1H, J=8.7), 4.73 (s, 2H).
Reaction SMILES: [CH3:1][OH:2].[CH2:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>[Pd]>[CH2:1]([OH:2])/[CH:8]=[CH:3]\[CH2:4]/[CH:5]=[CH:3]\[CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: C1CCCCC1
Reactant: CO
Agent: [Pd]
Product: CCCCC/C=C\C/C=C\CO
Yield: 95 %

Procedure:
6.2 G (37.8 mmole) of the carbinol obtained as indicated under letter i. above, dissolved in 50 ml of cyclohexane, were hydrogenated at atmospheric pressure in the presence of 120 mg of Lindlar type palladium catalyst. After filtration and evaporation, the obtained residue was chromatographed on a silica column, using as eluting agent a mixture of 1 to 10% ethyl acetate in cyclohexane, to give 5.9 g (yield: 95%) of undeca-2Z,5Z-dienol.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][N:5]2[CH:22]=1.[CH:23](=O)[CH2:24][CH2:25][CH3:26].N1CCCCC1>C(O)C>[CH:23](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[C:4]3[N:5]([CH:22]=[C:2]([CH3:1])[N:3]=3)[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC=O
Reactant: Cc1cn2cccc(OCCCCN3C(=O)CSC3=O)c2n1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCCCOc2cccn3cc(C)nc23)C1=O

Procedure:
To a solution of 1.36 g (4.26 mmol) 3-[4-(2-methylimidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 0.38 ml (4.26 mmol) of n-butyraldehyde in 20 ml of ethanol, 0.04 ml (0.4 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=0/1) to yield 1.23 g (77.2%, yellow oily substance) of the desired product.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:20][CH2:21][CH3:22])[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1>CO>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:20][CH2:21][CH3:22])[CH:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[OH:12])=[CH:6][CH:5]=1
Reactant: CCCC(C(=O)c1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCC(c1ccc(Br)cc1)C(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (917 mg, 24.25 mmol) was added to a MeOH solution (25 ml) containing the intermediate from Step C (6.53 g, 18.66 mol). After stirring for 1 hour at room temperature the solution was concentrated and the residue partitioned between water and EtOAc. The organic phase was washed with water, brine and dried over Na2SO4. The filtered solution was concentrated to give the title compound as an 8:1 mixture of diastereomers which was used in the next step without further purification. 1H NMR for major diastereomer (500 MHz, CDCl3): δ 7.44 (d, J=8.1 Hz, 2H); 7.30 (d, J=8.5 Hz, 2H); 7.19 (d, J=8.5 Hz, 2H); 7.07 (d, J=8.1 Hz, 2H); 4.71-4.68 (m, 1H); 2.81-2.74 (m, 1H); 1.56-1.48 (m, 1H); 1.42-1.32 (m, 1H); 1.12-0.95 (m, 2H); 0.75 (t, J=7.3 Hz, 3H). LC1 4.00 min. (M-OH)=335
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([OH:11])=O>>[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([NH:4][CH2:2][CH3:3])=[O:11]
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Reactant: CCN
Agent: Cl
Product: CCNC(=O)c1ccc(F)c(Cl)c1
Yield: 77 %

Procedure:
Using ethylamine hydrochloride and 3-chloro-4-fluorobenzoic acid in the general procedure for coupling of amines to carboxylic acids (Scheme C), the title compound was obtained (77% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.20 Hz, 3 H) 3.28 (qd, J=7.16, 5.56 Hz, 2 H) 7.53 (t, J=8.84 Hz, 1 H) 7.87 (ddd, J=8.72, 4.80, 2.15 Hz, 1 H) 8.06 (dd, J=7.33, 2.27 Hz, 1H) 8.61 (t, J=4.67 Hz, 1 H). ESI-MS: m/z 202.0 (M+H)+. mp=101.7-101.8° C.
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].Br[CH2:20][C:21]#[C:22][CH2:23][CH3:24]>>[CH2:20]([O:15][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([O:9][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])=[CH:18][CH:17]=1)[C:21]#[C:22][CH2:23][CH3:24]
Reactant: CCC#CCBr
Reactant: CC(C)CCCC(C)Oc1ccc(C(=O)O)cc1
Product: CCC#CCOC(=O)c1ccc(OC(C)CCCC(C)C)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(1,5-dimethylhexyl)oxy]benzoic acid with 1-bromo-2-pentyne, there is obtained p-[(1,5-dimethylhexyl)oxy]benzoic acid-2-pentynyl ester; nD24 = 1.5078.
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[NH:9][C:10]3[CH:11]=[CH:12][N:13]4[C:19]([C:20]5[N:25]=[CH:24][CH:23]=[CH:22][N:21]=5)=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:34]>C(#N)C>[Cl:34][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][C:15]2[C:14]3=[N:17][N:18]=[C:19]([C:20]4[N:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:13]3[CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: O=c1[nH]c2ccn3c(-c4ncccn4)nnc3c2cc1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: Clc1nc2ccn3c(-c4ncccn4)nnc3c2cc1-c1ccccc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8(7H)-one (2-4) (1.4 g, 4.1 mmol) and DMF (0.032 mL) in acetonitrile (20 mL) was added POCl3 (2.3 mL, 24.6 mmol). After stirring at 120° C. for overnight, the solvent was removed under reduced pressure, and the residue was diluted with acetonitrile, and added water. The resulting solid was collected by filtration to give 8-chloro-9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine (2-5) as a colorless solid.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[OH:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:21][CH2:22][O:23][CH3:24])[CH:4]=[CH:5]2.[Cl-].[C:26]([O:34][CH3:35])(=[O:33])[CH2:27][CH2:28][CH2:29][C:30]([O-])=[O:31]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[O:20][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:26]([O:34][CH3:35])=[O:33])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:21][CH2:22][O:23][CH3:24])[CH:4]=[CH:5]2
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reactant: COC(=O)CCCC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCl
Product: COCOc1ccc2c3c1O[C@H]1[C@@H](OC(=O)CCCC(=O)OC)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reaction time: 2 h

Procedure:
4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol (2.0 g, 6.1 mmol) and 4-dimethylaminopyridine (0.8 g, 6.5 mmol) were dissolved in absolute CH2Cl2 (20 ml) and methyl glutarate chloride (1.0 g, 6.08 mmol) were added dropwise whilst cooling with ice and the mixture was stirred for 2 hours at this temperature. The reaction mixture was poured onto water (50 ml), the organic phase was washed twice more with 30 ml of water and dried over MgSO4. The solvent was evaporated off and the residue was separated off by flash chromatography (CH2Cl2 /MeOH 9/1).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9]([O:11][CH3:12])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].Cl[Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23]>O>[I:1][C:2]1[C:10]2[C:9]([O:11][CH3:12])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH:3]=1
Reactant: COc1ncnc2[nH]cc(I)c12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncnc2c1c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.33 h
Yield: 34.2 %

Procedure:
5-Iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (35, 3.4 g, 12.0 mmol) and 20 mL of N,N-dimethylformamide were combined in a round bottom flask and sodium hydride (350 mg, 8.8 mmol) was added at room temperature. After 20 minutes, chloro-triisopropyl-silane (36, 1.9 mL, 8.8 mmol) was added. The reaction was stirred for 2 hours, then poured into water and extracted 3× with ethyl acetate. The organic layers were combined and washed with brine, then dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel flash column chromatography eluting with 0-25% ethyl acetate in hexane. Appropriate fractions were combined and solvents removed under vacuum to provide the desired compound (37, 1.3 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:17])=[CH:11]2.[OH-].[Na+].[CH3:20][C:21](N(C)C)=[O:22]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:17])=[C:11]2[C:21](=[O:22])[CH3:20]
Reactant: CC(=O)N(C)C
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c(C)c(C(C)=O)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
Dimethylacetamide (17.5 ml, 188.4 mmol) is added dropwise with stirring to phosphorous oxychloride (12.9 ml, 138.2 mmol) at 0° C. Stirring is maintained for 45 minutes, at which time the bath is removed and 5-methoxy-2-methylindole (20.25 g, 125.6 mmol) in 15 ml of dimethylacetamide is added dropwise over a period of 75 minutes. The resulting mixture is warmed to 40°-45° C. for 4 hours. The reaction mixture is cooled to 0° C., and 100 g of ice water is added followed by dropwise addition of a solution of sodium hydroxide (50 g) in water (75 ml). The first 1/3 of this sodium hydroxide solution is added slowly and the remainder is added quickly. The exothermic reaction is quickly warmed to boiling for 15 minutes, cooled to room temperature and refrigerated overnight. The resulting crystals are collected by filtration and rinsed four times with water. Recrystallization from ethanol/water gives 17.2 g (67.2%) of pure 1-(5-methoxy-2-methyl-lH-indol-3-yl)ethanone; mp 229.0°-230.5° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1([O:24][CH3:25])[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][CH2:6]1.[NH2:26][C:27]1[C:35]([Cl:36])=[CH:34][C:30]([C:31](O)=[O:32])=[C:29]([O:37][CH3:38])[CH:28]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[NH2:26][C:27]1[C:35]([Cl:36])=[CH:34][C:30]([C:31]([NH:3][CH2:4][C:5]2([O:24][CH3:25])[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:7][CH2:6]2)=[O:32])=[C:29]([O:37][CH3:38])[CH:28]=1
Reactant: COC1(CN)CCN(CCCCCC(=O)c2ccccc2)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1(OC)CCN(CCCCCC(=O)c2ccccc2)CC1
Yield: 49.5 %

Procedure:
4-Aminomethyl-4-methoxy-1-(6-oxo-6-phenylhexyl)piperidine dihydrochloride (2.25 g) as starting compound, triethylamine (2.4 ml), 4-amino-5-chloro-2-methoxybenzoic acid (1.16 g), 1-hydroxybenzotriazole (0.815 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.16 g) were reacted and treated in the same manner as in Example 270 to give 1.43 g of 4-amino-5-chloro-2-methoxy-N-((4-methoxy-1-(6-oxo-6-phenylhexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[C:17]([Br:19])[N:16]=[CH:15][C:14]=1[NH:20][C@@H:21]([CH3:24])[CH2:22][OH:23]>N1C=CC=CC=1>[Br:19][C:17]1[CH:18]=[C:13]([NH:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C:14]([NH:20][C@@H:21]([CH3:24])[CH2:22][OH:23])=[CH:15][N:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](CO)Nc1cnc(Br)cc1N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(Br)ncc2N[C@@H](C)CO)cc1
Temperature: 0 °C
Yield: 48.2 %

Procedure:
p-Toluenesulfonyl chloride (0.022 g, 0.114 mmol) was added to a 0° C. solution of (S)-2-(4-amino-6-bromopyridin-3-ylamino)propane-1-ol (0.028 g, 0.114 mmol) in pyridine (2.0 mL). The reaction mixture stirred at 0° C. and was allowed to warm to room temperature over 16 h. A second portion of p-toluenesulfonyl chloride (0.022 g, 0.114 mmol) was added, and the mixture stirred at room temperature overnight. The mixture was concentrated and the residue was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford a purple solid. This material was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 0-5% methanol-ethyl acetate) to afford (S)-N-(2-bromo-5-(1-hydroxypropan-2-ylamino)pyridin-4-yl)-4-methylbenzenesulfonamide (0.022 g, 48%) as a purple solid. MS (ESI, pos. ion) m/z 400, 402.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[CH3:30][O:31][CH2:32][C:33](Cl)=[O:34]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:33](=[O:34])[CH2:32][O:31][CH3:30])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: COCC(=O)Cl
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)COC)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 100, Step 1, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and methoxyacetyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23][C:22]=2[CH:32]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[N:23][C:22]=4[CH:32]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1ccc2oc(-c3ccccc3)nc2c1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1ccc(-c2nc3cc(COc4ccc(CCCn5ccnc5)cc4)ccc3o2)cc1
Yield: 67 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 5-chloromethyl-2-phenylbezoxazole to give 5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-phenylbenzoxazole. The yield was 67%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 137-138° C.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:36])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C@:5]1([CH2:43][NH:44][CH2:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1)[CH2:4][CH2:3]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:36])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:34][CH:35]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C@:5]1([CH2:43][NH:44][CH2:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCc3ccccn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(CNCCc3ccccn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 74 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((2-(pyridin-2-yl)ethylamino)methyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.119 g, 0.127 mmol) in DCM (1 ml) was added TFA (0.4 ml, 5.19 mmol). The mixture was stirred at rt for 3.5 h and the mixture was concentrated under reduced pressure. The residue was purified by prep. HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to give the title compound as a light-yellow foam (61 mg, 0.094 mmol, 74.3% yield). LCMS: m/e 647.4 (M−H)−, 2.20 min (method 6). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.42-8.48 (m, 1H),7.95 (d, J=8.28 Hz, 2H), 7.65 (td, J=7.65, 1.76 Hz, 1H), 7.17-7.24 (m, 2H), 7.14 (d, J=8.03 Hz, 2H), 5.29 (d, J=4.52 Hz, 1H), 4.71 (br. s., 1H), 4.61 (br. s., 1H), 3.45-3.59 (m, 2H), 3.18-3.32 (m, 3H), 2.74 (d, J=12.30 Hz, 1H), 2.45 (br. s., 1H), 1.70 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H), 0.98-2.13 (m, 24H), 0.96 (s, 3H), 0.94 (br. s., 3H), 0.92 (br. s., 3H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([Cl:28])[CH:19]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][C:14](=O)[CH2:13]2)=[N:6][CH:7]=1.Cl.[NH2:31][OH:32]>CO.N1C=CC=CC=1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([Cl:28])[CH:19]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][C:14](=[N:31][OH:32])[CH2:13]2)=[N:6][CH:7]=1
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=NO)C2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionamide (prepared as in Example 49, 190 mg, 0.38 mmol) and hydroxylamine hydrochloride (40 mg, 0.57 mmol) in methanol (0.90 mL) and pyridine (0.90 mL) was heated under reflux for 3 h. The reaction mixture was allowed to cool to 25° C. and was then concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layers were washed with a 1N aqueous hydrochloric acid solution (50 mL) and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 75% ethyl acetate/hexanes) afforded the N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-hydroxyimino-cyclopentyl)-propionamide 77%) as a yellow foam: mp 100–106° C.; (ES)+-HRMS m/e calcd for C19H20BrClN4O4S (M+H)+ 515.0150 found 515.0154.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[O:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:19](=[O:20])[CH2:18][CH2:17][C:16]([OH:21])=[O:15])=[CH:6][C:5]=1[C:11]([F:12])([F:13])[F:14])([O-:3])=[O:2]
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: O=C(O)CCC(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 37 %

Procedure:
To a solution of 4-nitro-3-(trifluoromethyl)aniline (2.0 g, 9.7 mmol) in toluene (30 mL) was added tetrahydrofuran-2,5-dione (1.2 g, 11.6 mmol) and the mixture refluxed for 1.5 h. The reaction mixture was cooled, filtered, and the solid washed with ether to provide 4-(4-nitro-3-(trifluoromethyl)phenylamino)-4-oxobutanoic acid (1.1 g, 39% yield). M+H m/z 307.3.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].C1COCC1.Cl[CH:17]([F:19])[F:18]>O>[F:18][CH:17]([F:19])[O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)Oc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
100 g (0.4.55 mol) of 4-iodophenol and 54.6 g (1.365 mol) of sodium hydroxide are added to a mixture of 300 ml of THF and 30 ml of water. After stirring for about 1/2 hour, the mixture is evaporated in a rotary evaporator; this is repeated after the addition of 200 ml of toluene. The residue is taken up in 400 ml of THF. The mixture is cooled to 0° C., 47.1 g (0.545 mol) of chlorodifluoromethane are introduced, and the mixture is then stirred for 1 hour. It is then stirred at about +5° C. for 18 hours. The solution above the resulting slurry-like precipitate was decanted off. It was evaporated in a rotary evaporator, and the residue was chromatographed through a silica gel column, using petroleum ether as eluent.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][C:5]2[CH:10]=[N:9][C:8]([N:11]=CN(C)C)=[N:7][C:6]=2[N:16]=1>C(O)C>[NH2:11][C:8]1[N:9]=[CH:10][C:5]2[CH:4]=[C:3]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C:2]([Cl:1])=[N:16][C:6]=2[N:7]=1
Reactant: COc1ccc(-c2cc3cnc(N=CN(C)C)nc3nc2Cl)cc1
Solvent: CCO
Product: COc1ccc(-c2cc3cnc(N)nc3nc2Cl)cc1
Yield: 32.2 %

Procedure:
A mixture of 10 g of N'-(7-chloro-6-(4-methoxyphenyl)-pyrido[2,3-d]pyrimidin-2-yl)-N,N-dimethyl-formamidine from Example 11 and 500 mL of 95% ethanol was refluxed for 3 hours. The solution was concentrated in vacuo and the precipitate collected by filtration. Crystallization from ethanol afforded 2.7 g of the title compound 2-amino-7-chloro-6-(4-methoxyphenyl)-pyrido[2,3-d]pyrimidine, mp 275-280° C. dec.
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH3:24][C:25]1[CH:26]=[C:27]([SH:31])[CH:28]=[CH:29][CH:30]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][C:3](=[O:23])[C:2]=1[S:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=1
Reactant: Cc1cccc(S)c1
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1cccc(SC2=C(O)CC(CCc3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 2.2 mmol of 3-methylbenzenethiol, and 2.2 mmol of piperidine in 30 mL of dichloromethane. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 68°-70° C.). 1H NMR (DMSO-d6) δ2.06 (s, 3H), 2.18-2.36 (m, 3H), 2.60 (m, 1H), 3.38 (2H+H2O), 6.26 (d, 1H), 6.46 (s, 1H), 6.75 (m, 1H), 6.83 (t, 1H), 7.15 (m, 3H), 7.24 (m, 2H), 7.45 (m, 5H).