Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH:24]([CH3:26])[CH3:25]>CN(C)C=O>[F:16][C:2]([F:1])([F:15])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[N:7]([CH:24]([CH3:26])[CH3:25])[CH:6]=1)=[O:4]
Reactant: CC(C)I
Reactant: O=C(c1c[nH]c2cc(Br)ccc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
A solution of 2,2,2-trifluoro-1-(6-bromo-1H-indol-3-yl)-ethanone (3.0 g, 10.27 mmol) in N,N-dimethylformamide (20 mL) at 25° C. was treated with potassium carbonate (3.54 g, 25.68 mmol). The resulting mixture was stirred at 25° C. for 15 min and then treated with 2-iodopropane (1.54 mL, 15.41 mmol). The reaction was heated at 65° C. for 18 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was then washed with a 1N aqueous hydrochloric acid solution (1×25 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 2/1 hexanes/ethyl acetate) afforded 2,2,2-trifluoro-1-(6-bromo-1-isopropyl-1H-indol-3-yl)-ethanone (3.38 g, 99%) as a pink solid: mp 77-79° C.; EI-HRMS m/e calcd for C13H11BrF3NO (M) 332.9976, found 332.9975.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O>[Pt]=O.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:10]
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc(N)c(F)c1
Yield: 93.1 %

Procedure:
A mixture of 11.4 grams (0.067 mole) of 2-fluoro-4-methoxynitrobenzene and 0.4 gram of platinum oxide catalyst in 100 mL of ethanol was placed in a hydrogenation bottle and hydrogenated at 50 psi using a Parr hydrogenator. The completion of the hydrogenation required about two hours. After this time the reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure, yielding 8.8 grams of 2-fluoro-4-methoxyaniline. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][CH2:27][CH2:26][C:25]3=[O:29])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[OH:33]/[N:32]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][C@H:10]([C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:28][CH2:27][CH2:26][C:25]2=[O:29])=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(N3CCCC3=O)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(N3CCCC3=O)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 1-{4-[(R)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-pyrrolidin-2-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=414.3 ([M+H]+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][C:4]([NH:13][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5]
Reactant: NC1CCCCC1
Reactant: O=C(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(CCCl)NC1CCCCC1

Procedure:
β-Chloropropionyl chloride (31.7 g.) is added dropwise to a stirred solution of cyclohexylamine (24.8 g.) and triethylamine (28.2 g.) in toluene (250 ml.). The mixture is cooled and filtered and the filtrate is evaporated to dryness under reduced pressure. There is thus obtained as residue β-chloro-N-cyclohexylpropionamide, m.p. 77°-80° C. β-Chloro-N- 2-furfurylpropionamide may similarly be obtained from furfurylamine.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@@H:6]([C:8]1[N:13]=[C:12]2[N:14]([CH3:23])[C:15](=[O:22])[N:16]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]2=[CH:10][CH:9]=1)[CH3:7])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][CH2:5][C@@H:6]([C:8]1[N:13]=[C:12]2[N:14]([CH3:23])[C:15](=[O:22])[N:16]([CH2:17][C:18]([CH3:20])([CH3:19])[CH3:21])[C:11]2=[CH:10][CH:9]=1)[CH3:7]
Reactant: C[C@@H](CCN=[N+]=[N-])c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](CCN)c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Reaction time: 8 h

Procedure:
To a stirred solution of 36-3 (0.13 g, 0.43 mmol) in ethanol (7 mL) under N2 was added 10% palladium on carbon (0.03 g, 0.03 mmol) in ethanol. The resulting mixture was flushed several times with H2 gas. The resulting mixture was stirred overnight under a balloon of hydrogen. The mixture was flushed with nitrogen and filtered through celite. The filtrate was concentrated to give 36-4. (0.10 g, 84%). LRMS (ES) (M+H)+: observed=291.2, calculated=291.4.
Reaction SMILES: [OH:1][C@H:2]([CH3:22])[C@H:3]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:7]=1)[CH3:4].CC(C)=[O:25]>>[C:6]([OH:25])(=[O:5])[CH3:15].[OH:1][C@H:2]([CH3:22])[C@H:3]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([N:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[N:7]=1)[CH3:4]
Reactant: CC(C)=O
Agent: C[C@@H](O)[C@@H](C)Oc1nc(N2CCNCC2)nc2ccccc12
Product: CC(=O)O

Procedure:
4-[(2R,3R)-(3-Hydroxybutan-2-yl)oxy]-2-(1-piperazinyl)quinazoline (cf. Example 50) (600 mg) is dissolved in acetone (30 ml), and the mixture is filtered. To the filtrate is added acetic acid (135 mg), and the mixture is evaporated to dryness under reduced pressure, and the residue is dissolved in ethyl acetate (6 ml), and the solution is allowed to stand at room temperature. The precipitated crystals are separated by filtration to give 4-[(2R,3R)-(3-hydroxybutan-2-yl)oxy]-2-(1-piperazinyl)quinazoline monoacetate (443 mg) as crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1>>[CH3:18][C:19]1[N:20]=[C:21]([CH2:25][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc(CCl)n1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Agent: Cl
Product: Cc1cc(C#Cc2cn(Cc3cccc(C)n3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=303.1 (M+H30), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloromethyl-6-methyl-pyridine hydrochloride.
Reaction SMILES: [CH3:1][C:2]([CH3:49])([CH3:48])[C:3](=[O:47])[O:4][CH2:5][O:6][P:7]([CH2:19][C:20]([N:22]1[C@H:30]([C:31]([O:33]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:32])[CH2:29][C:24]2([S:28][CH2:27][CH2:26][S:25]2)[CH2:23]1)=[O:21])([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:49])([CH3:48])[C:3](=[O:47])[O:4][CH2:5][O:6][P:7]([CH2:19][C:20]([N:22]1[C@H:30]([C:31]([OH:33])=[O:32])[CH2:29][C:24]2([S:25][CH2:26][CH2:27][S:28]2)[CH2:23]1)=[O:21])([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:8]
Reactant: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1)SCCS2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Reaction time: 1 h

Procedure:
(S)-7-[[[(2,2-Dimethyl-1-oxopropoxy)methoxy]-(4-phenylbutyl)phosphinyl]acetyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, diphenylmethyl ester (2.4 g) in dry dichloromethane is treated with 3.0 ml of trifluoroacetic acid under argon at room temperature. After 1 hour, the trifluoroacetic acid and dichloromethane are removed in vacuo and the resulting oil partioned between ethyl acetate and water. The layers are separated and the organic phase is washed with brine, dried (MgSO4) and evaporated. The residue (4.0 g) is chromatographed on 130 g of silica eluting with dichloromethane/acetic acid/methanol (18:1:1) to give (after azeotropic removal of acetic acid with toluene) 1.5 g of the title compound.
Reaction SMILES: [CH:1]1([N:5]2[CH:9]=[C:8]([N+:10]([O-])=O)[N:7]=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C.CCN(CC)CC.[N:26]1[C:35]2[C:30](=[CH:31][C:32]([CH2:36][C:37](O)=[O:38])=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.[Pd]>[CH:1]1([N:5]2[CH:9]=[C:8]([NH:10][C:37](=[O:38])[CH2:36][C:32]3[CH:31]=[C:30]4[C:35](=[CH:34][CH:33]=3)[N:26]=[CH:27][CH:28]=[CH:29]4)[N:7]=[CH:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccc2ncccc2c1
Reactant: O=[N+]([O-])c1cn(C2CCC2)cn1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc2ncccc2c1)Nc1cn(C2CCC2)cn1
Temperature: -10 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a Parr hydrogenation bottle was added 1-cyclobutyl-4-nitro-1H-imidazole (Preparation 1, 150 mg, 0.9 mmol) and ethyl acetate (10 mL), followed by 10% Pd on carbon (250 mg). The reaction mixture was placed on a Parr hydrogenation apparatus and was reacted for 6 h under 50 psi H2 at 23° C. The contents of the bottle were filtered through a short pad of celite and were rinsed with dry methylene chloride (25 mL) into a flame-dried flask under nitrogen. Et3N (626 uL, 4.5 mmol) was added and the reaction solution was cooled to −10° C. 6-Quinolylacetic acid (168 mg, 0.9 mmol) and tripropylphosphonic anhydride (530 uL, 1.7 M solution in ethyl acetate) were then added and the mixture was stirred at −10° C. for 2 h. The solution was diluted with methylene chloride (50 mL) and washed with water (2×). The aqueous layer was extracted with methylene chloride (3×) and the organic layers were combined and washed with brine (1×). The solvent was removed in vacuo, the residue was adsorbed onto silica gel and chromatographed using the Biotage Flash 12 system with SIM attachment (40:1 methylene chloride-methanol) to afford 130 mg (47% yield) of N-(1-cyclobutyl-1H-imidazol-4-yl)-2-quinolin-6-yl-acetamide (the title compound); 1H NMR (300 MHz, CDCl3) δ 9.48 (s, 1H), 8.87 (dd, J=1.6, 4.3 Hz, 1H), 8.11 (m, 2H), 7.76 (d, J=1.8 Hz, 1H), 7.67 (dd, J=2.0, 8.7 Hz, 1H), 7.44 (d, J=1.6 Hz, 1H), 7.38 (m, 1H), 7.25 (d, J=1.6 Hz, 1H), 4.5 (m, 1H), 3.90 (s, 2H), 2.4 (m, 2H), 2.3 (m, 2H), 1.85 (m, 2H); MS (AP/CI): 307.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7]>>[CH2:6]([N:8]([CH2:2][C:3]([OH:5])=[O:4])[CH2:9][CH3:10])[CH3:7]
Reactant: O=C(O)CCl
Reactant: CCNCC
Product: CCN(CC)CC(=O)O
Yield: 104.8 %

Procedure:
A solution of chloroacetic acid (30 g, 0.32 mol) in diethylamine (230 mL, 2.2 mol) was stirred overnight. The obtained white precipitate was removed by filtration. The filtrate was evaporated to dryness to afford yellow oil to which EtOAc (300 mL) was added. The obtained precipitate was again removed by filtration. The filtrate was evaporated to afford yellow solid residue (44 g) that was washed with hexane (2×100 mL), EtOAc (2×50 mL) and again with hexane (50 mL), and then dried in vacuo to afford title Intermediate 2 (38 g).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:14][C:15](=[O:27])[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4([C:25]#[N:26])[CH2:24][CH2:23]4)[CH:17]=3)[CH:10]=[CH:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[S-:30][C:31]#[N:32].[K+].BrBr>>[NH2:32][C:31]1[S:30][C:3]2[CH:4]=[C:5]([O:6][C:7]3[CH:8]=[C:9]([NH:14][C:15](=[O:27])[C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]5([C:25]#[N:26])[CH2:24][CH2:23]5)[CH:17]=4)[CH:10]=[CH:11][C:12]=3[CH3:13])[CH:28]=[CH:29][C:2]=2[N:1]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2c1
Yield: 20 %

Procedure:
Using N-[3-(4-aminophenoxy)-4-methylphenyl]-3-(1-cyanocyclopropyl)benzamide (1.92 g, 5.0 mmol), potassium thiocyanate (1.94 g, 20.0 mmol) and bromine (1.20 g, 7.50 mmol), and in the same manner as in Example A25(v), the title compound (0.44 g, 20%) was obtained as a pale-yellow powder. 1H-NMR (CDCl3, 300 MHz) δ 1.50 (2H, dd, J=5.1, 7.8 Hz), 1.76 (2H, dd, J=5.1, 7.8 Hz), 2.25 (3H, s), 6.50 (2H, br s), 6.98-7.04 (2H, m), 7.21-7.25 (2H, m), 7.41-7.65 (4H, m), 7.71-7.85 (3H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1>>[F:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([NH:1][CH2:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1cccc(F)c1C(=O)O
Reactant: O=Cc1ccncc1
Product: O=C(O)c1c(F)cccc1NCc1ccncc1

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from 2-amino-6-fluorobenzoic acid (Aldrich) and pyridine-4-carbaldehyde. 13C-NMR (DMSO-d6) δ 167.7, 162.7, 150.6, 149.5, 148.6, 133.8, 121.9, 107.3, 102.6, 101.9, 45.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH2:20][N:21]1C[CH2:25][CH2:24][CH2:23][CH2:22]1.N1CCCC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH2:20][N:21]1[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CN2CCCCC2)c1
Solvent: C1CCNC1
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CN2CCCC2)c1

Procedure:
Compound 66.65A was synthesized using a procedure analogous to that used for 66.64A using pyrrolidine in place of piperidine. MS ESI (pos.) m/e: 344 (M+H)+.
Reaction SMILES: [N:1]1([C@:4]23[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:37])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:53][S:54]([CH:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)(=[O:56])=[O:55]>O1CCOCC1>[CH3:22][C@:19]12[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:37])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:24])([CH3:25])[C:13]([C:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7][C@@H:6]1[C@H:5]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:4]1([NH:1][CH2:2][CH2:3][N:60]1[CH2:61][CH2:62][CH:57]([S:54]([CH3:53])(=[O:56])=[O:55])[CH2:58][CH2:59]1)[CH2:21][CH2:20]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CS(=O)(=O)C1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C
Yield: 51.1 %

Procedure:
To a flask containing a suspension of the crude ethyl 4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-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)cyclohex-3-enecarboxylate (0.055 g, 0.094 mmol) in 1,4-dioxane (2 mL) was added Hunig's base (0.098 mL, 0.561 mmol) followed by 4-(methylsulfonyl)piperidine (0.076 g, 0.468 mmol). The mixture was heated to 100° C. for 20.5 h then was cooled to rt and was purified by flash chromatography using a 20-80% ethyl acetate in hexanes gradient and a 12 g silica gel column. The fractions containing the expected product were combined and were concentrated under reduced pressure to give ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-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)cyclohex-3-enecarboxylate (0.036 g, 0.048 mmol, 51.2% yield) as an off-white solid. LCMS: m/e 751.7 (M+H)+, 2.29 min (method 1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][C:7]=1[O:14][CH3:15].[C:17]([Mg]Cl)#[CH:18]>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:13])[C:17]#[CH:18])=[CH:8][C:7]=1[O:14][CH3:15]
Reactant: C#C[Mg]Cl
Reactant: COC(=O)COc1ccc(C=O)cc1OC
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(OCC(=O)OC)c(OC)c1

Procedure:
[4-(1-Hydroxy-2-propynyl)-2-methoxy-phenoxy]-acetic acid methyl ester was prepared according to Method A above (except the Grignard reagent was added at −78° C.) from (4-formyl-2-methoxy-phenoxy)-acetic acid methyl ester (0.645 g, 2.9 mmol) (from Example 45) in THF (30 mL) and ethynylmagnesium chloride (3.45 mmol, 7 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 525 mg, 72%).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH:12]=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl.Cl.[CH3:16][N:17]([CH3:30])[C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(B)#N.[Na]>CO.C(O)(=O)C.CO.C(Cl)(Cl)Cl>[CH3:16][N:17]([CH3:30])[C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:20][N:21]([CH2:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:22][CH2:23]1
Reactant: CN(CCC=O)C(=O)OC(C)(C)C
Reactant: CN(C)C1(c2ccccc2)CCNCC1
Agent: BC#N
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(CCCN1CCC(c2ccccc2)(N(C)C)CC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.4 %

Procedure:
11.1 g (1.3 eq.) tert-butyl methyl(3-oxopropyl)carbamate were added to a solution of 11 g (1 eq.) N,N-dimethyl-4-phenylpiperidin-4-amine dihydrochloride in 110 ml methanol at 0° C. and the reaction mixture was stirred for 15 min at 0° C. 6.2 g (3 eq.) sodium cyanoboron hydride were then added in portions and the mixture was stirred for 30 min at room temperature. The reaction mixture obtained was adjusted to a pH of 5-6 with acetic acid and stirred for 12 h at room temperature. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCl3). As the conversion was still not complete, 2.4 g sodium cyanoboron hydride were added and the reaction mixture obtained was adjusted to pH 5-6 with acetic acid and stirred for 60 min at room temperature. Once the conversion was complete, the methanol was distilled off, the mixture was made alkaline with saturated NaHCO3 solution, the mixture obtained was extracted with chloroform (3×100 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 5% MeOH/CHCl3). 9 g (60%) of product were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][OH:25])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].O[N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][N:28]3[C:32](=[O:33])[C:31]4[C:30](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]3=[O:38])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCO)ccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCON3C(=O)c4ccccc4C3=O)ccc21
Reaction time: 0.17 h
Yield: 96 %

Procedure:
3-[5-(2-hydroxy-ethoxy)-indol-1yl]-3-phenyl-propionic acid ethyl ester (0.77 g, 2.10 mmol), N-hydroxyphthalimide (0.40 g, 2.40 mmol) and triphenylphosphine (0.85 g, 3.24 mmol) were dissolved in tetrahydrofuran (5 mL). The mixture was placed under an argon atmosphere at 0° C. and stirred for 10 minutes. Diisopropylazodicarboxylate (0.65 g, 3.24 mmol) was added all at once. After stirring overnight (16 h), the solvent was removed under vacuum, and the crude mixture was purified via column chromatogpraphy to afford the title compound (96% yield). 1H NMR (CDCl3) δ 7.79 (m, 2H), 7.70 (m, 2H), 7.15-7.29 (m, 7H), 7.03 (d, 1H, J=2.3 Hz), 6.69 (dd, 1H, J=2.5, 9.0 Hz), 6.43 (d, 1H, J=3.7 Hz), 5.99 (t, 1H, J=7.7 Hz), 4.56 (m, 2H), 4.34 (m, 2H), 4.02 (c, 2H, J=7.2 Hz), 3.27 (m, 2H), 1.06 (t, 3H, J=7.2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([F:9])[CH:3]=1.CS(CCO)(=O)=[O:12].CC(C)([O-])C.[K+]>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([OH:12])[CH:5]=[C:4]([F:9])[CH:3]=1
Reactant: CS(=O)(=O)CCO
Reactant: Fc1cc(F)cc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Oc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a solution of 1-bromo-3,5-difluorobenzene (30.6 mL, 0.266 mole) and 2-(methylsulfonyl)ethanol (66 g, 0.531 mole) in DMSO (240 mL) was added potassium tert-butoxide (76.6 g, 0.682 mole) at 0° C. The resulting mixture was stirred at room temperature for 3 h and quench with 4N HCl slowly to pH≦1. The desired product was extracted with Et2O (12 L) until no product was detected in the aqueous layer. The Et2O was evaporated under reduced pressure to one third the amount of the solvent and washed with 1N NaOH (12 L). Then, the NaOH solution was adjusted to pH=3 and extracted with Et2O until no desired product was detected in the aqueous layer. The Et2O was evaporated under reduced pressure and passed through an Al2O3 column eluted with Et2O to afford 3-bromo-5-fluorophenol as a colorless oil (48 g, 94% yield). LC-MS 190.33 (M+H); Analytical HPLC=2.26 minutes (0-100% CH3CN in H2O with 0.1% TFA in a 4-min run); 1H NMR (400 MHz, CD3OD) δ ppm 6.88-6.64 (m, 2H), 6.58-6.30 (m, 1H), 4.99 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:28](=[O:29])[C:18]3=[CH:19][NH:20][C:21]4[C:22]([F:27])=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]3=[N:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[F:27][C:22]1[C:21]2[NH:20][CH:19]=[C:18]3[C:28](=[O:29])[N:15]([C:12]4[CH:13]=[CH:14][C:9]([NH:8][C:3](=[O:4])[CH:2]([CH3:1])[CH2:6][CH3:7])=[CH:10][CH:11]=4)[N:16]=[C:17]3[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)cc1
Reactant: CCC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)C(=O)Nc1ccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.4 %

Procedure:
(±)-2-Methylbutyryl chloride (13.6 μl, 0.11 mmol) was added dropwise over 30 sec to a stirred solution of 2-(4-amino-phenyl)-6-fluoro-2,5-dihydro-pyrazolo[4,3-c]quinolin-3-one (Intermediate 2) (30 mg, 0.10 mmol), triethylamine (14 μl, 0.11 mmol) and 4-dimethylaminopyridine (2.4 mg, 0.02 mmol) in dichloromethane (1 ml) at room temperature. The mixture was stirred at room temperature for 16 h. The yellow solid was then filtered and purified by washing sequentially with a saturated solution of sodium bicarbonate (1 ml), ethyl acetate (1 ml) and ethyl alcohol (0.5 ml) and finally dried under suction to give the title compound (10 mg, 26%) as a bright yellow solid, LCMS m/z 379.36 [M+H]+ @ RT 1.18 min. δH(400 MHz, (CD3)2SO) 9.89 (1H, s), 8.52 (1H, s), 8.15 (2H, d J 9.0 Hz), 8.01 (1H, d J 7.0 Hz), 7.69 (2H, d J 9.0 Hz) 7.57–7.46 (2H, m), 2.46–2.39 (1H, m), 1.69–1.36 (2H, m), 1.11 (3H, d J 6.8 Hz), 0.91(3H, t J 7.3 Hz).