Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl[CH2:28][CH2:29][C:30]1(Cl)[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH2:31]1>>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]4[CH:24]=[CH:25][S:26][C:20]=4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])=[CH:31][CH:32]=1
Reactant: FC1=CCC(Cl)(CCCl)C=C1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Product: ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OCCc3ccc(F)cc3)cc12

Procedure:
6-[2-(4-Fluoro-phenyl)-ethoxy]-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime was prepared in 18% overall yield using the method described in example 127, starting from 6-Hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime (example 127B) and 1-(2-Chloro-ethyl)-4-fluorophenyl hydrochloride.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH2:7]O)=[CH:3][CH:2]=1.[BrH:15]>O>[Br:15][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:2][CH:3]=1
Reactant: Br
Reactant: OCc1ccc(-c2ccccc2)cc1
Solvent: O
Product: BrCc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
A mixture of biphenyl-4-yl-methanol (250 mg, 1.35 mmol) and aqueous HBr (48%) (3 mL) was stirred at 10° C. for 3 hrs. After completion of the reaction, the mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer collected was concentrated under reduced pressure to afford 330 mg (98.5% Yield) 4-bromomethyl-biphenyl. 4-Bromomethyl-biphenyl (120 mg, 0.485 mmol) was added to a stirred mixture of 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (134 mg, 0.44 mmol) (prepared according to Step 1 and 5 of the General Scheme), LiOH.H2O (40 mg, 0.97 mmol) and 4 Å molecular sieves (350 mg) in DMF (4 mL) and stirring was continued overnight. The reaction mixture was filtered and filtrate was diluted with cold water, extracted with ethyl acetate and organic layer was dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using neutral alumina and 5% MeOH in DCM as eluent) to afford 22 mg (11.4% Yield) of 2-[(biphenyl-4-ylmethyl)-amino]-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone. LC/MS [M+H]+: 435, 90.56%. 1H NMR (CDCl3): δ7.64-7.52 (m, 4H), 7.5-7.3 (m, 6H), 7.24-7.15 (dt, 1H), 7.0-6.86 (m, 2H), 4.6 (q, 1H), 4.0-3.8 (m, 3H), 3.7-3.6 (m, 3H), 3.5 (s, 2H), 3.4-3.3 (m, 1H), 2.0-1.8 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: CC(C)(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3Cc2ccccc2)cc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (50.0 mg, 0.222 mmol) using the same procedure employed for Example 2 (2), but with 4-tert-butylphenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (34.1 mg, 38%) having the following characteristics.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[C:6]([CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[CH:5]=[C:4]([C:27]2[C:32]([OH:33])=[CH:31][CH:30]=[CH:29][C:28]=2[O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[N:3]=1.[ClH:39]>O1CCOCC1>[ClH:39].[NH2:1][C:2]1[N:3]=[C:4]([C:27]2[C:28]([O:34][CH2:35][CH:36]3[CH2:37][CH2:38]3)=[CH:29][CH:30]=[CH:31][C:32]=2[OH:33])[CH:5]=[C:6]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:7]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3c(O)cccc3OCC3CC3)nc(N)c2Cn2ccnc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(-c2c(O)cccc2OCC2CC2)cc(C2CCNCC2)c1Cn1ccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 4-[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-(1H-imidazol-1-ylmethyl)-4-pyridinyl]-1-piperidinecarboxylate (0.260 g, 0.500 mmol) in 1,4-dioxane (10 mL) was added 4N HCl in dioxane (10 mL). The mixture was stirred at room temperature for 2 hrs. The resulting precipitate was collected by filtration, washed with acetonitrile, and dried under reduced pressure to give 2-[6-amino-5-(1H-imidazol-1-ylmethyl)-4-(4-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethoxy)phenol hydrochloride. (0.248 g, yield; quant.)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][C:14]1[C:18](B2OC(C)(C)C(C)(C)O2)=[C:17]([CH3:28])[O:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][C:14]1[C:18]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[CH3:12])=[C:17]([CH3:28])[O:16][N:15]=1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1-c1c(C)noc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of methyl 4-bromo-3-methylbenzoate (4 g; 17.5 mmol; 1 eq.), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)isoxazole (Fluorochem 11035; 4.28 g; 19.2 mmol; 1.1 eq.), potassium carbonate (12.1 g; 87.3 mmol; 5 eq.) and Pd(PPh3)4 (2.02 g; 1.75 mmol; 0.1 eq.) in toluene (20 mL) and water (20 mL) was refluxed for 4 hours. The reaction mixture was cooled down to room temperature and filtered through a pad of CELITE which was further washed with toluene (200 mL). The filtrate was concentrated in vacuo and the residue taken up in Ethyl acetate (250 mL). The organic layer was washed with sat. aq. NaHCO3 (100 mL), water (100 mL) and brine (100 mL) then dried over magnesium sulfate and concentrated in vacuo. The residue (3 g; 12.2 mmol; 1 eq.) was taken up in EtOH (90 mL), sodium hydroxide (5M; 7.34 mL; 36.7 mmol; 3 eq.) was added and the reaction mixture was stirred at 60° C. for one hour. After concentration in vacuo, the residue was taken up in water (200 mL) and the aqueous phase was washed with Ethyl acetate then acidified to pH 2 with conc. HCl. The solution was concentrated to ca. 100 mL and the precipitate filtered off and dried. Trituration in Et2O and filtration afforded the title compound as a beige solid.
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH:9]([CH3:13])[CH2:10]C#N)=[O:8])=[CH:5][CH:4]=1.Br.[OH-].[Na+].[C:19](=[O:22])(O)[O-:20].[Na+]>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]([CH3:10])[CH2:13][C:19]([OH:20])=[O:22])=[O:8])=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)C(C)CC#N)cc1
Reactant: O=C([O-])O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)C(=O)c1ccc(O)cc1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 78185.6 %

Procedure:
A 5 L three-necked round-bottomed flask equipped with a reflux condenser connected to a base trap, a glass rod air driven stirrer, and a thermometer was charged with 192.0 g (0.946 mmol) of (±)-3-(4'-methoxybenzoyl)-3-methylpropionitrile from Example G and 48% aqueous hydrogen bromide (1.0 L). The reaction mixture was heated over 1 hr to 65° C. then stirred at this temperature for 45 min (this effected complete hydrolysis of the nitrile moiety). The reaction temperature was increased to 110° C. and the solution was stirred for 3.5 hrs to effect demethylation. The solution was cooled to 23° C., diluted with water (1250 ml), cooled to 0° C. and the pH was adjusted to pH 8.5 with sodium hydroxide pellets (325 g) and powdered sodium bicarbonate (50 g). The aqueous solution was washed with EtOAc (2.5 L), transferred to a 4 L beaker in an ice/water bath and the pH was adjusted to pH 2 with 36% concentrated hydrochloric acid (Fisher, 150 ml). The aqueous solution was extracted with EtOAc (1L) and the organic layer was separated. The aqueous solution was saturated with solid sodium chloride (200 g) then extracted again twice with EtOAc (1×1L, 1×0.5L). The combined organic extracts were dried over anhydrous magnesium sulfate (10 g), filtered and concentrated in vacuo to provide 154.0 g (78%) of pure (±)-3-(4'-hydroxybenzoyl)-3-methylpropanoic acid, m.p. 122°-126° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1.[ClH:17].CO>CO>[ClH:17].[ClH:17].[F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Agent: Cl
Solvent: CO
Product: FCCN1CCNCC1
Temperature: 50 °C
Yield: 87 %

Procedure:
To the solution of 1,1-dimethylethyl 4-(2-fluoroethyl)-1-piperazinecarboxylate (from a different batch than previously described) (160 g, 0.68 mol) in MeOH (500 mL) was added HCl/MeOH (5M, 1000 mL), and the mixture was heated at 50° C. for 1 h before evaporating most of the solvent. The residue was filtered and washed with MeOH to give the title compound of Step B (122 g, 87% yield). 1H NMR (400 MHz, D2O) δ ppm 3.60-3.78 (m, 10H), 4.80 (t, J=4.4 Hz, 1H), 4.92 (t, J=4.4 Hz, 1H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:16][CH2:15][N:14]([C:17](=[O:27])/[CH:18]=[CH:19]/[CH2:20][N:21]([CH:23]4[CH2:26][CH2:25][CH2:24]4)[CH3:22])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:16][CH2:15][N:14]([C:17](=[O:27])/[CH:18]=[CH:19]/[CH2:20][N:21]([CH:23]4[CH2:26][CH2:25][CH2:24]4)[CH3:22])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=3)[C:3]=12
Reactant: CN(C/C=C/C(=O)N1CC[C@@H](n2nc(I)c3c(N)ncnc32)C1)C1CCC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: COCCOC
Product: CN(C/C=C/C(=O)N1CC[C@@H](n2nc(-c3ccc(Cl)cc3)c3c(N)ncnc32)C1)C1CCC1
Temperature: 80 °C

Procedure:
A mixture of (R,E)-1-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)-4-(cyclobutyl(methyl)amino)but-2-en-1-one (22) (400 mg, 0.832 mmol), 4-chlorophenylboronic acid (156 mg, 1 mmol), K3PO4.3H2O (664 mg, 2.5 mmol) and Pd(dppf)2Cl2 (34 mg, 0.04 mmol) in DME/H2O (8 mL/2 mL) was purged with N2 (3×) and then heated to 80° C. overnight. After cooling down to rt, the reaction mixture was concentrated and the residue was purified by prep. HPLC (15%-95% acetonitrile/H2O (0.2% NH3H2O)) to provided (R,E)-1-(3-(4-amino-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin 1-yl)pyrrolidin-1-yl)-4-(cyclobutyl(methyl)amino)but-2-en-1-one (23) as a white solid. (20 mg, 5%), LC-MS (ESI): m/z (M+1) 466.1. 1H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 7.64 (m, 2H), 7.56 (m, 2H), 6.60 (m, 1H), 6.36 (dd, J=29.6, 15.6 Hz, 1H), 5.44 (m, 1H), 3.85 (m, 4H), 2.96 (dd, J=20.5, 6.3 Hz, 2H), 2.78 (m, 1H), 2.40 (m, 2H), 1.96 (m, 5H), 1.73 (m, J2H), 1.56 (m, 2H).
Reaction SMILES: [CH2:1]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[CH2:1]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12][Cl:18])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Cc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(Cc2ccccc2)cc1
Temperature: 0 °C

Procedure:
4-benzylbenzyl alcohol (181.47 g) was dissolved into chloroform (100 ml), and thionyl chloride (66.8 ml) was added with stirring at a 0° C. After stirring at 0° C. for 4 hours, reaction mixture was concentrated under reduced pressure to give the title compound (198.34 g). This product was used in the subsequent procedure without purification.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([CH:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[N:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[NH4+].[OH-].CO>CCO.CCOC(C)=O>[N:26]1([C:2]2[N:10]=[C:9]3[C:5]([NH:6][CH:7]=[N:8]3)=[C:4]([CH:11]3[CH2:16][NH:15][CH2:14][CH2:13][N:12]3[C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[N:3]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: C[Si](C)(C)CCOC(=O)N1CCNCC1c1nc(Cl)nc2nc[nH]c12
Reactant: C1CNCCN1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOC(=O)N1CCNCC1c1nc(N2CCNCC2)nc2nc[nH]c12
Temperature: 145 °C
Yield: 95.8 %

Procedure:
2-Chloro-6-[N-(trimethylsilylethoxycarbonyl)-piperazinyl]purine (17.10 g, 44.66 mmol) and piperazine (23.08 g, 268 mmol) were suspended in EtOH (200 mL) in a bomb reactor. The bomb reactor was heated to 145° C. for 24 hours. The reaction progress was monitored by thin layer chromatography NH4OH:MeOH:EtOAc (5/5/90, v/v/v) which showed disappearance of starting material and formation of a new product spot after 24 hours. The EtOH was evaporated and water (700 mL) was added to the residue. The resulting precipitate was filtered and dried in a vacuum oven at 110° C. for 24 hours to give 18.5 g (96%) of the title compound. 1H NMR (CDCl3): δ 0.02 (s, 9H), 1.01 (t, 2H), 2.99 (bs, 4H), 3.61 (bs, 4H), 3.74 (bs, 6H), 4.23 (bm, 6H), 7.59 (s, 1H).
Reaction SMILES: N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C([NH:21][C@H:22]1[C:29](=[O:30])[N:28]2[C@@H:23]1[O:24][CH2:25][C:26]([O:38][CH3:39])=[C:27]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])(=O)C1C=CC=CC=1.C(NCC)C>C(Cl)Cl.CO>[NH2:21][C@H:22]1[C:29](=[O:30])[N:28]2[C@@H:23]1[O:24][CH2:25][C:26]([O:38][CH3:39])=[C:27]2[C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32]
Reactant: COC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](NC(=O)c3ccccc3)[C@H]2OC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCNCC
Product: COC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](N)[C@H]2OC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
0.4 ml (5 mmols--2.5 equivalents) of pyridine and then, all at once, 0.83 g (4 mmols--2 equivalents) of phosphorus pentachloride were added to a solution, cooled to -20° C., of 749 mg (2 mmols) of tert.-butyl (6R, 7R)-7-benzoylamino-3-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate in 3.7 ml of anhydrous methylene chloride. The mixture was stirred at 0° C. for 10 minutes and at +15° C. for 1 hour and cooled to -60° C., 12.2 ml of precooled anhydrous methanol were added rapidly and the mixture was subsequently stirred at room temperature for 30 minutes. It was then cooled to -15° C., 1.6 ml of distilled diethylamine was added and stirring was continued for 10 minutes at about -10° C. and the mixture was poured into ice-cold saturated NaHCO 3 solution, for working up. The mixture was extracted several times with methylene chloride and the extract was washed with water and dried over MgSO4. The solvent was evaporated off in vacuo and the residue was chromatographed on 60 g of silica gel (ethyl acetate:acetone 85:15). 158 mg (29%) of the title compound were obtained as a light rigid foam, RF : 0.33 (ethyl acetate:acetone 85:15).
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)(=O)[CH2:2][CH2:3][CH2:4][CH3:5].O.NN.[OH-].[K+]>C(O)COCCO>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)c1ccc(Br)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCCCc1ccc(Br)cc1
Temperature: 130 °C
Yield: 80 %

Procedure:
A mixture of 2A (77.1 g), hydrazine hydrate (46.4 g) and KOH (590 g) in diethylene glycol (250 ml) is heated at 130° C. for 2 h, the excess of hydrazine hydrate is distilled off and the temperature is raised to 200° C. for 2 h. The cooled mixture is poured into 18% HCl, the product is extracted into ether twice and the combined ethereal extracts are washed with water and dried (MgSO4). The solvent is removed in vacuo and the residue is distilled (bp 145°-148° C. at 20 mm Hg) to yield a colourless liquid (58.1 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([OH:22])=O)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[CH:4][N:3]=1.[F:24][C:25]([F:30])([F:29])[C@H:26]([NH2:28])[CH3:27]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([NH:28][C@H:26]([CH3:27])[C:25]([F:30])([F:29])[F:24])=[O:22])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[N:6][CH:7]=1
Reactant: C[C@@H](N)C(F)(F)F
Reactant: Nc1cnc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Product: C[C@@H](NC(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1)C(F)(F)F

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 504 using 4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and (R)-1,1,1-trifluoropropan-2-amine. MS (ESI): mass calcd. for C20H16F4N4O, 404.13; m/z found, 405.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J=8.8, 1H) 8.34 (s, 1H), 8.01 (d, J=1.2, 1H), 7.90-7.80 (m, 1H), 7.58-7.40 (m, 4H), 7.29-7.18 (m, 2H), 6.69 (s, 2H), 4.68-4.56 (m, 1H), 1.16 (d, J=7.0, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].C([N-]C(C)C)(C)C.[Li+].[CH:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1.C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:38][C:35]2[CH:36]=[CH:37][C:32]([C:29]3[CH:28]=[CH:27][CH:26]=[CH:31][CH:30]=3)=[CH:33][CH:34]=2)[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1(Cc2ccc(-c3ccccc3)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (13.19 mmol; 3.21 g) in dry THF (100 mL) under argon at −78° C. was added, dropwise, a 2M solution of lithium diisopropylamide (2M solution in heptanes/THF/ethylbenzene; 15.83 mmol; 7.92 mL). The resulting solution was stirred at −78° C. for 2 hours. 4-Biphenylmethyl bromide (15.83 mmol; 3.91 g) was added and the resulting solution was stirred at −78° C. for 2 hours, then allowed to warm to room temperature overnight. Ethyl acetate (150 ml) was added. The resulting solution was washed with a 1M aqueous hydrochloric acid solution (2×50 mL) and brine (50 mL) and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography (eluent gradient: 0 to 50% EtOAc in heptane) to yield 4-biphenyl-4-ylmethyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester. MS (ESI) m/z 432.3 [M+Na]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+].[O:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[CH2:9][CH2:8]1>C(Cl)Cl>[OH:7][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:11]=1[C:10](=[O:17])[CH2:9][CH2:8]2
Reactant: O=C1CCOc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCc2cccc(O)c21
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 75.2 %

Procedure:
37.0 g (278 mmol) of aluminum chloride was mixed with 3.70 g (61.3 mmol) of sodium chloride, the mixture was dissolved at 150° C. under heating, 6.40 g (43.2 mmol) of commercially available 2,3-dihydro-4H-chromen-4-one dissolved by heating (50° C.) was added to the mixture and the resulting mixture was stirred at 200° C. for 20 minutes. The reaction mixture (gum state) was cooled, and added to ice-cold hydrochloric acid (100 ml of conc. hydrochloric acid and ice were combined to make them 200 ml) little by little and stirred for 30 minutes. Methylene chloride was added to the mixture and the mixture was separated. The aqueous layer was filtered, and the filtrate was extracted with methylene chloride. The organic layers were combined, washed successively with water and brine, and dried over sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel chromatography (Wakogel C-100, hexane-ethyl acetate, gradient) to obtain 4.82 g (32.6 mmol, Yield: 75.2%) of 7-hydroxy-1-indanone.
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[NH2:49][CH2:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:21][C@:18]12[C@@:17]3([CH3:22])[C@@H:8]([C@:9]4([CH3:38])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=3)=[CH:11][CH2:10]4)[CH2:7][CH2:6][C@@H:5]1[C@H:4]1[C@H:39]([C:42]([CH3:44])=[CH2:43])[CH2:40][CH2:41][C@:3]1([CH2:1][NH:49][CH2:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[CH2:20][CH2:19]2
Reactant: NCCCN1CCOCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)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
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCOCC3)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
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-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)benzoate (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (1M in DCM) (0.167 ml, 0.167 mmol) and N-(3-Aminopropyl)morpholine (0.029 ml, 0.200 mmol). The mixture was stirred for 15 minutes at rt and sodium triacetoxyborohydride (0.071 g, 0.334 mmol) was added. The mixture was stirred at rt for 1.5 h and an additional 0.1 g of sodium triacetoxyborohydride was added. The mixture was stirred overnight at rt then was quenched with 7 ml of sat. NaHCO3. The mixture was extracted with dichloromethane (3×7 ml) and the combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The mixture was purified by flash chromatography using a 0-10% MeOH in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give the title compound as a white foam (69 mg, 0.095 mmol, 56.8% yield). LCMS: m/e 727.5 (M+H)+, 2.81 min (method 6).