Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:47])[CH2:9][NH:10][C:11]2[CH2:15][N:14](S(C(F)(F)F)(=O)=O)[C:13](=[O:23])[C:12]=2[C:24]2[N:28](C(OC(C)(C)C)=O)[C:27]3[CH:36]=[C:37]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[CH:38]=[C:39]([CH3:40])[C:26]=3[N:25]=2)[CH:5]=[CH:6][CH:7]=1.O.ClCCl.Cl>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:47])[CH2:9][NH:10][C:11]2[CH2:15][NH:14][C:13](=[O:23])[C:12]=2[C:24]2[NH:28][C:27]3[CH:36]=[C:37]([N:41]4[CH2:42][CH2:43][O:44][CH2:45][CH2:46]4)[CH:38]=[C:39]([CH3:40])[C:26]=3[N:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N2CCOCC2)cc2c1nc(C1=C(NC[C@@H](O)c3cccc(Cl)c3)CN(S(=O)(=O)C(F)(F)F)C1=O)n2C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(N2CCOCC2)cc2[nH]c(C3=C(NC[C@@H](O)c4cccc(Cl)c4)CNC3=O)nc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 138.9 %

Procedure:
To a stirred solution of (S)-4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-3-(1-tert-butyloxycarbonyl-4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-1-trifluoromethanesulfonyl-1,5-dihydro-pyrrol-2-one (0.014 g, 0.020 mmol) in N,N-dimethylformamide (2 mL) was added saturated sodium bicarbonate (10 drops) and this was heated at 80° C. for 6 hours. The reaction was cooled down to RT and water and dichloromethane were added. The pH of the aqueous phase was adjusted to 7 with 0.5 N hydrochloric acid. The aqueous phase was extracted with dichloromethane (5×). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue (0.012 g) was dissolved in dichloromethane (1.5 mL) and treated with SCX resin (0.750 g). This mixture was stirred at RT for 2 hours, then the resin was washed with dichloromethane, followed by ammonia (2N in methanol, diluted with dichloromethane (3 parts)). The ammonia solution was evaporated to give a residue (0.013 g) which was purified by Prep HPLC (acetonitrile/ammonium acetate/water) and afforded the acetic acid salt of the title material (0.0054 g, 51%) as a beige solid. HPLC: 95% (220 nm), LCMS (+ESI, M+H+) m/z 468, HRMS calcd for C24H26N5O3Cl=467.1724, found: 467.1715; IR ν (cm−1): 3382, 2922, 1636, 1597. 1H NMR (400 MHz, methanol-d4) δ (ppm): 1.89 (3H, s), 2.50 (3H, s), 3.11 (4H, br dd), 3.49 (1H, dd, J=13.7 and 7.9 Hz), 3.60 (1H, dd, J=13.7 and 4.1 Hz), 3.86 (4H, br dd), 4.15 (2H, d, JAB=18.1 Hz), 4.92 (1H, dd, J=7.0 and 4.3 Hz), 6.76 (1H, br s), 6.94 (1H, br s), 7.27–7.39 (3H, m), 7.50 (1H, s).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:46]=[C:45]2[C:40]([CH:41]=[CH:42][C:43](=[O:52])[N:44]2[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:46]=[C:45]3[C:40]([CH:41]=[CH:42][C:43](=[O:52])[N:44]3[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COCCCn1c(=O)ccc2ccc(CCl)cc21
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCn1c(=O)ccc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.262 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.148 g of 7-chloromethyl-1-(3-methoxypropyl)-1H-quinolin-2-one are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.28 (2:1 EtOAc-heptane); Rt=5.91.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[F-:25].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([F:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: C1CCOC1
Solvent: O
Product: F[C@H]1CCN(Cc2ccccc2)C1
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a solution of (R)-1-benzyl-3-pyrrolidinol-tosylate (3.06 g, 9.24 mmol) in THF (30 ml) was added 1.0M solution of tetrabutylammonium fluoride in THF (37.0 ml, 37.0 mmol) at room temperature. After 1.5 h stirring at reflux temperature, water (150 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate (100 ml×2). The combined extract was washed with water, brine, dried (Na2SO4), and concentrated to give brown oil, which was purified by column chromatography (silica gel: 80 g, CH2Cl2/MeOH: 50/1) to afford 1.18 g (71%) of brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Cl.[NH2:22][OH:23].N1C=CC=CC=1>CO.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]=[N:22][OH:23])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: NO
Reactant: O=Cc1ccc(-c2ccc(O)c(F)c2)c2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CO
Product: ON=Cc1ccc(-c2ccc(O)c(F)c2)c2ccccc12
Yield: 66.8 %

Procedure:
A mixture of 4-(3-fluoro-4-hydroxyphenyl)-naphthalene-1-carbaldehyde (570 mg, 2.13 mmol), hydroxylamine hydrochloride (297 mg, 4.27 mmol), and anhydrous pyridine (0.35 ml, 4.27 mmol) in MeOH (13 ml) was heated to reflux for 1.5 h. The mixture was then diluted with ether, washed with water, the organic layer was dried over anhydrous Na2SO4, passed through a silica plug and concentrated. Purification by reverse phase HPLC (water-CH3CN-0.1% TFA) afforded 400 mg (67%) of product as a white solid: mp 187–188° C.; 1H NMR (300 MHz, DMSO-d6): δ 7.12 (2H, m), 7.28 (1H, d, J=11.4 Hz), 7.45 (1H, d, J=7.4 Hz), 7.53–7.64 (2H, m). 7.83 (1H, d, J=7.5 Hz), 7.90 (1H, d, J=7.6), 8.73 (1H, d, J=8.1 Hz), 8.81 (1H, s), 10.08 (1H, s), 11.46 (1H, s); MS m/z 282 ([M+H]+).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl.Cl[CH2:21][C:22]#[C:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C1COCC1>[CH3:3][C:2]([CH3:4])([CH2:21][C:22]#[C:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)C
Reactant: ClCC#CCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CC#CCN1CCOCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a solution of ethyl isobutyrate (530 μl; 4.08 mmol) in THF (5 mL) was added lithium bis(trimethylsilyl)amide (7.30 mL; solution 1.00 M in THF; 7.30 mmol) at −78° C. The mixture was removed from the cooling bath and stirred for 30 min. It was then cannulated over a suspension of 4-(4-chlorobut-2-yn-1-yl)morpholine hydrochloride (prepared as described by Gomez et al., 1997 Tetrahedron, 53(50), 17201-17210; 714 mg; 3.40 mmol) in THF (5 mL) maintained at −78° C. The reaction mixture was left in the cooling bath and allowed to warm up to rt. After 3 h, it was quenched with water and extracted twice with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtrated and concentrated. Purification of the crude by flash chromatography on silica (gradient DCM:MeOH 100:0 to 90:10) gave the title compound as a colorless oil (600 mg, 70% yield). 1H NMR (DMSO-d6) δ: 4.11 (qd, J=7.1 Hz, 2H), 4.14 (m, 4H), 3.31 (t, J=2.1Hz, 0.6H), 3.25 (m, 1.4H), 2.52 (m, 4H), 2.43 (t, J=2.3 Hz, 2H), 1.25 (s, 6H), 1.23 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:56]=[C:57]([NH2:64])[C:58]4[CH:59]=[N:60][NH:61][C:62]=4[CH:63]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1>CN(C=O)C>[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:63]=[C:62]4[C:58]([CH:59]=[N:60][NH:61]4)=[C:57]([NH:64][C:7](=[O:9])[C:6]4[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=4[O:11][CH3:12])[CH:56]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1
Reactant: COc1ccc(C)cc1C(=O)O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C)cc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 3 h

Procedure:
To a solution of 5-methyl-2-(methyloxy)benzoic acid (67 mg, 0.40 mmol) in DMF (1 ml), HATU (248 mg, 0.40 mmol) and DIPEA (156 mg, 1.208 mmol) were added. The reaction was stirred for 30 mins under nitrogen before addition of 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.20 mmol). The reaction was stirred for 3 h then it was loaded onto a PS-aminopropyl cartridge and left for 3 h. The cartridge was washed with 10% MeOH in DCM. Appropriate fractions were combined and the solvent was evaporated. The residue was dissolved in MeOH:DMSO (1 ml; 1:1, v/v) and purified by Mass Directed Automated Preparative HPLC using method B. The solvent was dried under a stream of nitrogen. The residue was dissolved in DMSO and further purified by HPLC using the following conditions:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH3:3].[N:12]([O-])=O.[Na+].[Cl:16][Sn]Cl.O>Cl.O>[ClH:16].[CH:2]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][NH2:12])=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1ccc(NN)cc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a stirred solution of 4-(propan-2-yloxy)aniline (5.0 g, 33.07 mmol, 1.00 equiv) in 2N hydrochloric acid (35 mL) at 0° C. was added dropwise a solution of sodium nitrite (2.4 g, 34.78 mmol, 1.05 equiv) in water (8 mL). The reaction mixture was stirred at 0-5° C. for 1 h. A solution of SnCl2.H2O (15 g, 66.37 mmol, 2.01 equiv) in 12N hydrochloric acid (20 mL) was then added dropwise at 0-5° C. The resulting mixture was stirred at room temperature overnight. The precipitates was collected by filtration to give 4.7 g (70%) of crude (4-isopropoxyphenyl)hydrazine hydrochloride as a purple solid. The product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:40]=[C:39]([OH:41])[C:38]([C:42]([OH:44])=[O:43])=[CH:37][N:36]=2)=[CH:31][CH:30]=1.C(N(CC)CC)C>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[N:40]=[C:39]([OH:41])[C:38]([C:42]([OH:44])=[O:43])=[CH:37][N:36]=2)=[CH:33][CH:34]=1)=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Solvent: CC#N
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 96.1 %

Procedure:
A solution of 5.67 g (30 mmol) of N-t-butoxycarbonyl-L-alanine in 75 ml of acetonitrile is stirred at 0° and 6.36 g (63 mmol) of N-methylmorpholine is added and the mixture cooled to -20° C. Next 3.62 g (30 mmol) of pivaloyl chloride is added and the mixture stirred at -15° C. for 1.5 hrs and a solution cooled to -10° C., containing 3.46 g (15 mmol) of 2-(4-aminophenyl) 4-hydroxy-5-pyrimidine carboxylic acid, 75 ml of acetonitrile, and 4.17 ml (30 mmol) of triethylamine is added. After stirring for 2 hrs at -10° C. the mixture is then kept at room temperature for 18 hrs. The solution is evaporated to near dryness in vacuo and treated with 200 ml of water. The pH is adjusted to 2.8 with citric acid and the product filtered, washed with water and ether, and dried to give 5.8 g of 2-[4-(N-t-butoxycarbonyl-L-alanylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid. [α]D23 -28.5° (cl, pH 7).
Reaction SMILES: O[CH2:2][C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@H:25]([CH2:42][C:43]3[CH:52]=[C:51]([CH3:53])[C:46]4[NH:47][C:48](=[O:50])[O:49][C:45]=4[CH:44]=3)[C:26]([N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:38][CH2:37][CH2:36][C@H:35]4[C:39]([OH:41])=[O:40])[CH2:30][CH2:29]3)=[O:27])=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:54]=[CH:55][CH:56]=[CH:57][C:11]=2[NH:10]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:8]=[C:9]1[N:15]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C@H:25]([CH2:42][C:43]3[CH:52]=[C:51]([CH3:53])[C:46]4[NH:47][C:48](=[O:50])[O:49][C:45]=4[CH:44]=3)[C:26]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]4[CH2:38][CH2:37][CH2:36][C@H:35]4[C:39]([O:41][CH2:2][C:3](=[O:4])[N:5]([CH3:7])[CH3:6])=[O:40])[CH2:32][CH2:33]3)=[O:27])=[O:23])[CH2:20][CH2:21]2)[CH2:14][CH2:13][C:12]2[CH:54]=[CH:55][CH:56]=[CH:57][C:11]=2[NH:10]1
Reactant: CN(C)C(=O)CO
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@H]3C(=O)O)CC2)cc2oc(=O)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@H]3C(=O)OCC(=O)N(C)C)CC2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6 mg (0.06 mmol) 2-hydroxy-N,N-dimethyl-acetamide were added to a solution of 34 mg (0.05 mmol) (R)-2-[4-((S)-2-carboxy-pyrrolidin-1-yl)-piperidin-1-yl]-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 18 mg (0.06 mmol) TBTU and 8 μL triethylamine in 2 mL DMF and the reaction mixture was shaken overnight at RT. The reaction solution was purified by HPLC without working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C-:10]#[N:11].[K+].C(O)(C)(C)C.[C:18]([O:21]C(=O)C)(=[O:20])[CH3:19]>C(Cl)Cl.[Ti]>[C:18]([OH:21])(=[O:20])[CH3:19].[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[C:10]#[N:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccccc1Cl
Reactant: [C-]#N
Agent: [Ti]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CC(=O)O
Product: N#CC(O)c1ccccc1Cl
Reaction time: 5.75 h

Procedure:
o-Chlorobenzaldehyde (1.0 g, 0.82 ml, 7.11 mmol) was added via syringe to an agitated mixture of potassium cyanide (1.85 g, 28.46 mmol) and a titanium dimer catalyst of Formula (8) (72.8 mg, 0.06 mmol) in CH2Cl2 (18 ml), followed by t-butanol (0.56 g, 0.72 ml, 7.49 mmol). The slurry was cooled to a temperature of −5° C. and acetic anhydride (2.905 g, 2.68 ml, 28.46 mmol) was added via a syringe. The slurry was agitated at a temperature of −5° C. to 0° C. Analysis by G.C. showed that the reaction had gone to 31% conversion (49% e.e.) after 4 hrs and to 33% conversion (51% e.e.) after 5.75 hrs.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][NH:10][CH2:11][CH3:12])[C:5]2[C:13](I)=[N:14][N:15]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[CH:3]=1.CC([O-])(C)C.[Na+].C1COCC1>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:15]([C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:14]=[C:13]3[C:5]2=[C:6]([CH2:8][CH2:9][N:10]3[CH2:11][CH3:12])[N:7]=1
Reactant: CCNCCc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCN1CCc2nc(Cl)cc3c2c1nn3C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 55 °C

Procedure:
2-(6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N-ethylethanamine (160 mg, 0.270 mmol) and RuPhos pre-catalyst (19.6 mg, 0.027 mmol) were charged in a 1 dram vial, evacuated and backfilled with nitrogen and taken in toluene (1.8 mL) before a solution of 2M NaOtBu in THF (0.34 ml, 0.675 mmol) was added. The reaction mixture was heated at 55° C. for 1 hour before it was diluted with EtOAc and washed with water, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-50% EtOAc-hexanes) gave 7-chloro-3-ethyl-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridine. MS ESI calc'd. for C29H25ClN4 [M+H]+ 465. found 465.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:27])[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1>[C:29]([O:27][C@H:22]1[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@@H:20]([CH2:19][CH2:18][C@@H:17]3[C@@H:16]2[CH2:15][CH2:14][C@@:13]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])[CH2:21]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Solvent: c1ccncc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 7-dehydrocholesterol (1, 50.0 g, 0.13 mol; Aldrich Chemical Co.) dissolved in dry pyridine (120 mL) was added, with stirring, benzoyl chloride (28 mL, 34.1 g, 0.24 mol). After the addition, the reaction mixture was heated at reflux for 5 min and was then left at ambient temperature for 20 min. The reaction mixture was poured with stirring into ice water (1.5 L). The precipitate was allowed to rest for 1 h and was then taken up on a filter and washed successively with water (350 mL), 5% sodium bicarbonate (200 mL), water (350 mL) and finally acetone (5×25 mL). The crude material was air dried and subsequently recrystallized. The crude material was dissolved in hot chloroform (100 mL) and to this solution was added acetone (250 mL). The flask was left at ambient temperature and then at -20° C. overnight. The crystalline material was collected by filtration, and then washed with a small amount of acetone. Total yield compound 2 after drying, 58.3 g (92%). Melting point and spectral data agree with previous reported values (Wilson et al., J. Org. Chem. 53:1713 (1988)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:25]2[OH:33])[CH:6]=1.[C:35](Cl)(Cl)=[O:36]>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[CH2:22][N:23]2[CH:24]3[CH2:32][C:31]4[C:26]([CH:25]3[O:33][C:35]2=[O:36])=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:6]=1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CNC2Cc3ccccc3[C@@H]2O)c1
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN2C(=O)OC3c4ccccc4CC32)c1

Procedure:
Prepared according to the procedure described in Example 45, Step 4, using the following starting materials: (3-{2-[((S)-1-hydroxy-indan-2-ylamino)-methyl]-4-trifluoromethyl-phenoxy}-phenyl)-acetic acid methyl ester and phosgene (1.9M in toluene).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[O:27])[CH2:12][O:13][C:14](=[O:26])[CH2:15][CH2:16][CH:17]([OH:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].N1C=CC=CC=1.[CH3:34][CH:35]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:36][CH2:37][OH:38].Cl[C:48]([O-])=[O:49]>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[O:27])[CH2:12][O:13][C:14](=[O:26])[CH2:15][CH2:16][CH:17]([O:25][C:48]([O:38][CH2:37][CH2:36][CH:35]([CH3:34])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:49])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C([O-])Cl
Reactant: CCCCCCCC(O)CCC(=O)OCC(=O)c1ccc2ccccc2c1
Reactant: CC(CCO)CCc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCC(CCC(=O)OCC(=O)c1ccc2ccccc2c1)OC(=O)OCCC(C)CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a solution of 4.00 g of 4-hydroxy-undecanoic acid-2-naphthalen-2-yl-2-oxo-ethyl ester and 1.71 g of pyridine in 20 ml of THF, a solution of 2.91 g of 3-methyl-5-phenyl-pentanol-chloroformate in 10 ml of THF was dropped in at 0° C. The mixture was stirred for 3 hours at room temperature. Then, the reaction mixture was quenched with water and extracted with ether. The organic phase was washed with 2N HCl, saturated sodium bicarbonate, and water. Then, the mixture was dried, filtered, and evaporated to dryness. The resulting yellow oil was purified by chromatography to yield 5.46 g of a colorless oil.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.C[O-].[Na+].[NH2:26][NH:27][C:28](=O)[CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32]>C(O)C.CO>[CH2:31]([N:30]([CH2:33][CH3:34])[CH2:29][C:28]1[NH:27][N:26]=[C:5]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:6]=1)[CH3:32]
Reactant: CCN(CC)CC(=O)NN
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCN(CC)Cc1nc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)n[nH]1
Temperature: 0 °C
Yield: 11 %

Procedure:
A suspension of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (0.400 g, 1.25 mmol) in 4 mL of anhydrous ethanol was prepared and cooled to 0° C. An excess of a commercial solution of sodium methoxide in methanol (0.858 mL, 4.37 M)) was added followed by 3 equivalents of N-amino-2-(diethylamino)acetamide (0.545 g, 3.75 mmol) as a solid. The reaction mixture was heated to reflux temperature in a sealed tube for 2 days. The reaction was then quenched with water, the pH adjusted to neutral and the crude product extracted with ethyl acetate. The residue was purified by preparative HPLC (0.052 g, 11% yield): 1H NMR (CD3OD) δ 8.70 (s, 1H), 8.11-8.02 (m, 3H), 7.67 (d, 1H), 7.29 (td, 2H), 3.8 (s, 1H), 2.68 (q, 4H), 1.15 (t, 3H); ES-MS (m/z) 365 [M+H]+.