Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:36][C@@H:37]([CH2:49][OH:50])[C@H:38]([C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)[OH:39]>>[OH:39][C@@H:38]([C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)[C@@H:37]([NH:36][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:30]1[CH:29]=[CH:28][C:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])=[CH:32][CH:31]=1)=[O:7])=[O:18])[CH2:49][OH:50]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: N[C@@H](CO)[C@@H](O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)N[C@@H](CO)[C@@H](O)c2ccc([N+](=O)[O-])cc2)N(C(=O)c2ccc(-c3ccccc3OC)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, the title compound was obtained in 61% purity by HPLC. MS(ESI+): m/z=563.
Reaction SMILES: [CH:1](=[C:8]([CH2:12][OH:13])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.O.[H][H]>CO.[C].[Pd]>[OH:13][CH2:12][CH:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)C(=Cc1ccccc1)CO
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: O
Product: O=C(O)C(CO)Cc1ccccc1
Yield: 93 %

Procedure:
2-Benzylidene-3-hydroxypropionic acid (490.4 mg, 2.752 mmols) was dissolved in 7 ml of methanol, and 0.5 ml of 28% aqueous ammonia and 2 ml of water were added thereto. Then, 38 mg (water content 52.7%) of 5% palladium-carbon were added thereto, and catalytic reduction was conducted in a hydrogen atmosphere for 160 minutes. After the completion of the reaction, the reaction solution was filtered with Celite to remove the palladium-carbon. The resulting filtrate was subjected to the HPLC analysis. As a result, the filtrate contained 461 mg (2.558 mmols) of the above title compound (yield 93.0%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:10][C:9]([C:11]2[S:12][C:13]([Sn](CCCC)(CCCC)CCCC)=[CH:14][CH:15]=2)=[CH:8][CH:7]=1)CCC.Br[C:38]1[CH:43]=[CH:42][C:41]([CH:44]([CH3:46])[CH3:45])=[CH:40][CH:39]=1>CN(C)C=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>[CH:44]([C:41]1[CH:42]=[CH:43][C:38]([C:13]2[S:12][C:11]([C:9]3[S:10][C:6]([C:38]4[CH:43]=[CH:42][C:41]([CH:44]([CH3:46])[CH3:45])=[CH:40][CH:39]=4)=[CH:7][CH:8]=3)=[CH:15][CH:14]=2)=[CH:39][CH:40]=1)([CH3:46])[CH3:45]
Reactant: CC(C)c1ccc(Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2ccc([Sn](CCCC)(CCCC)CCCC)s2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)c1ccc(-c2ccc(-c3ccc(-c4ccc(C(C)C)cc4)s3)s2)cc1
Yield: 61.6 %

Procedure:
A solution of 1.8 g of 5,5′-bis(tributylstannyl)-2,2′-bithiophene, 1.3 g of 1-bromo-4-isopropylbenzene, and 80 mg of Pd(PPh3)4 in 35 milliliters (“mL”) of N,N-dimethylformamide was heated at 70° C. for 2 days under nitrogen. After cooling, 0.6 g of yeliow-green solid was obtained after washing with methanol and ether, verified pure by nuclear magnetic resonance spectroscopy (“NMR”), and used directly for film and crystal studies.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([O:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.CO.C1COCC1.[Li+].[OH-]>O>[Cl:1][C:2]1[S:6][C:5]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(Cl)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)COc1ccc(Cl)s1
Reaction time: 16 h
Yield: 93.8 %

Procedure:
To a solution of ethyl 5-chloro-2-thienyloxyacetate (0.39 g, 1.77 mmol) in 9 mL of a 1:1:1 mixture of CH3OH:THF:water is added LiOH (0.38 g, 9.0 mmol). The solution is stirred for 16 hours. After this time, the solution is concentrated to ⅓ its volume. The resulting solution is acidified to pH=3 with 1N HCl. The aqueous solution is extracted with CH2Cl2. The organic layer is dried over MgSO4, filtered and concentrated under vacuum. The title compound (0.32 g, 1.66 mmol) is obtained as a white solid. 1H NMR (CDCl3, 300 MHz) δ6.50 (d, 1H), 6.07 (d, 1H), 4.66 (s, 2H).
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:17]([NH2:19])[CH3:18])=[N:9][C:10]3[C:15]([CH:16]=2)=[N:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:21]12[N:29]=[CH:28][N:27]=[C:26]1[C:25](Cl)=[N:24][CH:23]=[N:22]2.CCN(C(C)C)C(C)C>CCCCO>[C:1]1([C:7]2[C:8]([CH:17]([NH:19][C:25]3[N:24]=[CH:23][N:22]=[C:21]4[C:26]=3[N:27]=[CH:28][NH:29]4)[CH3:18])=[N:9][C:10]3[C:15]([CH:16]=2)=[N:14][CH:13]=[CH:12][CH:11]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC12N=CN=C(Cl)C1=NC=N2
Reactant: CC(N)c1nc2cccnc2cc1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2cccnc2cc1-c1ccccc1
Temperature: 25 °C
Yield: 81 %

Procedure:
1-(3-Phenyl-1,5-naphthyridin-2-yl)ethanamine (46 mg, 0.19 mmol), 4-amino-6-chloropurine (28.5 mg, 1.0 eq) and hunig's base (39 μL, 1.2 eq) in n-BuOH (2 mL) was heated to 130° C. overnight. The mixture was cooled to rt, concentrated, and purified by reverse phase HPLC (MeCN/H2O/0.1% TFA, 10% to 60%) to give a white powder (50 mg) as TFA salt. 1H NMR (400 MHz, CD3OD) δ ppm 9.05 (1H, d, J=4.0 Hz), 8.65 (1H, d, J=8.0 Hz), 8.50-8.47 (2H, m), 8.29 (1H, s), 7.90 (1H, dd, J=8.0, 4.0 Hz), 7.62-7.47 (5H, m), 6.12-6.01 (1H, m), 1.63 (3H, d, J=8.0 Hz); LC-MS (ESI) m/z 368 [M+H]+.
Reaction SMILES: [Si:1]([O:18][CH2:19]C1N=CC=C(Cl)N=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]12[CH2:34][CH2:33][N:30](C[CH2:32]1)CC2.[C:35](#[N:37])[CH3:36]>[C-]#N.C([N+](CC)(CC)CC)C>[Si:1]([O:18][CH2:19][C:35]1[N:37]=[CH:32][N:27]=[C:34]([C:33]#[N:30])[CH:36]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: C1CN2CCN1CC2
Reactant: CC(C)(C)[Si](OCc1nccc(Cl)n1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Product: CC(C)(C)[Si](OCc1cc(C#N)ncn1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, to a solution of (((tert-butyldiphenylsilyl)oxy)methyl)-6-chloropyrimidine (18.6 g) and 1,4-diazabicyclo[2.2.2]octane (8.18 g) in acetonitrile (97 mL) was added tetraethylammonium cyanide (7.59 g) at room temperature, and the mixture was stirred at 50° C. for 30 min. The solvent of the reaction mixture was evaporated under reduced pressure and the insoluble solid was removed by filtration. The solvent of the filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (11.3 g) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[C:28]2[C:7]([CH2:8][C@:9]3([CH2:27]2)[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11](COCC[Si](C)(C)C)[C:10]3=[O:26])=[CH:6][C:5]=1[CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])([O-:3])=[O:2].Cl.[OH-].[Na+].C(N)CN>CO>[N+:1]([C:4]1[CH:29]=[C:28]2[C:7]([CH2:8][C@:9]3([CH2:27]2)[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]3=[O:26])=[CH:6][C:5]=1[CH2:30][C:31]([OH:33])=[O:32])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)Cc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: NCCN
Solvent: CO
Product: O=C(O)Cc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)Nc2ncccc21
Reaction time: 18 h

Procedure:
A solution of tert-butyl ((2S)-6-nitro-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]5-yl)acetate from Step C (2.01 g, 3.83 mmol) in MeOH (25 mL) was saturated with HCl (g) and stood at ambient temperature for 18 h. The mixture was concentrated to dryness in vacuo, then redissolved in MeOH (25 mL). This stirred solution was adjusted to pH 10 with 10 N NaOH and ethylene diamine (0.26 mL, 3.83 mmol) was added. The resulting mixture was stirred for 3 h, then concentrated to dryness in vacuo. The residue was dissolved in THF (25 mL) and 1 N NaOH (25 mL, 25 mmol) was added. The mixture was stirred at ambient temperature for 18 h, then the THF was removed under reduced pressure. The residual mixture was partitioned between saturated aqueous NaHCO3 (50 mL) and EtOAc (100 mL). The organic layer was discarded and the aqueous layer was adjusted to pH 2 with aqueous HCl, then extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=340 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[CH2:27]([C:34]1[S:35][C:36]([CH3:40])=[C:37]([CH3:39])[CH:38]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([C:34]1[S:35][C:36]([CH3:40])=[C:37]([CH3:39])[C:38]=1[C:6]([C:5]1[CH:9]=[C:10]([CH2:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([CH2:1][CH3:2])[CH:4]=1)=[O:8])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCc1cc(C(=O)O)cc(CC)c1OC
Reactant: Cc1cc(Cc2ccccc2)sc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Product: CCc1cc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc(CC)c1OC
Yield: 98.9 %

Procedure:
The title compound was prepared according to the procedure in Example 1, step 4, using 3,5-diethyl-4-methoxybenzoic acid (9.45 g, 45.5 mmol), oxalyl chloride (4.35 mL, 50.0 mmol), N,N-DMF (2 drops), tin(IV) chloride (5.85 mL, 50.0 mmol) and 2-benzyl-4,5-dimethylthiophene (11.0 g, 54.6 mmol) to give 17.67 g (99%) of the title compound. 1H NMR δ 1.13 (t, 6 H), 1.83 (s, 3 H), 2.27 (s, 3 H), 2.64 (q, 4 H), 3.73 (s, 3 H), 3.85 (s, 2 H), 7.04 (d, 2 H), 7.12-7.24 (m, 3 H), 7.43 (s, 2 H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29]Cl)[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[CH3:34][NH:35][CH2:36][CH:37]([C:39]1[S:40][CH:41]=[CH:42][CH:43]=1)[OH:38].O>CN(C=O)C>[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29][N:35]([CH2:36][CH:37]([OH:38])[C:39]4[S:40][CH:41]=[CH:42][CH:43]=4)[CH3:34])[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Reactant: CNCC(O)c1cccs1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1cccs1
Temperature: 90 °C
Yield: 62.6 %

Procedure:
N,N-Diisopropylethylamine (0.14 mL) and N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.150 g) were added to a solution of rac-2-(methylamino)-1-thien-2-ylethanol (Preparation 46, 0.130 g) in DMF (10 mL). The reaction mixture was heated to 90° C. for 1 h. The mixture was allowed to cool to room temperature and was poured into water (25 mL). The suspension was filtered and the resulting solid was purified by column chromatography (CH2Cl2/methanol; 99/1, 98/2) followed by recrystallization from ethyl acetate to yield 0.125 g of the title compound as a white solid. Physical characteristics. M.p. 145-147° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.65, 8.54, 7.41-7.32, 6.97-6.93, 6.87, 6.42, 5.52, 4.984.93, 4.55, 3.91, 3.76, 2.70-2.60, 2.30; 13C NMR (100 MHz, CDCl3) δ 168.9, 159.9, 148.3, 145.6, 140.3, 136.2, 132.4, 127.9, 124.1, 123.8, 121.8, 119.8, 119.0, 112.0, 109.9, 101.8, 61.3, 59.6, 49.2, 37.7, 37.0, 32.9; MS (ESI+) m/z 486 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([CH3:14])([CH3:13])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[N:6]1>[C].[Pd].C(O)C.C(OCC)(=O)C>[CH3:1][N:2]([CH3:15])[C:3]([CH3:13])([CH3:14])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1
Reactant: CN(C)C(C)(C)Cn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)C(C)(C)Cn1ccc(N)n1
Reaction time: 2 h
Yield: 93.7 %

Procedure:
N,N,2-trimethyl-1-(3-nitro-1H-pyrazol-1-yl)propan-2-amine (70.6 mg) was dissolved in a mixed solution (ethanol-ethyl acetate, 4:1, 5 mL). Then, 10% palladium-carbon (7 mg) was added to the prepared solution, and the solution was subjected to catalytic reduction at 101 kPa for about 2 hours. The reaction mixture was filtrated through Celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel NH, ethyl acetate:hexane=1:1) to give the title compound as a yellow oil (56.8 mg, yield: 94%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)=[CH:20][N:21]=3)[N:18]=2)[CH2:8][CH2:7]1)=[O:4].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:28][C:24]1[CH:23]=[C:22]([C:19]2[N:17]3[N:18]=[C:13]([NH:12][C@H:9]4[CH2:10][CH2:11][C@H:6]([NH:5][C:3](=[O:4])[CH2:2][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:7][CH2:8]4)[CH:14]=[CH:15][C:16]3=[N:21][CH:20]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: C1COCCN1
Reactant: O=C(CCl)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCOCC1)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-N-(trans-4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)acetamide (50 mg, 0.12 mmol), morpholine (0.3 mL) and DIPEA (0.2 mL) in CH2Cl2 (0.6 mL) was stirred at 50° C. for 3 h. LCMS showed the reaction was complete. The mixture was concentrated in vacuo. The residue was partitioned between water (100 mL) and EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give EX. 8-84 (9.6 mg, 17%) as a white solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([CH:42]=O)[CH:36]=3)=[CH:32][CH:33]=2)[CH:28]=[N:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[C:44]([O:48][C:49](=[O:55])[N:50]([CH2:52][CH2:53][NH2:54])[CH3:51])([CH3:47])([CH3:46])[CH3:45]>ClC(Cl)C.O>[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([CH2:42][NH:54][CH2:53][CH2:52][N:50]([C:49]([O:48][C:44]([CH3:47])([CH3:45])[CH3:46])=[O:55])[CH3:51])[CH:36]=3)=[CH:32][CH:33]=2)[CH:28]=[N:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(-c3ccc(F)c(C=O)c3)ccc21
Reactant: CN(CCN)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: O
Product: CN(CCNCc1cc(-c2ccc3c(cnn3C(=O)OC(C)(C)C)c2)ccc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
Sodium triacetoxyborohydride (250 mg, 1.2 mmol) and acetic acid (42 mg, 1.2 mmol) were added to a mixture of 5-(4-fluoro-3-formylphenyl)-indazole-1-carboxylic acid tert-butyl ester (270 mg, 0.8 mmol) and (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester (210 mg, 1.2 mmol) in 8 mL of dichloroethane. The mixture was stirred at ambient temperature overnight, and then it was diluted with water, the layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were washed with sequentially with water, saturated sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with methanol/dichloromethane) provided 400 mg of product. LC/MS: Retention time, 2.66 min; (M+H)=499.
Reaction SMILES: C([O:4][C@H:5]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C:11]=3[C:12](=[O:39])[CH2:13][C@@H:14]2[C@H:15]([CH3:29])[CH2:16][CH2:17][CH2:18][C:19]([F:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.O>CO>[OH:4][C@H:5]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C:11]=3[C:12](=[O:39])[CH2:13][C@@H:14]2[C@H:15]([CH3:29])[CH2:16][CH2:17][CH2:18][C:19]([F:28])([C:24]([F:25])([F:26])[F:27])[C:20]([F:22])([F:23])[F:21])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CCC3=C4C(=O)C[C@H]([C@H](C)CCCC(F)(C(F)(F)F)C(F)(F)F)[C@@]4(C)CC[C@@H]32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: C[C@H](CCCC(F)(C(F)(F)F)C(F)(F)F)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C
Yield: 69.5 %

Procedure:
A solution of 3β-acetoxy-25,26,26,26,27,27,27-heptafluoro-5α-cholest-8(14)-en-15-one (59 mg) in methanol (4 ml) was stirred with potassium carbonate (30 mg) for 5 h at room temperature. Ethyl acetate (10 ml) and water (20 ml) were added and the resulting mixture was extracted twice with ethyl acetate (25 ml portions). The organic extract was washed with water (10 ml), dried over anhydrous sodium sulfate, and evaporated to dryness. The resulting residue (51 mg) was subjected to chromatography on a silica gel column (3.5 cm×0.8 cm). Using 5% ethyl acetate in hexane (100 ml) and 10% ethyl acetate in hexane (250 ml) as the eluting solvents, fractions 50 ml in volume were collected. The contents of fractions 4-7 were pooled to give, after evaporation of the solvent, 49 mg of material which was then recrystallized from hexane to give 3β-hydroxy-25,26,26,26,27,27,27-heptafluoro-5α-cholest-8(14)-en- 15-one (38 mg; 69% yield); MP 177°-179° C. HPLC analyses at 259 nm and 210 nm on a Spherisorb ODS-II column (solvent, 7% methanol in water) showed a single component (>99.8% purity) with a retention time of 6.92 min. GC-MS analysis of the 3β-trimethylsilyl derivative showed a single component. The structure was confirmed by I.R., N.M.R., and M.S. analyses.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]2)[N:21]=1>CN(C=O)C.O>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:32][CH:29]2[CH2:30][CH2:31][N:26]([C:22]3[N:21]=[N:20][CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCN(c2cccnn2)CC1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(c3cccnn3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 28.3 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.240 g, 0.80 mmol), 1-pyridazin-3-ylpiperidin-4-amine (0.257 g, 1.02 mmol) and TEA (0.324 g, 3.2 mmol), was dissolved in dry DMF (10 ml) and heated in a microwave reactor at 120° C. for 30 mins. The reaction mixture was diluted with water (300 ml) and extracted with EtOAc (2×150 ml). The combined organic phases were dried (MgSO4), filtered and evaporated and the residue was purified by silica gel column chromatography using EtOAc as eluant, to give the title compound (0.10 g, 31%). 1H NMR (500 MHz, CDCl3): δ 8.55-8.52 (m, 1H), 7.55-7.50 (m, 2H), 7.47-7.42 (m, 3H), 7.19-7.14 (m, 1H), 6.85-6.82 (m, 1H), 5.21 (d, 1H), 4.17-4.11 (m, 2H), 3.22-3.13 (m, 1H), 2.60-2.52 (m, 2H), 1.80-1.73 (m, 2H), 1.72 (s, 9H), 1.42-1.32 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 159.5, 143.1, 133.8, 131.6, 129.9, 128.7, 127.4, 125, 112.8, 107.2, 61.6, 50.1, 43.6, 31.7, 27.5; Mass Spectrum: M−H+ 442.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.Br[CH:11]([Cl:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[Cl:13][CH2:11][CH2:12][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(Cl)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: ClCCn1cnc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
A mixture of benzimidazole (4.72g, 40 mmol), bromochloroethane (3.4 ml, 41 mmol), potassium carbonate (5.52 g, 40 mmol) and dimethylformamide (60 ml) was stirred at room temperature for 20 hours. To the reaction mixture were added ethyl acetate and water, which was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous sodium chloride solution, followed by drying (anhydrous sodium sulfate). The solvent was distilled off, and the residue was subjected to a silica gel chromatography (3.0×40 cm: ethyl acetate-hexane=2:1) to give 1-(2-chloroethyl)benzimidazole (5.56 g, 38%) as a colorless oily substance.
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2Cl)[C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[NH3:32].CO>>[C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH2:32])[C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1cnc2c(Cl)ncnc21
Reactant: N
Solvent: CO
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1cnc2c(N)ncnc21
Reaction time: 20 h
Yield: 67 %

Procedure:
A solution of 49 (4.2 g. 8.65 mmol) in 60 ml of 6M NH3/MeOH was sealed in a 100 ml Parr bomb and heated with stirring for 20 hrs. The reaction was cooled and concentrated to a white solid, which was re-crystallized from 10% ethyl acetate/hexane to afford 2.7 g (67%) of 50 as white crystals. 1H NMR (DMSO-d6): δ 8.10 (s, 1H), 8.02 (s, 1H), 7.16 (s, 2H), 4.18 (m, 1H), 4.06 (m, 1H), 4.00 (m, 1H), 3.53 (m, 2H), 2.29 (m, 1H), 1.16 (d, J=6 Hz, 3H), 0.84 (s, 9H), 0.79 (s, 9H), 0.01 (s, 6H), −0.10 (s, 6H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:18]=[CH:17][C:10]2[N:11]([CH3:16])[C:12](=[O:15])[N:13]([CH3:14])[C:9]=2[CH:8]=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:29])[CH:27]=[O:28])=[C:22]([Cl:30])[CH:21]=1.O>C1COCC1>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:29])[CH:27]([C:7]2[CH:18]=[CH:17][C:10]3[N:11]([CH3:16])[C:12](=[O:15])[N:13]([CH3:14])[C:9]=3[CH:8]=2)[OH:28])=[C:22]([Cl:30])[CH:21]=1
Reactant: Cn1c(=O)n(C)c2cc(Br)ccc21
Reactant: CC(C=O)c1ccc(Br)cc1Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccc(Br)cc1Cl)C(O)c1ccc2c(c1)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.4 %

Procedure:
A 1.6M solution of n-BuLi in hexanes (0.62 ml) was added at −78° C. to a solution of 5-bromo-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (241 mg) in THF at (10 ml). The gray suspension was stirred for 10 min, then a solution of 2-(4-bromo-2-chloro-phenyl)-propionaldehyde (248 mg) in THF (2 ml) was added. The mixture was stirred for 10 min at −78° C. and then warmed to room temperature. Water (25 ml) was added and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0 to 100% EtOAc/heptane) to give the title compound (194 mg) as a colorless oil. MS (m/e)=409.1 [M+H+].