Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=O)=[C:8]([CH3:15])[CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:32]=[CH:33][C:34]=1[NH2:35])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=1)=[O:22].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:35][C:34]3[CH:33]=[CH:32][C:20]([C:21](=[O:22])[NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=4)=[CH:19][C:18]=3[N:17]=2)=[C:8]([CH3:15])[CH:7]=1
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Reactant: COC(=O)CNc1cc(C)c(C=O)c(C)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CNc1cc(C)c(-c2nc3cc(C(=O)Nc4ccc(C)c(C)c4)ccc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (4-formyl-3,5-dimethylphenylamino)-acetic acid methyl ester (800 mg) and 3,4-diamino-N-(3,4-dimethylphenyl)-benzamide (694 mg) in DMSO (15 mL) was added Yb(OTf)3 (390 mg) and Cu(OTf)2 (228 mg). The solution was stirred at room temperature for 18 h then the reaction mixture was partioned between water and EtOAc The aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified by flash chromatography (amino-column) using hexanes/ethyl acetate (1:4) to give {4-[5-(3,4-dimethylphenylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethylphenylamino}-acetic acid methyl ester as a light yellow solid. MS (ESI)m/z 457 (M+H); 1H NMR (MeOD, 400 MHz) δ 8.21 (s, 1H), 7.85 (dd, 1H), 7.67 (s, 1H), 7.47 (d, 1H), 7.42 (dd, 1H), 7.12 (d, 1H), 6.42 (s, 2H), 3.97 (s, 2H), 3.75 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H), 2.09 (s, 6H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=[O:3].[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:10][C:6]1[CH:5]=[C:4]([C:2]2([CH3:1])[O:13][CH2:12][CH2:11][O:3]2)[CH:9]=[CH:8][CH:7]=1
Reactant: OCCO
Reactant: CC(=O)c1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2cccc(Br)c2)OCCO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3-bromoacetophenone (10 mL, 75.6 mmol), ethylene glycol (10.1 mL, 181 mmol), and p-toluenesulfonic acid hydrate in toluene (120 mL) was heated with azeotropic removal of water. After 4 hours, a second portion of ethylene glycol was added and the mixture heated at refluxed for 48 hours. The reaction was cooled to room temperature and washed with saturated aqueous sodium bicarbonate solution and brine, and dried over sodium sulfate. Removal of the volatiles in vacuo provided a residue that was purified by flash chromatography. Concentration of the product-rich fractions afforded 2-(3-bromophenyl)-2-methyl-[1,3]dioxolane as a clear oil. Yield: 2.44 g.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5](CS([O-])(=O)=O)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH3:2].[N-:20]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C1COCC1.O>[CH2:1]([O:3][CH2:4][CH:5]([NH2:20])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOCC(COc1ccc(F)cc1)CS(=O)(=O)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOCC(N)COc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 52.4 %

Procedure:
Dissolve [1-(ethoxymethyl)-2-(4-fluorophenoxy)ethyl]methanesulfonate (2.3 g, 7.87 mmol) in DMF (3 mL) and add sodium azide (1 g, 15.38 mmol) to the mixture. Stir the mixture at 70° C. for 3 hours. Add Et2O (150 mL) and wash with water (3×10 mL). Separate the phases; dry the organic phase over Na2SO4; filter; and concentrate the filtrate under reduced pressure to give a clear oil. Dissolve the oil in a mixture of THF (50 mL) and H2O (12.5 mL). Add triphenylphosphine (3.0 g, 11.44 mmol) and stir at 30° C. for 2 hours. Purify the reaction mixture via SCX-ion exchange chromatography with 1N NH3/MeOH to provide the product fractions. Concentrate the select fractions under reduced pressure and then purify via flash column chromatography using a gradient of 1% to 10% of MeOH in DCM collecting fractions at wavelength of 214 nm. Concentrate under reduced pressure to give the title compound as a colorless oil (880 mg, 33.5%). MS (m/z): 214 (M+1).
Reaction SMILES: Br[CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH:6]([OH:14])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[CH:3]1Br.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1>[CH:18]1[C:4]2[C:3]#[C:2][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH2:7][CH:6]([OH:14])[C:5]=2[CH:15]=[CH:16][CH:17]=1
Reactant: OC1Cc2ccccc2C(Br)C(Br)c2ccccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1Cc2ccccc2C#Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
To a stirred solution of 44 (1.528 g, 4 mmol) in tetrahydrofuran (40 ml) was added dropwise lithium diisopropylamide in tetrahydrofuran (2.0 M) (8 ml, 16 mmol) under an atmosphere of Argon at room temperature. The reaction mixture was stirred for 0.5 hour at room temperature, after which it was quenched by addition of dropwise water (0.5 ml). The solvents were evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (2:1-0:1 v/v hexanes/CH2Cl2) to give the product as white solid (0.503 g, 57%). 1H NMR (300 MHz, CDCl3): δ 7.67 (1H, aromatics), 7.37-7.18 (7H, aromatics), 4.57 (1H, dd, J=2.1, 14.7 Hz, CHOH), 3.04 (1H, dd, J=2.1, 14.7 Hz, CH2), 2.86 (1H, dd, J=2.1, 14.7 Hz, CH2). 13C NMR (75 MHz, CDCl3): δ154.5, 150.6, 128.6, 127.1, 1127.0, 126.0, 125.8, 125.1, 124.7, 123.0, 122.7, 121.7, 111.9, 109.6, 74.2, 47.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([N:22]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[N:14]2)([CH2:11][CH3:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([N:22]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[S:23]([CH3:26])(=[O:24])=[O:25])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[N:14]2)([CH2:11][CH3:12])[CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: CCC(CO)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCC(C=O)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Reaction time: 1.5 h

Procedure:
A solution of N-(1-(2-(4-chlorophenyl)-1-hydroxybutan-2-yl)-1H-indazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (560 mg, 1.07 mmol) in DCM (10 mL) was added to Dess-Martin periodinane (590 mg, 1.39 mmol) in portion at 0° C. and stirred for 1.5 h. The mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE/EA=8/1) to afford the title compound as a yellow solid. LC/MS m/z=522.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([CH:19]=[O:20])=[C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([Li])[CH2:22][CH2:23][CH3:24].CCCCCC.[Cl-].[NH4+]>C1COCC1>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:12]1[N:13]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[S:10][C:11]=1[CH:19]([OH:20])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C=O)s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC(O)c1sc(NC(=O)OC(C)(C)C)nc1-c1ccco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
Compound 92 (298 mg, 1.01 mmol) was dissolved in THF (10 mL), and a 1.59 mol/L solution of n-butyllithium in n-hexane (5.70 mL, 9.06 mmol) was added thereto in a stream of argon at −78° C., followed by stirring at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=3:1) to afford the entitled Compound 395 (224 mg, 63%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]([OH:16])=[O:15])[CH:8]=[N:7]2)([O-:3])=[O:2].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:28](O)[CH3:29]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]([O:16][CH2:28][CH3:29])=[O:15])[CH:8]=[N:7]2)([O-:3])=[O:2]
Reactant: O=C(O)c1cnc2cc([N+](=O)[O-])ccc2n1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cnc2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of 6-nitroquinoxaline-2-carboxylic acid (6) (5.00 g, 22.8 mmol) (Higashida, S.; Sakurai, M.; Yabe, Y.; Nishihgaki, T.; Komai, T.; Handa, H. Preparation of peptide inhibitors of HIV protease, peptides capable of inhibiting the activity of HIV protease, their preparation and their therapeutic use. European Patent, EP 0 587 311, 1994) in dry ethanol (50 mL), was added under argon, concentrated sulfuric acid (750 μL). After being stirred at reflux for 7 h, the reaction mixture was cooled to room temperature and a saturated aqueous sodium carbonate solution (50 mL) was added. The solution was extracted with dichloromethane (3×30 mL) and the combined organic layers were dried on magnesium sulfate, filtered and evaporated to dryness to afford ester 7 (3.79 g, 15.3 mmol) as a brown solid. Yield 67%; mp 221-223° C.; IR (KBr) ν 1282, 1347, 1531, 1741 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.58 (t, 3H, J=7 Hz), 4.68 (q, 2H, J=7 Hz), 8.53 (d, 1H, J=9 Hz), 8.68 (dd, 1H, J=2.5, 9 Hz), 9.14 (d, 1H, J=2.5 Hz), 9.72 (s, 1H); MS m/z 248 (M+1, 4), 203 (36), 175 (100), 128 (23), 101 (32), 75 (24).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C>[CH2:17]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CC1(C)CC(=O)c2cc(O)ccc21
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc2c(c1)C(=O)CC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
Under nitrogen, a solution of 28.5 g (0.16 mol) of 6-hydroxy-3,3-dimethylindan-1-one (J. Org. Chem. 19; 1954; 305) in 200 ml of DMF was added dropwise to a solution of 5.6 g (0.19 mol) of 80% sodium hydride in 250 ml of DMF. After 1 h at RT, 30.4 g (0.17 mol) of 1-iodobutane were added, and the mixture was stirred at RT for 2 h. The solvent was distilled off under reduced pressure, the residue was taken up in EA and water and the organic phase was washed successively with dil. hydrochloric acid and dil. sodium hydroxide solution. This procedure gave 31.3 g of 6-butoxy-3,3-dimethylindan-1-one.
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10]#[N:11])=[C:8]([I:12])[C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[NH2:1][C:4]1[C:9]([C:10]#[N:11])=[C:8]([I:12])[C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=1
Reactant: COc1cc([N+](=O)[O-])c(C#N)c(I)c1OC
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(N)c(C#N)c(I)c1OC
Temperature: 85 °C
Reaction time: 5 h
Yield: 91.7 %

Procedure:
In a reactor vessel, a suspension of 6-nitro-2-iodo-3,4-dimethoxybenzonitrile (see Example 1(d) of WO 98/30560, 10 kg) in ethanol (60 l) at room temperature was charged with a solution of sodium dithionite (15.6 kg of technical grade material) in water (67.5 l) over 45 mins maintaining the temperature below 35° C. The addition vessel was washed with water (10 l). The resulting mixture was warmed to reflux (ca. 85° C.) for ca. 90 mins and then the temperature adjusted to 65° C. A solution of 6M aqueous hydrochloric acid (12.5 l) was added over ca. 10 mins and the resulting mixture stirred at 65° C. for ca. 5 hours before being cooled to room temperature. The pH was adjusted to the range 7–8 using 40% sodium hydroxide (2 l), the resulting mixture left to stir for 3 hours, filtered and washed with water (50 l). The damp cake was slurried in water (90 l) overnight at room temperature, filtered, washed with water (100 l) and dried in vacuo to give 8.35 kg (92%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:12][C@@H:11]([NH:13][C:14]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]=3[OH:26])=[O:15])[CH2:10][C@H:9]2[C:27](O)=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:30]1[CH2:33][CH2:32][CH2:31]1>>[N:30]1([C:27]([C@H:9]2[N:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:12][C@@H:11]([NH:13][C:14]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]=3[OH:26])=[O:15])[CH2:10]2)=[O:28])[CH2:33][CH2:32][CH2:31]1
Reactant: C1CNC1
Reactant: O=C(N[C@H]1C[C@@H](C(=O)O)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O
Product: O=C(N[C@H]1C[C@@H](C(=O)N2CCC2)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O

Procedure:
Hydroxy-naphthalene-2-carboxylic acid [(3S,5S)-5-(azetidine-1-carbonyl)-1-cyclohexylmethyl-pyrrolidin-3-yl]-amide was prepared from (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid and azetidine in an analogous manner to example 1. MS calcd for C26H34N3O3 [(M+H)+] 436.0, obsd. 436.0.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].Br[C:61]1[C:71]2[C:72]3[C:64]([CH2:65][CH2:66][C:67]=3[CH:68]=[CH:69][CH:70]=2)=[CH:63][CH:62]=1>C1(C)C=CC=CC=1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:65]1[C:64]2=[C:72]3[C:71](=[CH:61][CH:62]=[CH:63]2)[C:70]([N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)=[CH:69][CH:68]=[C:67]3[CH2:66]1
Reactant: C[C@@H]1CNCCN1
Reactant: Brc1ccc2c3c(cccc13)CC2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc3c4c(cccc24)CC3)CCN1

Procedure:
A mixture of 2-(R)-methylpiperazine (0.124 g, 1.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (49 mg, 0.05 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (69 mg, 0.10 mmol) and sodium tert-butoxide (0.148 g, 1.5 mmol) were stirred in toluene (50 mL) under nitrogen for 15 min to give a blood red solution. 5-Bromo-1,2-dihydroacenaphthylene (0.256 g, 1.1 mmol) was added, the solution stirred under nitrogen and heated at reflux for 3 h. The mixture was cooled, diluted with dichloromethane and filtered through celite. The organic phase was washed with water, dried (MgSO4), filtered and evaporated in vacuo. The crude product was taken forward to the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[N:19]=3)[N:14]=[CH:13][CH:12]=2)[OH:10])[CH2:4]1.[O:23]=[C:24]1[CH2:29][S:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.[BH4-].[Na+]>C(Cl)Cl.CCO>[OH:10][C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[N:19]=2)[N:14]=[CH:13][CH:12]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@@H:3]([CH2:2][NH:1][CH2:34][C:32]2[CH:31]=[CH:30][C:27]3[S:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=3[N:33]=2)[CH2:4]1
Reactant: COc1ccc2nccc([C@H](O)CN3CC[C@@H](CN)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2nccc([C@H](O)CN3CC[C@@H](CNCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 24 h
Yield: 52.9 %

Procedure:
To a stirred solution of (1S)-2-[(3S)-3-(aminomethyl)-1-pyrrolidinyl]-1-[6-(methyloxy)-1,5-naphthyridin-4-yl]ethanol (72 mg, 0.24 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (20 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (47 mg, 0.24 mmole). After 24 h at RT, was added NaBH4 (10 mg, 0.26 mmole). After 2 h, silica gel (5 g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (61 mg, 54%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J=4.5 Hz, 1H), 8.23 (d, J=9.1 Hz, 1H), 7.84 (d, J=4.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.12 (d, J=9.1 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 5.74 (m, 1H), 4.04 (s, 3H), 3.82 (s, 2H), 3.46 (s, 2H), 3.00-3.11 (m, 1H), 2.58-2.83 (m, 6H), 2.33-2.58 (m, 1H), 2.01 (m, 2H), 1.65 (m, 1H). LC-MS (ES) m/e 481 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](=[NH:10])[NH:7][NH:8][CH3:9])=[CH:4][N:3]=1.[CH:13](O)=O>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]2[N:10]=[CH:9][N:8]([CH3:13])[N:7]=2)=[CH:4][N:3]=1
Reactant: O=CO
Reactant: CNNC(=N)c1ccc(Cl)nc1
Product: Cn1cnc(-c2ccc(Cl)nc2)n1

Procedure:
A solution of 6-chloro-N′-methylnicotinimidohydrazide (2BX) (2.4 g, 13 mmol) in Formic Acid (99%, 10 ml) was stirred at reflux temperature for 1 hour. Reaction was cooled and solvent evaporated. The residue was extracted with EtOAc (100 ml) and Aqueous NaHCO3 (50 ml), organic layer was separated, dried over Na2SO4, filtered and solvent evaporated. The residue chromatographed on silica gel eluting with 10% MeOH:CH2Cl2 yielding title product as a solid (1.8 g, 72%) MS (MH, 195)
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](O)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2].C(Cl)(C(Cl)=O)=O.[NH2:43][C@H:44]1[CH2:47][C@@H:46]([C:48]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:49])[C:45]1([CH3:57])[CH3:56].CCN(CC)CC>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:31])[NH:43][C@H:44]4[CH2:47][C@@H:46]([C:48]([N:50]5[CH2:55][CH2:54][O:53][CH2:52][CH2:51]5)=[O:49])[C:45]4([CH3:57])[CH3:56])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: CC1(C)[C@@H](N)C[C@H]1C(=O)N1CCOCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
To a (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.4 g, 0.803 mmol) in DCM (1 ml) 2M solution of (COCl)2 in DCM (4 ml, 8.03 mmol) was added at about 0° C. and the reaction mixture was stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC) the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a solution of ((1R,3S)-3-amino-2,2-dimethylcyclobutyl)(morpholino)methanone (Intermediate 11, 0.306 g, 1.45 mmol) in DCM (5 ml) and Et3N (0.22 ml, 1.61 mmol) at about 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC) the reaction mixture was diluted with DCM and washed with water, 1N HCl, water brine and dried with Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 10% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.380 g: Yield: 68.4%; 1H NMR (300 MHz, CDCl3): δ 5.88 (d, 1H), 4.73 (s, 1H), 4.58 (s, 1H), 4.51-4.42 (m, 1H), 4.17-4.06 (m, 1H), 3.80-3.41 (m, 7H), 3.17-3.08 (m, 1H), 2.93-2.84 (m, 1H), 2.50-2.29 (m, 2H), 2.05 (s, 3H), 1.99-1.86 (m, 3H), 1.80-1.02 (m, 22H), 0.95, 0.92 (s, 9H), 0.83 (s, 15H); Mass: [M+Na]+ 693 (100%); M.R: 144.8° C.-156.2° C.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:23]=[CH:22][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH3:21])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][CH:50]2[CH2:52][O:51]2)=[CH:44][CH:43]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH3:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:52][C@H:50]([OH:51])[CH2:49][O:48][C:45]3[CH:46]=[CH:47][C:42]([OH:41])=[CH:43][CH:44]=3)=[CH:23][CH:22]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: CNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: CNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 16.7 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-methyl-1-piperidinecarboxamide formate (0.322 g, 1.0 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.364 g, 0.90 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.1 g, 0.15 mmol).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19])C1C=CC=CC=1>CO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([C:18]([F:19])([F:20])[F:21])[CH:11]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(O)c(C(F)(F)F)c1
Reaction time: 4 h
Yield: 89.6 %

Procedure:
To the suspension of 1-benzyloxy-4-nitro-2-trifluoromethylbenzene (575 mg, 1.96 mmol) in methanol was added catalytic amount of 5% palladium on carbon under a hydrogen atmosphere. The mixture was stirred for 4 hrs and filter through celite. The filtrate was concentrated to afford 4-amino-2-trifluoromethylphenol (311 mg, 90%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[Na].[CH3:10][NH:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1>CO>[CH3:10][N:11]1[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[N:2][C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:12]1
Reactant: CNNCc1ccc(Cl)cc1
Reactant: N#Cc1ccncc1
Agent: [Na]
Solvent: CO
Product: Cn1nc(-c2ccc(Cl)cc2)nc1-c1ccncc1
Reaction time: 0.5 h

Procedure:
To 4-cyanopyridine (2 g.) in methanol (30 ml.) is added sodium (0.1 g.). After standing at room temperature 0.5 hour the solution is added to 1-methyl-2-p-chloro-benzylhydrazine (3.6 g.) in methanol (40 ml.). The reaction mixture is refluxed for 5 hours and concentrated to an oil which is solidified. After recrystallization from ethyl alcohol 0.5 g. of 1-methyl-3-(p-chlorophenyl)-5-(4-pyridyl)-1,2,4-triazole m.p. 191° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][S@@](C(C)(C)C)=O)[CH3:9])=[CH:4][C:3]=1[CH3:17].C1(C2(CC(O)(C)C)OC(=O)N([C@H](C3C=CC(C4C=CN(C)C(=O)C=4)=CC=3)C)CC2)CC1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc([C@H](C)N[S@](=O)C(C)(C)C)ccc1Br
Agent: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC(CC(C)(C)O)(C2CC2)OC1=O
Product: Cc1cc([C@H](C)N)ccc1Br

Procedure:
The title compound was prepared from (R)-2-methyl-propane-2-sulfinic acid [(S)-1-(4-bromo-3-methyl-phenyl)ethyl]-amide following a procedure analogous to that described in Step 3 of Intermediate 1. LC-MS (Method 4): tR=3.56 min; Mass spectrum (ESI+): m/z=214/216 (Br) [M+H]+.