Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([O:46][CH3:47])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[NH:20][C:19]2=[O:45])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].Br[C:54]1[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=1>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([O:46][CH3:47])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:54]3[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=3)[C:19]2=[O:45])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccnc1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4ccccc34)(OC)C(=O)Nc3ccccc32)C(C)C)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4ccccc34)(OC)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Temperature: 120 °C
Yield: 70.5 %

Procedure:
To a stirring suspension of 570 mg (0.90 mmol) of 2-[3-(1-Benzyl-1H-indazol-3-ylmethyl)-3-methoxy-2,4-dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part A, and 172 mg (2.71 mmol, 3.0 equiv) of Cu0 powder in 10 mL of DMF is added 117 mg (1.80 mmol, 2.0 equiv of potassium acetate, followed by 285 mg (1.80 mmol, 2.0 equiv) of 3-bromopyridine). The resulting mixture is heated to 120° C. for 4 h, then an additional 285 mg of 3-bromopyridine is added and the reaction heated to 120° C. for an additional 15 h. The reaction mixture is then cooled to RT and filtered through a pad of Celite to remove the Cu0 powder. The reaction mixture is then poured into 100 mL of EtOAc-Et2O (1:1) and extracted with H2O (2×100 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 450 mg of the title compound as a light tan solid: mp 223°-224° C.; 1H NMR (CDCl3, 400 MHz) δ8.47 (d, 1H, J=3.8), 8.31 (s, br, 1H), 8.04 (d, 1H, J=8.2), 7.51 (d, 1H, J=7.3), 7.38 (d, 1H, J=7.7), 7.31-6.93 (m, 15H), 6.64 (d, 1H, J=7.5), 5.52 (s, 2H), 5.04 (m, 1H), 4.46 (d, 1H, J=15.9), 4.26 (d, 1H, J=15.8), 4.00 (m, 2H), 3.84 (s, 3H), 3.15 (s, 3H), 1.11 (2×d, 6H, J=6.7); low resolution MS (FAB)m/e 709 (MH+), 293, 265; Anal. (C42H40N6O5) Calcd. C, 71.17; H, 5.69; N, 11.86; Found C, 70.90; H, 5.74; N, 11.65.
Reaction SMILES: CC1(C)O[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([F:20])[CH:14]=2)=[N:4]C1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.Cl>CCOCC>[F:20][C:15]1[CH:14]=[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:5]#[N:4])[CH:18]=[CH:17][C:16]=1[CH3:19]
Reactant: Cc1ccc(-c2ccccc2C2=NCC(C)(C)O2)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 25 °C

Procedure:
97.0 g (343 mmol) of the compound from Example III are initially introduced into 500 ml of pyridine, and 31.3 ml (343 mmol) of phosphorus oxychloride are added at 0° C., while stirring. The mixture is heated slowly, and is finally boiled under reflux for 1 hour. After cooling to room temperature, ether and an amount of 1M hydrochloric acid such that the pH of the aqueous phase is 1.5 are added. The organic phase is washed three more times with 1M sulphuric acid, dried with sodium sulphate and evaporated on a rotary evaporator and the residue is freed from the residual solvent under a high vacuum.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]([C:16]([CH3:26])([S:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[CH3:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[O-:15].Cl>N1C=CC=CC=1>[CH3:1][S:2]([OH:4])(=[O:6])=[O:3].[CH3:1][S:2]([O:6][CH:7]([C:16]([CH3:26])([S:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1)[CH3:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[O-:15])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(SC(C)(C)C(O)Cc2cccc[n+]2[O-])cc1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)O
Product: Cc1ccc(SC(C)(C)C(Cc2cccc[n+]2[O-])OS(C)(=O)=O)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 44.2 %

Procedure:
1.25 g of methanesulphonyl chloride were added dropwise at 20° C. to a stirred solution of 2.73 g of 2-[2-hydroxy-3-methyl-3-(4-methylthiophenoxy)butyl]pyridine N-oxide in 10 ml of pyridine and the mixture was stirred at 20° C. for 16 hours. A further 1.25 g of methanesulphonyl chloride were then added and the stirring was continued for 3 hours. The mixture was then poured into 2M hydrochloric acid and extracted with ethyl acetate. The solvent was removed by evaporation and the residue was crystallized from ethyl acetate to give 0.95 g of 2-[2-methanesulphonyloxy-3-methyl-3-(4-methylthiophenoxy)butyl]pyridine N-oxide methanesulphonic acid salt in the form of a white solid of melting point 126-128° C.
Reaction SMILES: C=C1CC[N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C[N+]1([O-])CC[O:19]CC1.S([O-])([O-])=O.[Na+].[Na+].[O:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.O>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[OH:19][C:32]1([CH2:33][OH:29])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:30][CH2:31]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(CO)CC1
Reaction time: 2 h

Procedure:
To a solution of 98 mg of t-butyl 4-methylenetetrahydro-pyridine-1(2H)-carboxylate in 2 ml of tetrahydrofuran-water (1:1), 88 mg of N-methyl morpholine-oxide and 0.1 ml of 2% osmium tetraoxide were added at 0° C., followed by 2 hours' stirring at the same temperature. Adding sodium sulfite to the reaction liquid, the reaction liquid was further stirred for 30 minutes, diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 115 mg of the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.[CH2:10]=[O:11]>CC(C)=O>[F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][N:6]([CH2:10][OH:11])[CH:7]=1
Reactant: C=O
Reactant: FC(F)(F)c1cn[nH]c1
Solvent: CC(C)=O
Product: OCn1cc(C(F)(F)F)cn1
Temperature: 130 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
The mixture of 0.59 g of 4-(trifluoromethyl)-1H-pyrazole and 0.26 g of paraformaldehyde was stirred at 130° C. for 4 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The residue was concentration under reduced pressure to obtain 0.60 g of 4-(trifluoromethyl)-1H-pyrazole-1-ylmethanol.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:14]>C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:14])=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)c2ccccc12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Product: COc1cnc(Cl)c2ccccc12
Reaction time: 2 h
Yield: 46.4 %

Procedure:
To a solution of 1-chloroisoquinolin-4-ol (5.0 g, 27.8 mmol) in acetonitrile (50 mL) was added TMS-diazomethane (12.73 g, 111.2 mmol) at 0° C. The reaction mixture was allowed to come to room temperature and stirred for 2 h. Solvent was evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get 1-chloro-4-methoxyisoquinoline (2.5 g, 46.4%) as off-white solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.29-8.17 (m, 2H), 7.97 (s, 1H), 7.91-7.82 (m, 2H), 4.05 (s, 3H); MS: MS m/z 194.7 (M++1).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[Cl:14][S:15](O)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: CC1(c2ccccc2)CCOCC1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CC1(c2ccc(S(=O)(=O)Cl)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred mixture of 4-methyl-4-phenyl-tetrahydro-pyran (1.10 g, 6.24 mmol) in dry methylene chloride (50 mL) cooled in an ice bath was added 2.07 mL of chlorosulfonic acid (3.64 g, 31.2 mmol) dropwise under dry nitrogen. The reaction was stirred overnight at room temperature; the reaction was added to ice and the product was extracted with methylene chloride (3×100 mL). The organic layer was washed with saturated brine, dried (MgSO4), filtered and concentrated. e product was chromatographed on silica gel using ethyl acetate-hexane mixtures (2-20% hexane). Removal of solvent provided pure product as a colorless syrup which crystallized on standing: 1H NMR (CDCl3) δ 7.99 (d, 2H, J=8.8 Hz), 7.56 (d, 2H, J=8.8 Hz), 3.79 (ddd, 1H, J=11.7 Hz, J=8.4 Hz, J=3.3 Hz), 3.70 (ddd, 1H, J=11.7 Hz, J=6.0 Hz, J=3.8 Hz), 2.11 (ddd, 1H, J=13.8 Hz, J=8.4 Hz, J=3.8 Hz), 1.81 (dm, 1H, J=13.8 Hz), 1.35 (s, 3H). MS: m/z 275 (M++1).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.B1([C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)OCCCO1.C(=O)(O)[O-].[Na+]>COCCOC.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>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)[CH:19]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
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: [Na+]
Solvent: COCCOC
Product: Nc1ccc(-c2cccnc2)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 105.6 %

Procedure:
To a solution of 4-bromo-2-nitroaniline (4.8 g, 22 mmol) in DME (100 mL) was added pyridine-3-boronic acid 1,3-propanediol cyclic ester (4 g, 24 mmol), sodium bicarbonate (45 mL, 1M), and tetrakis(triphenylphosphine)palladium (0.05 eq). The resulting mixture was heated at 90° C. for 8 hours then cooled to room temperature. The solids were collected, washed with water, 5% EtOAc in Hexane and dried to afford the title compound (5 g). 1H NMR (CDCl3) δ 8.8 (d, 1H), 8.55 (m, 1H), 8.35 (d, 1H), 7.85 (dd, 1H), 7.65 (dd, 1H), 7.35 (m, 1H), 6.95 (d, 1H), 6.25 (br s, 2H).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[C:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([O:16][CH3:17])=[O:15])C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[C:18]1([CH:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[C:14]([O:16][CH3:17])=[O:15])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)C(=C1CCCN1Cc1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(c1ccccc1)C1CCCN1
Reaction time: 72 h

Procedure:
To a solution of methyl 2-(1-benzylpyrrolidin-2-ylidene)(phenyl)acetate (0.505 g, 1.64 mmol) in 5 mL of methanol was added palladium(II) hydroxide (231 mg, 1.64 mmol), and the reaction was stirred under a balloon of hydrogen gas. After 3 days, the mixture was filtered through celite, the pad was rinsed with CH2Cl2/MeOH, and the filtrate was concentrated in vacuo to provide methyl phenyl(pyrrolidin-2-yl)acetate as a mixture of two diastereomers. ESI+MS: 220.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[OH:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: OB(O)c1ccccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one and pyridine-2-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=1.01 min, m/z=416.21; 1H NMR (CD3OD) 1.30 (m, 1H), 1.55 (d, 3H), 1.62 (m, 1H), 1.94 (m, 2H), 2.20 (m, 1H), 2.32 (m, 1H), 2.48 (m, 1H), 3.09 (m, 1H), 3.44 (m, 2H), 5.57 (m, 1H), 7.03 (d, 2H), 7.29-7.40 (m, 6H), 7.67 (d, 2H), 7.73 (d, 1H), 7.84 (t, 1H), 8.55 (d, 1H).
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[OH:26][N:25]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCC(=NO)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 60.9 %

Procedure:
In a manner similar to Example 4, Step (c), 4-oxo-4-(4′-trifluoromethyl-biphenyl-4-yl)-butyric acid (1.20 g, 0.00372 mol) was allowed to react with hydroxylamine hydrochloride (0.3115 g, 0.00448 mol) in the presence of sodium carbonate (0.4768 g, 0.00450 mol) in absolute ethanol (20 mL) to give 0.764 g of 4-hydroxyimino-4-(4′-trifluoromethyl-biphenyl-4-yl)-butyric acid as a white solid; mp 134-136° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([N:6]([CH3:16])[C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:10]#[N:11])[CH3:5]>CO>[CH2:4]([N:6]([CH3:16])[C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:10]([NH:2][OH:3])=[NH:11])[CH3:5]
Reactant: NO
Reactant: CCN(C)c1cc(C#N)cc(C)n1
Agent: Cl
Solvent: CO
Product: CCN(C)c1cc(C(=N)NO)cc(C)n1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a solution of K tert butylate (574 mg, 5.11 mL) in methanol (10 mL), hydroxylamine hydrochloride (304 mg, 4.38 mmol) is added. To the stirred suspension, a solution of 2-(ethyl-methyl-amino)-6-methyl-isonicotinonitrile (256 mg, 1.46 mmol) in methanol (10 mL) is added and the resulting mixture is stirred at 60° C. for 15 h. The mixture is filtered, and the filtrate is concentrated. The residue is treated with 1 N aq. HCl, washed with DCM and then basified by adding 1 N aq. NaOH. The mixture is extracted three times with EA. The combined EA extracts are dried over MgSO4, filtered, concentrated and dried to give the title compound as a pale yellow oil; LC-MS: tR=0.45 min, [M+1]+=209.10; 1H NMR (D6-DMSO): δ 1.06 (t, J=6.5 Hz, 3H), 2.29 (s, 3H), 2.98 (s, 3H), 3.56 (q, J=6.3 Hz, 2H), 5.82 (s, 2H), 6.64 (s, 1H), 6.69 (s, 1H), 9.74 (s, 1H).
Reaction SMILES: [CH2:1]([N:5]([CH2:18][CH2:19][CH2:20][CH3:21])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=O)=[C:8]([O:16][CH3:17])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:22]([C:24]1[C:25](=[C:32]([C:35]#[N:36])[C:33]#[N:34])[O:26][C:27]([CH3:31])([CH3:30])[C:28]=1[CH3:29])#[N:23].C([O-])(=O)C.[NH4+]>C(O)C>[CH2:1]([N:5]([CH2:18][CH2:19][CH2:20][CH3:21])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:29][C:28]2[C:27]([CH3:30])([CH3:31])[O:26][C:25](=[C:32]([C:33]#[N:34])[C:35]#[N:36])[C:24]=2[C:22]#[N:23])=[C:8]([O:16][CH3:17])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc(C=CC=O)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC=CC2=C(C#N)C(=C(C#N)C#N)OC2(C)C)c(OC)c1
Temperature: 50 °C
Yield: 74.2 %

Procedure:
In 5 ml of ethanol were dissolved 170 mg (0.59 mmol) of 3-(4-dibutylamino-2-methoxyphenyl)propenal and 129 mg (0.65 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene) propanedinitrile. To this mixture was added 46 mg of ammonium acetate, and the mixture was stirred with heating at 50° C. for 2 hours. The solvent was evaporated off and the residue was purified by silica gel column chromatography to give 206 mg of a dark greenish brown crystal (yield: 74.5%; mp: 181-184° C.)
Reaction SMILES: FC(F)(F)CCC([N:7]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11][C:8]21[CH2:10][CH2:9]2)=O.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35]>C1COCC1>[CH3:40][O:39][CH2:38][CH2:37][O:36][C:34]([N:7]1[CH:8]2[CH2:9][CH2:10][CH:14]1[CH2:13][N:12]([C:15]1[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=1)[CH2:11]2)=[O:35]
Reactant: COCCOC(=O)Cl
Reactant: O=C(CCC(F)(F)F)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOC(=O)N1C2CCC1CN(c1ncnc3[nH]ccc13)C2
Reaction time: 16 h

Procedure:
4-(3,8-Diaza-bicyclo[3.2.1]oct-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 4) (0.05 mmol) was dissolved in THF (1.0 mL). Triethylamine (0.12 mmol) and 2-methoxyethyl chloroformate (0.06 mmol) was added. The reaction mixture was left at rt for 16 hours. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:27])[C@H:16]([CH2:25][OH:26])[NH:17]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C.CCCCCC.[ClH:40]>O1CCOCC1>[ClH:40].[CH2:1]([O:8][C:9](=[O:28])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:27])[C@H:16]([CH2:25][OH:26])[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCCCCC
Product: N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
N-t-butyloxycarbonyl-L-seryl-L-proline benzylester (33.99 g, 86.6 mmole) was dissolved in 4N hydrochloric acid in dioxane (300 ml) solution, and stirred for 1 hour at room temperature. To the solution, diethyl ether (500 ml) and n-hexane (100ml) were added to give L-seryl-L-proline benzylester hydrochloride (yield: 28.03 g, 98.4%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>COCCOC>[CH3:31][O:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1Br
Reactant: COc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cccc(-c2ccccc2SCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1
Yield: 54.3 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-phenylsulfanyl)-acetyl]-N′-isopropyl-hydrazide (100 mg, 0.246 mmol) in DME (5 ml)/2M Na2CO3 (0.430 ml, 0.86 mmoles) was treated with 3-methoxyphenylboronic acid (75 mg, 0.491 mmol) and Pd[PPh3]4 (29 mg, 0.025 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient to afford the product as a solid (58 mg, 55%). MS m/e 435.22 (M+H+)
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[C:7]([CH3:15])=[CH:6]1)(=[O:4])=[O:3].[ClH:16].CS(N1C2C(=CC=C(N=[C:31]3[NH:35][CH2:34][CH2:33][NH:32]3)C=2)C=C1)(=O)=O>>[ClH:16].[NH:32]1[CH2:33][CH2:34][NH:35][C:31]1=[N:14][C:11]1[CH:12]=[C:13]2[C:8]([C:7]([CH3:15])=[CH:6][N:5]2[S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][CH:10]=1
Reactant: Cc1cn(S(C)(=O)=O)c2cc(N)ccc12
Reactant: CS(=O)(=O)n1ccc2ccc(N=C3NCCN3)cc21
Agent: Cl
Product: Cc1cn(S(C)(=O)=O)c2cc(N=C3NCCN3)ccc12

Procedure:
Imidazolidin-2-ylidene-(1-methanesulfonyl-3-methyl-1H-indol-6-yl)-amine hydrochloride (mp 236.4-236.7° C.) was prepared from 1-methanesulfonyl-3-methyl-6-amino-1H-indole by a procedure which was similar to that for the preparation of N-methanesulfonyl-6-(imidazolidin-2-ylideneamino)indole hydrochloride.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[C:12]3[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=3[N:14]=2)=[CH:5][CH:4]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.O.CCOC(C)=O>CN(C=O)C>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:21]([C:11]1[C:12]2[CH:17]=[N:16][N:15]([CH:18]([CH3:19])[CH3:20])[C:13]=2[N:14]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:4][CH:5]=2)[CH:10]=1)=[O:22]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CBr)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h
Yield: 15 %

Procedure:
To a stirred solution of 6-(4-(bromomethyl)phenyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) in dry DMF, morpholine (5 equiv.) was added at 0° C. and reaction mixture was stirred for overnight. After completion of reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water; dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by column chromatography/preparative HPLC to give the desired compound (15% yield). LCMS: 515.25 (M+1)+; HPLC: 99.80% (@ 254 nm) (Rt; 5.168); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 10.01 (bs, 1H), 8.94 (bs, 1H), 8.39 (s, 1H), 8.35 (d, J=7.6 Hz, 2H), 8.18 (s, 1H), 7.68 (d, J=7.2 Hz, 2H), 5.90 (s, 1H), 5.30 (m, 1H), 4.44-4.41 (m, 4H), 3.98 (m, 2H), 3.63-3.60 (m, 2H), 3.37-3.30 (m, 2H), 3.16 (m, 2H), 2.23 (s, 3H), 2.13 (s, 3H), 1.55 (d, J=6.4 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[O:17]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH2:19][CH:18]1[C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28]>C(O)CCC>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:2]([NH2:1])=[N:3][C:4]([N:32]3[CH2:33][CH2:34][N:29]([C:27]([CH:18]4[O:17][C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[O:20][CH2:19]4)=[O:28])[CH2:30][CH2:31]3)=[N:5][C:6]2=[CH:7][C:8]=1[O:14][CH3:15]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1COc2ccccc2O1)N1CCNCC1
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(C(=O)C4COc5ccccc5O4)CC3)nc(N)c2cc1OC
Temperature: 75 °C
Yield: 80.6 %

Procedure:
4-amino-2-chloro-6,7-dimethoxyquinazoline (3.2 g, 13.35 mmol) and compound 1 (3.4 g, 13.75 mmol) prepared from Example 3 were dissolved in 72 mL of n-butanol. The mixture was refluxed under nitrogen for 3.5 hours. After cooling to 75° C., the solid product was obtained by filtration and dried to afford 5.25 g of hydrochloride salt of Doxazosin (10.76 mmol, 81% yield). 1 N NaOH solution was added to the salt. The mixture was heated to help the salt dissolved. After cooling, the mixture was extracted with 150 mL of dichloromethane twice. The organic layer was dried with anhydrous sodium sulfate and concentrated to afford 4.61 g of Doxazosin.