Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39](O)=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.Cl.Cl.[NH2:45][CH2:46][C:47]1[NH:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[NH:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[CH2:46][NH:45][C:39]([C:11]1[CH:10]=[CH:9][C:8]2[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:15]3[C:16]4[CH:38]=[CH:37][CH:36]=[CH:35][C:17]=4[CH:18]=[C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])[CH2:20][N:14]3[C:13]=2[CH:12]=1)=[O:40]
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Reactant: NCc1nc2ccccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1nc2ccccc2[nH]1)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 4 h
Yield: 14.6 %

Procedure:
To a stirred solution of 13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (134 mg, 0.24 mmol) in DMF (500 μL) were added 2-aminomethyl benzimidazole dihydrochloride hydrate (75 mg, 0.32 mmol), N,N-diisopropylethylamine (165 μL, 0.95 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol), and 1-hydroxybenzotriazole (44 mg, 0.33 mmol). The suspension was allowed to stir at r.t. for 4 hr, at which point the solvent was removed under reduced pressure. CH2Cl2 (5 mL) was added, and the suspension filtered through Celite, and chromatographed on silica gel (gradient elution: 0%→10% MeOH in CH2Cl2) to afford the title compound as a pale yellow solid (24 mg, 14% yield). LC/MS (ESI) retention time: 1.57 min, m/z 683 (MH+); 1H NMR (400 MHz, CDCl3) δ 1.07-1.53 (m, 4 H) 1.63-1.78 (m, 3 H) 1.99 (s, 4 H) 2.25 (t, J=11.08 Hz, 1 H) 2.39 (s, 4 H) 2.59-2.87 (m, 3 H) 3.63 (s, 4 H) 4.14 (s, 1 H) 4.73-5.00 (m, 3 H) 6.78 (s, 1 H) 7.17 (ddd, J=9.63, 3.90, 3.59 Hz, 2 H) 7.34 (dd, J=7.05, 1.76 Hz, 1 H) 7.40-7.47 (m, 2 H) 7.50-7.58 (m, 4 H) 7.73 (d, J=8.31 Hz, 1 H) 8.16 (s, 1 H) 8.68 (s, 1 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5](=[O:26])[CH2:6][PH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)[Cl:28]>>[Cl-:28].[OH:1][CH2:2][CH2:3][CH2:4][C:5](=[O:26])[CH2:6][P+:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CCCO)C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCCl
Product: O=C(CCCO)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 50 °C

Procedure:
2.3 g of (5-hydroxy-2-oxopentyl)triphenylphosphorane was dissolved in methylene chloride and extracted 4 times with aqueous hydrochloric acid (pH 1 to 2) and the extracts were combined, sodium chloride added and then extracted with methylene chloride (4×50 ml). The organic extracts were combined, dried over sodium sulfate, and the solvent removed under nitrogen gas followed by heating to 50° C./0.5 mm Hg for 6 hours and crystallization from acetone to give 1.9 g of product, m.p. 143°-145° C. identical with that obtained by the process in Example 10.
Reaction SMILES: C([C@H](N[C:12](=[O:27])[C@H:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:17]([F:26])[CH:16]=1)[CH3:14])CO)C1C=CC=CC=1.[OH:28]S(O)(=O)=O>O1CCOCC1.O>[F:26][C:17]1[CH:16]=[C:15]([C@H:13]([CH3:14])[C:12]([OH:27])=[O:28])[CH:20]=[CH:19][C:18]=1[NH:21][S:22]([CH3:25])(=[O:23])=[O:24]
Reactant: C[C@H](C(=O)N[C@H](CO)Cc1ccccc1)c1ccc(NS(C)(=O)=O)c(F)c1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](C(=O)O)c1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
A solution of N-[(1S)-1-Benzyl-2-hydroxyethyl]-(2S)-2-[3-fluoro-4-(methylsulfonylamino)phenyl]propionamide (100 mg, 0.234 mmol) in 3 N H2SO4 (1 mL) and 1,4-dioxane (1 mL) was heated to 100° C. for 5 h and cooled to room temperature. The solution was diluted with water and extracted with CH2Cl2 several times. The combined organic layers were washed with water, dried over MgSO4, and concentrated in vacuo to afford (2S)-[3-Fluoro-4-(methylsulfonylamino)phenyl]propionic acid.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH:11]([Cl:14])[CH2:12][CH3:13].C([O-])(O)=O.[Na+]>C(#N)C>[Cl:14][CH2:11][CH2:12][CH2:13][NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCC(Cl)Br
Reactant: NCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: ClCCCNCCc1ccccc1
Reaction time: 16 h
Yield: 26.5 %

Procedure:
A mixture of phenethylamine (7.1 g, 7.38 ml, 58.5 mmol) and bromochloropropane (3.07 g, 1.93 ml, 19.5 mmol) in acetonitrile (15 ml) is stirred for 16 h. In the course of the reaction a white crystalline solid forms. Saturated aqueous NaHCO3 solution is added to adjust the pH to 9-10. The free amine is extracted three times with AcOEt. The combined organic phases are dried over Na2SO4. Evaporation of the solvent in vacuo yields a yellow oil. It is purified by chromatography on silica-gel (dichloromethane/MeOH, 95:5), yielding the title compound (1.02 g) in 26% as a slightly yellow oil which crystallizes on standing: 1H-NMR (CDCl3): δ (ppm) 1.91 (quint., 2H, CH2CH2N), 2.75 (m, 4H), 2.81-2.89 (m, 2H), 3.59 (t, 2H, CH2Cl), 7.20 (m, 3Harom), 7.24-7.32 (m, 2Harom).
Reaction SMILES: [OH-:1].[K+].[NH2:3][C:4]1[N:9]=[C:8]([NH:10][C@@H:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][OH:14])[C:7]([CH2:18][C:19]2[CH:20]=[C:21]([CH2:26][C:27]#N)[CH:22]=[CH:23][C:24]=2[F:25])=[C:6]([CH3:29])[N:5]=1.Cl.[CH2:31]([OH:35])CCC>O>[NH2:3][C:4]1[N:9]=[C:8]([NH:10][C@@H:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][OH:14])[C:7]([CH2:18][C:19]2[CH:20]=[C:21]([CH2:26][C:27]([O:35][CH3:31])=[O:1])[CH:22]=[CH:23][C:24]=2[F:25])=[C:6]([CH3:29])[N:5]=1
Reactant: CCCCO
Reactant: [OH-]
Reactant: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1cc(CC#N)ccc1F
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1cc(CC(=O)OC)ccc1F
Temperature: 100 °C

Procedure:
Aq. 5M KOH (0.5 mL) was added to a stirred solution of the product from step (v) (70 mg) in butan-1-ol (1 mL) and heated to 100° C. for 15 h. The mixture was allowed to cool, diluted with water (2 mL) and then adjusted to ˜pH 7 with conc. HCl. The organic phase was separated and the aqueous was extracted with butan-1-ol (5 mL). The combined organic extracts were evaporated, the residue was dissolved in MeOH and conc. HCl (0.3 mL) was added and the mixture heated to 70° C. for 1 h. After cooling the reaction was poured into sat. NaHCO3 (10 mL) and extracted with EtOAc, dried and the solvent removed. The crude product was purified by RPHPLC to afford the title compound as a colourless gum, 22 mg.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH3:29])[CH2:28][O:27]2)=[CH:22][CH:21]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:29][C:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)([OH:27])[CH3:28])[C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: CC1(c2ccc(Cl)cc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCc2c(n(CC(C)(O)c3ccc(Cl)cc3)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.6 %

Procedure:
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (61 mg, 0.254 mmol) in 5 mL of DMF, 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.2 g, 0.852 mmol) was added and stirred at RT for 5 min. 2-(4-Chlorophenyl)-2-methyloxirane (214 mg, 1.27 mmol) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, water was added, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by reverse phase chromatography to afford 150 mg of (1-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-chlorophenyl)propan-2-ol) as the TFA salt.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16](/[C:29](/[CH3:39])=[CH:30]\[CH:31]=[CH:32]\[C:33](\[CH3:38])=[CH:34]\[C:35]([OH:37])=[O:36])=[CH:17][C:18]2[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]=2[CH:24]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>C1COCC1>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16](/[C:29](/[CH3:39])=[CH:30]\[CH:31]=[CH:32]\[C:33](\[CH3:38])=[CH:34]\[C:35]([OH:37])=[O:36])=[CH:17][C:18]2[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]=2[CH:24]=1
Reactant: C/C(=C/C=C/C(C)=C/C(=O)O)c1cc2c(cc1OCCCCCO[Si](C)(C)C(C)(C)C)C(C)(C)CCC2(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C/C(=C/C=C/C(C)=C/C(=O)O)c1cc2c(cc1OCCCCCO)C(C)(C)CCC2(C)C

Procedure:
A mixture of (E,E,Z)-7-{3-[5-(tert-butyldimethylsilyloxy)pentyloxy]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl}-3-methyl-2,4,6-octatrienoic acid (850 mg, 1.5 mmol) and a 1M solution in THF of tetrabutylammonium fluoride (TBAF) (3.1 ml) in THF (10 ml) was stirred at room temperature for 1 h and then treated with ethyl acetate and with water. After settling, the organic phase was separated and washed twice with water, dried over anhydrous magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [ClH:1].Cl.N[CH2:4][CH:5]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]([S:22]([CH3:25])(=[O:24])=[O:23])[C@H:13]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:12]1)[C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.[C:33]([O-])(=O)C.[Na+].C=O.[BH3-][C:41]#[N:42].[Na+]>CO.C(O)(=O)C.C(OCC)(=O)C>[ClH:1].[ClH:1].[CH3:33][N:42]([CH3:41])[CH2:4][CH:5]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]([S:22]([CH3:25])(=[O:23])=[O:24])[C@H:13]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:12]1)[C:6]1[N:7]=[CH:8][NH:9][CH:10]=1
Reactant: CC(=O)[O-]
Reactant: CS(=O)(=O)N1Cc2ccccc2N(C(CN)c2c[nH]cn2)C[C@H]1Cc1ccccc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)CC(c1c[nH]cn1)N1C[C@@H](Cc2ccccc2)N(S(C)(=O)=O)Cc2ccccc21
Reaction time: 0.25 h

Procedure:
To a stirred solution of the free base of Example 258 (20 mg) in methanol (1 mL) and acetic acid (0.5 mL) with sodium acetate (100 mg), was added 30 μL of formaldehyde (37% aq. solution), followed by NaCNBH3 (15 mg). The mixture was stirred for 15 min, additional formaldehyde (30 μL) and NaCNBH3 were added and the mixture was stirred for 30 min and diluted with ethyl acetate and quenched with 3 mL of NH4OH solution. The organic layer was separated, washed with 1 N NH4OH solution and brine, dried, and concentrated. The residue was converted to its HCl salt as described in Example 257 (23 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[C@@H:4]([NH:12]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.CO.CNC.CO>C1COCC1>[NH2:12][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1)[C:3]([N:2]([CH3:31])[CH3:1])=[O:30]
Reactant: CN(C)C(=O)[C@H](Cc1ccncc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CNC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H](N)Cc1ccncc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
To a solution of 1.61 g of the compound obtained in Step 83-1 in a mixed solution of MeOH and THF (25 ml 4:1; v/v) was added a solution of 2 mol/L dimethylamine MeOH (5.8 ml) and the reaction mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under vacuum, and the obtained residue was purified by column chromatography (silicagel 60; mobile phase: CHCl3/MeOH=9/1 to 5/1; v/v) to obtain 0.59 g of the title compound (brown oil).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]#[N:31])[CH:20]=1.N1C=CC=CC=1.CCCP(=O)=O>CC1CCCO1>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([NH:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]#[N:31])[CH:20]=1)=[O:6]
Reactant: Cc1cc(Cl)c(C(=O)O)cc1-c1ccccn1
Reactant: N#Cc1cc(N)n(-c2ccccc2)n1
Agent: CCCP(=O)=O
Solvent: c1ccncc1
Solvent: CC1CCCO1
Product: Cc1cc(Cl)c(C(=O)Nc2cc(C#N)nn2-c2ccccc2)cc1-c1ccccn1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
A mixture of 2-chloro-4-methyl-5-(pyridin-2-yl)benzoic acid (Preparation 25, 234 mg, 0.94 mmol), 5-amino-1-phenyl-1H-pyrazole-3-carbonitrile (Preparation 53, 191 mg, 1.04 mmol) and pyridine (0.23 mL, 2.83 mmol) in 2-methyl tetrahydrofuran (20 mL) was heated at reflux for 10 minutes. To this refluxing mixture was added propylphosphonic anhydride solution (2.8 mL, 50% w/w in EtOAc) and the reaction heated at reflux under an atmosphere of argon for 18 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and 2M aqueous sodium hydroxide solution (50 mL). The organic layer was washed with 2M aqueous sodium hydroxide solution (50 mL), saturated aqueous ammonium chloride solution (50 mL), water (50 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-20% EtOAc in DCM followed by trituration with diethylether to afford the title compound as a white solid (119 mg, 31%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]1C=CC=CC=1.C(OC(OCCCC)=O)(OCCCC)=O.C(=O)(O)[O-].[NH4+]>O1CCOCC1>[NH2:18][C:15]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:17]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOCC1
Reactant: c1ccncc1
Agent: CCCCOC(=O)OC(=O)OCCCC
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(C(N)=O)CCOCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of the commercially available 4-[(tert-butoxycarbonyl)amino]tetrahydro-2H-pyran-4-carboxylic acid in dioxane, pyridine (0.6 eq.), di-butyl dicarbonate (1.3 eq) and ammonium bicarbonate (1.26 eq) were added and the mixture was stirred at room temperature for 20 hours. Dioxane was concentrated and the residue dissolved in ethyl acetate and washed with HCl 1N, saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and evaporated in vacuo to obtain the solid compound (C-25).
Reaction SMILES: [OH:1][B:2]1[O:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][O:3]1.[C:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)#[N:14].N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[C:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([O:1][B:2]2[O:3][CH2:4][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6][O:7]2)=[O:20])=[CH:17][CH:16]=1)#[N:14]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CCCCCC1COB(O)OC1
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1COB(OC(=O)c2ccc(C#N)cc2)OC1

Procedure:
17.2 g of 2-hydroxy-5-pentyl-1,3,2-dioxaborinane (prepared from trichloroborane and 2-hydroxymethylheptan-1-ol, followed by hydrolysis), 16.6 g of 4-cyanobenzoyl chloride and 15 ml of pyridine in 500 ml of toluene are heated at reflux temperature for 4 hours. Water is added to the mixture, the phases are separated, the organic phase is washed with water, dried over sodium sulphate and evaporated, and (5-pentyl-1,3,2-dioxaborinan-2-yl) 4-cyanobenzoate is obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:3]1.[CH3:13][N:14]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][CH:16]=[N:15]1.C1C(=O)N([Br:32])C(=O)C1>C(#N)C>[Br:32][C:5]1[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:3][N:2]([CH3:1])[CH:6]=1.[Br:32][C:17]1[CH:16]=[N:15][N:14]([CH3:13])[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1ccc(-c2ccccc2)n1
Reactant: Cn1nccc1-c1ccccc1
Solvent: CC#N
Product: Cn1cc(Br)c(-c2ccccc2)n1
Product: Cn1ncc(Br)c1-c1ccccc1
Temperature: 70 °C
Yield: 34 %
Yield: 20 %

Procedure:
The mixture of isomers, 1-methyl-3-phenyl-1H-pyrazole and 1-methyl-5-phenyl-1H-pyrazole (1.0 g, 6.3 mmol) and NBS (1.1 g, 6.3 mmol) are combined in acetonitrile (25 ml), stirred and heated to 70° C. for 1 hr. The solution is concentrated and the crude product is purified by chromatography using a hexane-ethyl acetate gradient (100% hexane to 25% ethyl acetate in hexane) to elute 4-bromo-1-methyl-3-phenyl-1H-pyrazole (504 mg, 34% yield) and 4-bromo-1-methyl-5-phenyl-1H-pyrazole (295 mg, 20% yield), respectively:
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]#[C:13][CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)=[CH:11][C:6]=2[C:5](=[O:22])[CH2:4][S:3]1(=[O:24])=[O:23].C(N(CC)CC)C.[Cl:32][C:33]1[CH:42]=[CH:41][C:36]([CH2:37][N:38]=[C:39]=[O:40])=[CH:35][CH:34]=1.Cl>CS(C)=O>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][NH:38][C:39]([C:4]2[S:3](=[O:23])(=[O:24])[N:2]([CH3:1])[C:7]3[CH:8]=[CH:9][C:10]([C:12]#[C:13][CH2:14][O:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][O:17]4)=[CH:11][C:6]=3[C:5]=2[OH:22])=[O:40])=[CH:41][CH:42]=1
Reactant: O=C=NCc1ccc(Cl)cc1
Reactant: CN1c2ccc(C#CCOC3CCCCO3)cc2C(=O)CS1(=O)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1c2ccc(C#CCOC3CCCCO3)cc2C(O)=C(C(=O)NCc2ccc(Cl)cc2)S1(=O)=O
Reaction time: 4 h
Yield: 28.4 %

Procedure:
To a solution of 1-methyl-6-(3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl)-1H-2,1-benzothiazin4(3H)-one 2,2-dioxide (Preparation 52, 1.00 g) and triethylamine (0.60 mL) in DMSO (25 mL) is added a solution of 4-chlorobenzylisocyanate (0.72 g) inDMSO (5 mL) at ambient temperature. After 4 h, 10% HCl (100 mL) is added to the reaction vessel and the aqueous layer is extracted with EtOAc (3×100 mL). The organic layers are combined, dried over MgSO4, filtered, and concentrated in vacuo to afford 0.42g (28%) of the title compound as a lime green solid. Physical characteristics: m.p. 148-149° C.; 1H NMR (300 MHz, CDCl3) δ 15.81, 8.22, 7.93, 7.71, 7.33, 7.16, 4.91, 4.60, 4.52, 3.91, 3.60, 3.48, 1.86, 1.62; IR (diffuse reflectance) 3373, 2940, 1616, 1574, 1543, 1493, 1390, 1327, 1297, 1279, 1253, 1116, 1097, 1077, 1037 cm−1; MS (FAB) m/z 517 (MH+); HRMS (EI) m/z 516.1140 (C25H25ClN2O6S). Anal. Found: C, 57.55; H, 4.95; N, 5.63.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)=[O:6].C([C:29]1[C:30]([N:35]=[CH:36][N:37]([CH3:39])C)=[N:31][CH:32]=[CH:33][CH:34]=1)#N.NC1C=C(C=CC=1SC1C=CC(O)=CC=1)C(NC1C=CC(Br)=CC=1)=O>>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:5](=[O:6])[C:4]2[CH:16]=[CH:17][C:18]([S:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[C:2]([NH:1][C:39]3[C:29]4[CH:34]=[CH:33][CH:32]=[N:31][C:30]=4[N:35]=[CH:36][N:37]=3)[CH:3]=2)=[CH:10][CH:11]=1
Reactant: CN(C)C=Nc1ncccc1C#N
Reactant: Nc1cc(C(=O)NCc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Agent: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Product: O=C(NCc1ccc(Br)cc1)c1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3ncccc23)c1
Yield: 26 %

Procedure:
The product of Example 33A was reacted with the product of Example 29A using the procedure of Example 22C substituting the product of Example 33A for the product of Example 22B and substituting the product of Example 29A for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (26 mg, 26%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 4.41 (d, J=5.88 Hz, 2 H) 6.76-6.96 (m, 1 H) 6.83 (d, J=8.46 Hz, 2 H) 7.20-7.33 (m, 4 H) 7.51 (d, J=8.46 Hz, 2 H) 7.58-7.80 (m, 2 H) 7.82-7.97 (m, 1 H) 8.52-8.69 (m, 1 H) 8.86-9.18 (m, 3 H) 9.94 (s, 1 H) 10.28 (s, 1 H); MS (ESI+) m/z 558/560 (M+H)+.
Reaction SMILES: [C:1](OCC)(=[S:5])[C:2]([NH2:4])=O.BrC[C:11](=O)[C:12](C)([CH3:14])[CH3:13].[Na].[BH4-].[Na+].[CH2:20]([OH:22])[CH3:21]>>[C:12]([C:2]1[N:4]=[C:21]([CH2:20][OH:22])[S:5][CH:1]=1)([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCOC(=S)C(N)=O
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Product: CC(C)(C)c1csc(CO)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
Ethyl thiooxamate (4.94 g, 37.1 mmol) was dissolved in anhydrous ethanol (250 ml), added with 1-bromopinacolone (4.99 ml, 37.1 mmol), and refluxed by heating for 4 hours. The reaction mixture was concentrated, neutralized with saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was dissolved in anhydrous ethanol (200 ml), added with sodium hydroboride (2.10 g, 55.6 mmol), and stirred at room temperature for 16 hours. The reaction solution was further added with sodium borohydride (500 mg, 13.2 mmol) and stirred at room temperature for 4 hours, and then the solvent was evaporated under reduced pressure. The residue was cooled to −78° C., and the resulting white solid was taken by filtration to obtain the title compound (2.77 g, 44%).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])=[C:9]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=O)[CH:8]=1)=[O:4].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)S2)=CC=1.O.[CH:53]([NH:55][NH2:56])=O>C1(C)C=CC=CC=1>[CH3:29][C:2]([CH3:1])([CH3:28])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])=[C:9]([C:22]2[N:24]([CH:25]([CH3:26])[CH3:27])[CH:53]=[N:55][N:56]=2)[CH:8]=1)=[O:4]
Reactant: COc1ccc(F)c(-c2ccc(COC(=O)C(C)(C)C)cc2C(=O)NC(C)C)c1
Reactant: NNC=O
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(F)c(-c2ccc(COC(=O)C(C)(C)C)cc2-c2nncn2C(C)C)c1
Temperature: 120 °C
Yield: 52.2 %

Procedure:
To a room temperature solution of 29.3 (244 mg, 608 μmol) in toluene was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (369 mg, 912 μmol, Acros Organics). The mixture was heated at 120° C. for 1.0 hour, cooled to room temperature, treated with water, and then extracted with EtOAc. After removal of organic solvent under reduced pressure, the residue was dissolved in dioxane (4 mL). To the solution was added formohydrazide (208 mg, 3461 μmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) and mercuric acetate (202 μL, 2076 μmol, Acros Organics). The resulting mixture was heated at 130° C. for 1.5 hours, cooled to room temperature, treated with water, and extracted with 30% IPA. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 0-60% EtOAc/hexanes for elution gave 29.4 as a colorless oil (135 mg, 52%).