Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH:4]([NH2:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C.[N:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>ClCCl>[CH3:1][O:2][C:3](=[O:11])[CH:4]([NH:10][C:27]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:28])[CH2:5][C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: COC(=O)C(N)CC(C)(C)C
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(CC(C)(C)C)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Amino-4,4-dimethyl-pentanoic acid methyl ester (5.35 g, 27.4 mmol) was dissolved in 100 mL of dichloromethane. Hunig's base (7.07 g, 54.7 mmol) and 4-morpholinecarbonyl chloride (4.08 g, 27.4 mmol) were added and the reaction was stirred at ambient temperature 16 h. The reaction mixture was concentrated in vacuo and taken up in 150 mL EtOAc. A white precipitate formed and was filtered and washed with EtOAc. EtOAc solutions were combined and washed with 3×50 mL 1 N HCl (aq), 3×50 mL saturated NaHCO3 (aq), and 1×50 mL brine. The organic layer was dried over Na2SO4, decanted, and concentrated to a white solid (6.33 g). MS, m/z 273=M+1
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3([OH:24])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:25]N1C(C)(C)C(=O)N(Br)C1=O.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([Br:25])[CH:9]=[C:10]([C:11]3([OH:24])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc3c(N)ncnn23)C1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2cc(Br)c3c(N)ncnn23)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 144.2 %

Procedure:
To a cooled (−20° C.) solution tert-butyl 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-hydroxypiperidine-1-carboxylate (1.00 g, 3.00 mmol) in THF (16 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (429 mg, 1.50 mmol) in 3 portions over 10 min. The mixture was allowed warm to 0° C. and stirred for 2 h. The mixture was then stirred at rt for 64 h. Saturated, aqueous Na2SO3 (50 mL) was added and the mixture was warmed to rt. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated. The crude mixture was purified via ISCO® chromatography using a gradient of 50 to 75% ethyl acetate in hexanes to afford 892 mg (72%) of the desired product. ES-MS m/z 412.26 [M+H]+, HPLC RT (min) 2.62.
Reaction SMILES: [C:1]([NH:9]/[C:10](/SC)=[N:11]/[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([NH:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH2:22]([N:29]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CS/C(=N\C(=O)c1ccccc1)NC(=O)c1ccccc1
Reactant: NNCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc(-c2ccccc2)n(Cc2ccccc2)n1)c1ccccc1
Reaction time: 48 h

Procedure:
To a stirred solution of the crude (Z)-methyl N,N′-dibenzoylcarbamimidothioate (0.895 g, 3 mmol) in DMF (8 ml) was added benzylhydrazine (0.367 g, 3.00 mmol) at 40° C. The reaction was stirred for 2 days. The stirred reaction was diluted with water. The resulting precipitates were collected to yield the crude N-(1-benzyl-5-phenyl-1H-1,2,4-triazol-3-yl)benzamide. LCMS method A, (M+H)+355.1, ret T=1.32 min.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](=[O:17])[CH2:15]Br)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:20]([OH:23])(=[O:22])[CH3:21]>>[C:20]([O:23][CH2:15][C:14]([C:13]1[CH:18]=[CH:19][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=1)=[O:17])(=[O:22])[CH3:21]
Reactant: CC(=O)O
Reactant: CCCCCCCCOc1ccc(C(=O)CBr)cc1
Product: CCCCCCCCOc1ccc(C(=O)COC(C)=O)cc1

Procedure:
Following the procedure of Example 1, 5 grams of 4-n-octyloxyphenacyl bromide are reacted with 5 grams of acetic acid to obtain 4-n-octyloxyphenacyl acetate, m.p. 44°-45° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:23][CH3:24])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)=[O:5])[CH3:2].NC1C=C2C(=CC=1)[N:31]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[N:30]=[CH:29]2>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:23][CH3:24])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:15][C:16]1[CH:21]=[C:20]2[C:19](=[CH:18][CH:17]=1)[N:31]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[N:30]=[CH:29]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncnc(Nc3ccc(Br)cc3)c2c1CC
Reactant: Nc1ccc2c(cnn2Cc2ccccc2)c1
Product: CCOC(=O)c1cn2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1CC

Procedure:
The title compound was prepared from compound B of Example 139 using the process described for the preparation of example 139 except 5-amino-1-benzyl-1H-indazole was used to add to the chloroimidate. MS: (M+H)+=441.24
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[CH:6]=[C:7]([NH:11]C(=O)C3C=CC=CC=3)[C:8](=[O:10])[O:9][C:4]=2[CH:3]=1.Cl.C(=O)([O-])O.[Na+]>C(O)CC>[NH2:11][C:7]1[C:8](=[O:10])[O:9][C:4]2[CH:3]=[C:2]([OH:1])[CH:21]=[CH:20][C:5]=2[CH:6]=1
Reactant: O=C(Nc1cc2ccc(O)cc2oc1=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Product: Nc1cc2ccc(O)cc2oc1=O
Yield: 87.4 %

Procedure:
A mixture of N-(7-hydroxy-2-oxo-2H-1-benzopyran-3-yl)benzamide (230 mg, 0.82 mmol), 1-propanol (6 ml) and concentrated hydrochloric acid (2 ml) was refluxed for 3 hours. Then, hydrochloric acid (2 ml) was added and the mixture was refluxed for further 7 hours. After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, and after the layer was dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (eluent: dichloromethane/ethyl acetate=2/1) to give the title compound as a yellow solid (127 mg, 87.7%).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:14][O:15][C:16]=2[CH2:17][OH:18])=[N:6][CH:5]=1.[OH-].[Na+]>O1CCOCC1>[CH2:19]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:23])=[O:2])=[CH:5][N:6]=2)=[C:16]([CH2:17][OH:18])[O:15][N:14]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCc1noc(CO)c1COc1ccc(C(=O)OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCc1noc(CO)c1COc1ccc(C(=O)O)cn1
Temperature: 90 °C
Reaction time: 17 h
Yield: 102.4 %

Procedure:
To a solution of 6-[3-butyl-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (490 mg, 1.53 mmol) in dioxane (20 mL) was added aqueous sodium hydroxide (2 M, 10 mL) and the reaction mixture was stirred at 90° C. for 17 h. The mixture was concentrated and the residue was acidified with aqueous hydrochloric acid (2 M, 15 mL) and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to a yellow oil to afford the title compound (480 mg, 100%). MS: m/e=305.4 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([NH:15][CH3:16])[CH:13]=[CH2:14]>C(#N)C>[CH2:12]([N:15]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[CH3:16])[CH:13]=[CH2:14]
Reactant: C=CCNC
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Solvent: CC#N
Product: C=CCN(C)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 93.4 %

Procedure:
4-chloro-1-fluoro-2-nitro-benzene (2.53 g, 14.41 mmol) was dissolved in anhydrous acetonitrile (80 mL). Allyl methyl amine (1.64 mL, 17.29 mmol) was added dropwise while the solution was stirred. The mixture was heated at 80° C. overnight, concentrated with silica gel powder (18 g), and purified by flash chromatography eluting with 10% ethyl acetate in hexanes (1 L) to give the title compound (3.05 g, 93%). MS (DCI) m/z 227.09 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 2.80 (s, 3 H) 3.76 (d, J=5.43 Hz, 2 H) 5.16–5.29 (m, 2 H) 5.85 (m, 1 H) 7.00 (d, J=9.16 Hz, 1 H) 7.33 (dd, J=8.99, 2.54 Hz, 1 H) 7.74 (d, J=2.71 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=4[O:31][CH3:32])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: Clc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(Cl)ccc23)CC1
Yield: 36.1 %

Procedure:
A stirred mixture of 6-chloro-3-(4-piperidinyl)-l,2-benzisoxazole (4.7 g, 20 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.8 g, 20 mmol), K2CO3 (2.8 g), several crystals of KI and acetonitrile (120 ml) was refluxed for 16 hours. The reaction was filtered and the filtrate was concentrated to yield a solid-oil mixture. The residue was chromatographed on a Waters Prep 500 utilizing silica columns and eluting with methylene chloride/methanol (5%). Concentration of the desired fractions yielded 3.2 g of a beige solid, which upon recrystallization from ethanol afforded 2.7 g (31%) of 1-[4-[3-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl-3-methoxyphenyl]-ethanone as a beige solid, m.p.=116°-118° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:23][C@H:24]([N:26](C(OC(C)(C)C)=O)[CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH2:37][CH3:38])[CH3:25])=[CH:17][C:18]=2[C:20](=[O:22])[NH2:21])[CH:13]=[CH:12]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.C(=O)(O)[O-].[Na+]>C(O)(C)C.O>[C:1]([O:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:23][C@H:24]([NH:26][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH2:37][CH3:38])[CH3:25])=[CH:17][C:18]=2[C:20](=[O:22])[NH2:21])[CH:13]=[CH:12]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)[C@H](C)Cc1cc(C(N)=O)c2c(ccn2CCCOC(=O)C(C)(C)C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCOc1ccccc1OCCN[C@H](C)Cc1cc(C(N)=O)c2c(ccn2CCCOC(=O)C(C)(C)C)c1
Yield: 79.5 %

Procedure:
(R)-3-[5-[2-[N-(tert-Butoxycarbonyl)-N-[2-(2-ethoxy-phenoxy)ethyl]amino]propyl]-7-carbamoyl-1H-indol-1-yl]propyl pivalate (7.81 g) was dissolved in isopropanol (78 ml), and concentrated hydrochloric acid (39 ml) was added dropwise over a period of 10 minutes to the solution under ice-cooling with stirring. After the mixture was stirred for 4 hours at room temperature, the reaction mixture was adjusted to pH 8 by adding sodium bicarbonate powder under ice-cooling with stirring. The mixture was diluted with water (200 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution, water and brine subsequently, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate) and recrystallized from diethyl ether/hexane(2/1) to give (R)-3-[7-carbamoyl-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1H-indol-1-yl]propyl pivalate (5.21 g) as colorless crystals.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.C[Mg]Br.O1CC[CH2:25][CH2:24]1>CCOCC>[CH2:24]([C:2]1([OH:1])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:4][CH2:3]1)[CH3:25]
Reactant: C1CCOC1
Reactant: O=C1CCC(CNC(=O)OCc2ccccc2)CC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CCC1(O)CCC(CNC(=O)OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a vigorous stirring solution of benzyl (4-oxocyclohexyl)methylcarbamate (1 g) in tetrahydrofuran (20 mL) at −78° C. was slowly added 1 Methylmagnesium bromide (11.48 ml, 11.48 mmol) in ether. After completion of the addition, the mixture was stirred at −78° C. for 2 hours and was warmed to 0° C., and stirred in an ice bath for 30 minutes. The reaction was quenched with a cold NH4Cl aqueous solution. The precipitates were filtered off and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in dichloromethane and loaded onto Analogix purification system, and was eluted with 0-50% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: O.[OH-].[Li+].[C:4]([S:7][C:8]1[N:9]=[C:10]([CH3:20])[N:11](C(OC(C)(C)C)=O)[CH:12]=1)(=O)[CH3:5].BrCC1[C:33]2[CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29][CH2:28][C:27]=2[CH:26]=[CH:25][C:24]=1[Cl:41]>CO>[C:37]([O:36][C:34]([N:30]1[CH2:31][CH2:32][C:33]2[C:5]([CH2:4][S:7][C:8]3[NH:9][C:10]([CH3:20])=[N:11][CH:12]=3)=[C:24]([Cl:41])[CH:25]=[CH:26][C:27]=2[CH2:28][CH2:29]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CBr)c2CC1
Reactant: CC(=O)Sc1cn(C(=O)OC(C)(C)C)c(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ncc(SCc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)[nH]1
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
Add lithium hydroxide hydrate (42 mg, 1 mmol) to a stirred solution of 4-acetylsulfanyl-1-tert-butoxycarbonyl-2-methyl-imidazole (290 mg, 1.13 mmol) and 6-bromomethyl-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (368 mg, 0.98 mmol) in methanol (12 mL) and stir the resulting mixture for 30 min. Partition the mixture between EtOAc and water and extract the aqueous phase three times with EtOAc. Dry the combined organic extracts over MgSO4, filter, and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (40 g) eluting with hexane/EtOAc [100:0 (5 min), 19:1 (5 min), 85:15 (5 min), 4:1; flow rate: 50 mL/min] to give 3-tert-butoxycarbonyl-7-chloro-6-(2-methyl-3H-imidazol-4-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (310 mg, 54%). MS (ES+) m/z: 508 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:12][C:13]([OH:15])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][N:7]=[CH:8]3)[S:20][CH:21]=1
Reactant: O=C(O)Cc1c(F)ccc2cnccc12
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cc1c(F)ccc2cnccc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-fluoroisoquinolin-5-yl)acetamide was prepared from 2-(6-fluoroisoquinolin-5-yl)acetic acid and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according to protocol A. Retention time (min)=1.901, method [7], MS(ESI) 432.0 (M+H); 1H NMR (300 MHz, DMSO-d6) 11.96 (b s, 1H), 9.58 (s, 1H), 8.64 (d, J=6.05 Hz, 1H), 8.46-8.41 (m, 1H), 8.24 (d, J=6.05 Hz, 1H), 7.84 (t, J=9.34 Hz, 1H), 7.27 (s, 1H), 4.46 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:16]C)=[C:4]([C@@H:9]2[C@H:14]3[C@@H:10]2[CH2:11]O[C:13]3=[O:15])[C:5]([F:8])=[CH:6][CH:7]=1.[BrH:18].CC(O)=O>O>[Br:18][CH2:11][C@H:10]1[C@@H:9]2[C@H:14]1[C:13](=[O:15])[O:16][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[C:5]([F:8])[C:4]=12
Reactant: Br
Reactant: COc1c(F)ccc(F)c1[C@H]1[C@H]2COC(=O)[C@H]21
Solvent: O
Solvent: CC(=O)O
Product: O=C1Oc2c(F)ccc(F)c2[C@@H]2[C@H](CBr)[C@H]12
Temperature: 90 °C
Reaction time: 4 h
Yield: 100.6 %

Procedure:
(1S,5R,6S)-6-(3,6-difluoro-2-methoxyphenyl)-3-oxabicyclo[3.1.0]hexan-2-one (130 mg, 0.55 mmol) was mixed with 1.2 ml of 30% HBr/AcOH (6 mmol) and heated in a sealed vessel at stirring for about 4 h at 90° C. The reaction mixture was then cooled down, mixed with water and extracted into diethyl ether (3×20 ml). Ether extract was washed with sat. sodium bicarbonate solution and brine. Dried over magnesium sulfate. Concentration gave 160 mg of white solid material. 98% yield.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][C:15]=3[N:14]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29]C)=[C:25]([F:31])[CH:24]=3)[N:13]=2)=[CH:8][CH:7]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][C:15]=3[N:14]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([F:31])[CH:24]=3)[N:13]=2)=[CH:8][CH:7]=1
Reactant: COc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
BBr3 (0.13 mL) was added slowly to a 0° C. solution of 0.022 g of 3-(4-chloro-phenyl)-1-(3-fluoro-4-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 96) in CH2Cl2 (20 mL). After 1 h, the mixture was warmed to RT and stirred for 18 h. The reaction was then cooled back to 0° C. and quenched by the addition of 5 mL of satd. aq. NaHCO3. The aqueous layer was extracted with methanolic CH2Cl2 (2×). The combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by preparative TLC (9:1 CH2Cl2/2 M NH3 in MeOH) to afford the title compound (0.016 g) as a tan solid. MS (ESI): exact mass calculated for C20H19ClFN3O, 371.12; found, m/z 372.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.50-7.42 (m, 4H), 6.86-6.79 (m, 3H), 5.26 (s, 2H), 3.31-3.26 (m, 2H), 2.96-2.95 (m, 4H), 2.90-2.87 (m, 2H), 2.81-2.79 (m, 2H). 13C NMR (100 MHz, CD3OD): 154.2, 151.8, 149.6, 146.1, 146.0, 143.8, 134.8, 133.4, 131.1, 130.3, 130.2, 129.7, 124.0, 119.1, 115.6, 115.4, 53.1, 50.4, 29.0, 27.5.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH:9](OC(=O)C)=[O:10]>C(O)=O>[CH:9]([NH:1][CH:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[O:10]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(=O)OC=O
Solvent: O=CO
Product: CC(C)C(NC=O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To valine (15 g, 0.129 mol) in 88% formic acid (52 ml) is added acetic formic anhydride (33 g, 0.386 mol) over 0.75 hr at 5°. The reaction mixture is warmed to RT and stirred overnight. The reaction is worked up by distilling off (bath temp. 45°-50°) the solvent, excess anhydride and acetic acid, to give, as a white solid, 2-(N-formylamino)-3-methylbutanoic acid, recrystallized from hot ethanol, m.p. 143°-145°.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]([CH2:26][C:27]2[N:28]=[C:29]([NH2:32])[S:30][CH:31]=2)[CH3:25])[N:20]=[C:19]([Cl:33])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.[ClH:41]>CO.O1CCOCC1>[ClH:33].[ClH:41].[ClH:33].[NH2:32][C:29]1[S:30][CH:31]=[C:27]([CH2:26][N:24]([CH3:25])[C:21]2[NH:20][C:19]([Cl:33])=[N:18][C:17](=[N:9][NH2:8])[C:22]=2[F:23])[N:28]=1
Reactant: CN(Cc1csc(N)n1)c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN(Cc1csc(N)n1)c1[nH]c(Cl)nc(=NN)c1F
Yield: 83 %

Procedure:
Tris(1,1-dimethylethyl)2-{6-[[(2-amino-1,3-thiazol-4-yl)methyl](methyl)amino]-2-chloro-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (220 mg, 0.36 mmol) was dissolved in 10 mL of methanol and stirred. To this solution, 5 mL of 4M HCl in dioxane was slowly added. The mixture was stirred for 3 days and was evaporated to provide 6-[[(2-amino-1,3-thiazol-4-yl)methyl](methyl)amino]-2-chloro-5-fluoro-4(1H)-pyrimidinone hydrazone trihydrochloride (150 mg, 83%). LCMS: (M+H)+: 303.9.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C1COCC1.C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: COC(=O)c1ccc(O)c(I)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O)c(C#C[Si](C)(C)C)c1
Temperature: 50 °C
Yield: 50.3 %

Procedure:
Methyl 4-hydroxy-3-iodobenzoate (5.56 g, 20 mmol) is combined with trimethylsilylacetylene (3.96 mL, 28 mmol), bis(triphenylphosphine)palladium dichloride (414 mg, 0.6 mmol) and cuprous iodide (57 mg, 0.3 mmol) in THF (20 mL)/CHCl3 (40 mL) in a dry flask, under nitrogen. TEA (8.7 mL, 62.3 mmol) is added and the mixture heated to 50° C. for 4 h. The mixture is diluted with CHCl3 (60 mL), washed with 5% HCl (2×40 mL), dried (MgSO4) and concentrated to a brown solid. The crude material is adsorbed onto silica gel and chromatographed over 200 g silica gel, eluting with 15% EtOAc/hexane (2 L) followed by 20% EtOAc/hexane (1 L). Fractions are combined and concentrated to afford 2.50 g (50%) of methyl 4-hydroxy-3-[(trimethylsilyl)ethynyl]benzoate as a yellow solid. HRMS (FAB) calcd for C13H16O3SI+H: 249.0947, found 249.0955 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:11])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4].Cl>C(OC(C)C)(=O)C.C(O)(C)C>[CH3:11][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:1])[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4]
Reactant: CC(C)(c1ccccn1)C(N)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CC(=O)OC(C)C
Product: CC(C)(c1ccccn1)[C@H](N)c1ccccc1

Procedure:
(R)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine is prepared starting from racemic 2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine using chiral SFC chromatography. This oil is dissolved in isopropyl acetate and a solution of 5-6 N HCl in isopropyl alcohol is added. The mixture is concentrated, and triturated in ether to yield the title compound as a white solid. M.p.=188° C. 1HNMR (300 MHz, CD3OD): δ 1.59 (s, 3H), 1.76 (s, 3H), 5.09 (s, 1H), 7.25-7.28 (m, 2H), 7.38-7.40 (m, 3H), 8.00 (t, J=6.6 Hz, 1H), 8.11 (d, J=6.9 Hz, 1H), 8.56 (t, J=7.8 Hz, 1H), 8.77 (d, J=5.7 Hz, 1H). MS: m/z 227.
Reaction SMILES: C(OC(=O)[N:7]=[C:8]([NH:25]C(OC(C)(C)C)=O)[N:9]([CH3:24])[CH2:10][C:11](=[O:23])[N:12]1[CH2:17][C@H:16]([OH:18])[C@@H:15]([OH:19])[C@@H:14]([OH:20])[CH:13]1[CH2:21][OH:22])(C)(C)C>FC(F)(F)C(O)=O.O>[CH3:24][N:9]([CH2:10][C:11](=[O:23])[N:12]1[CH2:17][C@H:16]([OH:18])[C@@H:15]([OH:19])[C@@H:14]([OH:20])[CH:13]1[CH2:21][OH:22])[C:8]([NH2:25])=[NH:7]
Reactant: CN(CC(=O)N1C[C@H](O)[C@@H](O)[C@@H](O)C1CO)C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)N1C[C@H](O)[C@@H](O)[C@@H](O)C1CO)C(=N)N

Procedure:
In a dry, round bottomed flask, equipped with a magnetic stirrer, 23.81 g (0.050 mol) of tert-butyl(tert-butoxycarbonylamino)(methyl(2-oxo-2-((3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)ethyl)amino)methylenecarbamate is dissolved in 275 mL of a trifluoroacetic acid:H2O (1:1) mixture. The resultant mixture is stirred for 2 hours at room temperature, after which it is concentrated under reduced pressure and then purified by flash chromatography (ethyl acetate/hexanes; 2/3) to yield the creatine deoxygalactonojirimycin amide, 1-methyl-1-(2-oxo-2-((3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)ethyl)guanidine.