Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]([C@H:21]([C@H:29]1[CH2:33]OS(=O)(=O)[O:30]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[N+:19]=[N-:20].S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1.CO>[N:18]([C@@H:21]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:29]([OH:30])[CH2:33][N:9]1[C@H:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=N[C@@H](Cc1ccccc1)[C@H]1COS(=O)(=O)O1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)N=[N+]=[N-]
Temperature: 25 °C
Yield: 13.3 %

Procedure:
A solution of 237 mg (1 mmol) of N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 300 mg (1.1 mmol) of 4(S)-[1(S)-azido-2-phenylethyl]-1,3,2-dioxathiolane 2,2-dioxide in 10 ml of tetrahydrofuran was stirred at room temperature under an argon atmosphere for 2 days, during which time some white solid deposits formed. The mixture was evaporated to give a white powder which was taken up in a 10% solution of sulphuric acid in 70% aqueous methanol and heated under reflux for 30 minutes. After cooling to room temperature the solution was adjusted to pH 10 with 10% aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The ethyl acetate extracts were combined, washed with sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. Purification of the crude product by flash chromatography on silica gel using n-hexane/ethyl acetate (4:1) for the elution gave 57 mg of 2 -[3(S)-azido-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide; MS: m/e 428 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[N:16]=2)[NH:11][CH:10]=1.CCN=C=NCCCN(C)C.Cl.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:72][N:73]([CH3:82])[CH2:74][CH2:75][N:76]1[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]1>CN(C=O)C>[CH3:72][N:73]([CH3:82])[CH2:74][CH2:75][N:76]1[CH2:81][CH2:80][N:79]([C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:15]3[N:16]=[C:17]4[C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])=[CH:10][NH:11][C:12]4=[N:13][CH:14]=3)[CH:19]=2)=[O:22])[CH2:78][CH2:77]1
Reactant: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)O)c3)nc12
Reactant: CN(C)CCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)N4CCN(CCN(C)C)CC4)c3)nc12
Temperature: 70 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
To a mixture of 3-[7-(2-Methoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-benzoic acid (35 mg, 0.1 mmol), EDCl (77 mg, 0.40 mmol), HBTU (3.8 mg, 0.01 mmol) and diisopropylethylamine (175 μl, 1.0 mmol) in DMF (1 mL) was added 2-(dimethylamino)ethylpiperzine (55 μl, 0.3 mmol). The mixture was stirred at 70° C. for 5 hours before the solvents were removed. The resulting yellow oil was washed with water, dissolved in DMSO and purified on reverse phase HPLC to afford the title compound (8.6 mg, 12% over 2 steps) as yellow solid. MS: m/z 485.2 [MH+].
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].IC>CS(C)=O>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH3:24])[CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)[nH]c2)c1=O
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: Cn1cc(-c2c(-c3cccc(F)c3)nc(N)n(C)c2=O)ccc1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 20.4 %

Procedure:
To a solution of 2-amino-6-(3-fluorophenyl)-3-methyl-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone (20 mg, 0.06 mmol) in dimethyl sulfoxide (1 mL) were added potassium carbonate (20 mg, 0.12 mmol) and iodomethane (20 μL, 0.30 mmol), followed by stirring at 50° C. for 16 hours. After filtering off the insoluble matters, the filtrate was purified by HPLC, to give the title compound (4 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1.C([O-])(=O)C.[Na+].[OH-].[Na+].C(=O)(O)[O-].[Na+]>O.CC(O)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(N[C@H]2CC[C@H](O)CC2)nc(N)n1
Temperature: 99 °C
Reaction time: 48 h

Procedure:
A suspension mixture of 2-amino-4-chloro-6-methylpyrimidine (144 g, 1.0 mol), trans-4-aminocyclohexanol (140 g, 1.2 mol), AcOH (5 mL) in water (0.6 L) was heated at 99° C. in a 3.0 L flask. After 6 h at same temperature, Sodium acetate (82.0 g, 1 mol) was added to the reaction mixture. After 48 h, at the same temperature aq NaOH (50 mL, 10 N) was added. The reaction mixture was heated to 99° C. for 2 additional days. The reaction can be stopped if 2-amino-4-chloro-6-methylpyrimidine is less than 2% by HPLC analysis. If the reaction is slow another portion of aq. NaOH can be added to the reaction mixture as long as the pH is ˜7 to 8. The reaction mixture was then neutralized with Sodium bicarbonate and cooled to 0° C. Filtration gave trans-4-(2-amino-6-methylpyrimidin-4-ylamino)cyclohexanol (˜85%). Wet material is used for next step.
Reaction SMILES: [OH:1][C:2]1[CH:39]=[CH:38][C:5]2[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:27][CH2:28][CH2:29][CH2:30][C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])[C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C[OH:41].O>O1CCOCC1>[OH:1][C:2]1[CH:39]=[CH:38][C:5]2[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:27]([CH2:28][CH2:29][CH2:30][C:31]([F:37])([F:36])[C:32]([F:33])([F:34])[F:35])=[O:41])[C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Reactant: CO
Solvent: C1COCCO1
Solvent: O
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylthio)nonyl]-2,3-dihydro-4H-benzopyran (47 mg, 0.08 mmol) was dissolved in 1,4-dioxane (1 ml), methanol (1 ml) and water (0.25 ml). NaIO4 (20 mg, 0.093 mmol) was added dropwise thereto, and the reaction mixture was stirred for 12 hours at room temperature and then filtered. The filtrate was concentrated and the residue was subjected to column chromatography (n-hexane:ethyl acetate=3:1→1:1) to obtain 35 mg (yield: 73%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:3]1([C:6]2([C:14]([NH2:16])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[CH2:12]O)[CH2:5][CH2:4]1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>O1CCCC1>[C:1]([C:3]1([C:6]2([C:14]([NH2:16])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[CH2:12][Br:36])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(C2(C(N)=O)CCCCC2CO)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CC1(C2(C(N)=O)CCCCC2CBr)CC1
Reaction time: 8 h

Procedure:
(1-Cyanocyclopropyl)-2-hydroxymethyl-cyclohexane-carboxamide was dissolved, along with triphenylphosphine (2.77 g, 10.58 mmol) in tetrahydrofuran (100 mL) (Note—heating was required to effect dissolution). The reaction mixture was cooled carefully in an ice/water bath, ensuring the solution remained homogeneous. N-bromosuccinimide (1.88 g, 10.58 mmol) was added in small portions. Once a clear solution had formed, the cooling bath was removed, and the reaction mixture was permitted to stir overnight. The solvent was evaporated and the residue was purified on a short plug of silica gel (30-60% ethyl acetate/hexane) to give (1-cyanocyclopropyl)-2-bromomethylcyclohexanecarboxamide. MS [ESI, (M+H)+] m/z=285, 287.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25](Br)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:9])([F:11])[F:10])[C:2]2=[O:1])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: Oc1ncccc1C(F)(F)F
Product: Cc1nc(-n2cccc(C(F)(F)F)c2=O)sc1C(=O)NCc1ccccc1
Yield: 37 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 2-hydroxy-3-(trifluoromethyl)pyridine in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 37% yield: mp 203-204° C.; 1H NMR (300 MHz, CDCl3) δ 9.01 (d, J=7.2 Hz, 1H), 7.87 (d, J=7.2 Hz, 1H), 7.36-7.23 (m, 5H), 6.53 (t, J=7.2 Hz, 1H), 6.10 (s, 1H), 4.57 (d, J=5.4 Hz, 2H), 2.69 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7, 156.6, 152.2, 152.1, 139.3, 139.2, 137.4, 135.1, 128.9, 128.8, 127.8, 123.8, 121.9, 106.0, 44.2, 17.2; MS (ES+) m/z 394.2 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3=[N:26][CH:27]=[N:28][C:29]([O:30][C:31]4[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=4)=[C:24]3[CH:23]=[N:22]2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])C.ClC(O[C:42]1[CH:47]=CC=C[CH:43]=1)=O.C(N(CC)CC)C>ClCCl.O>[C:8]1([O:12][C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4=[N:26][CH:27]=[N:28][C:29]([O:30][C:31]5[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=5)=[C:24]4[CH:23]=[N:22]3)[CH2:17][CH2:16]2)=[O:14])[CH:11]=[CH:47][CH:42]=[CH:43][CH:10]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.5 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of 4-[4-(2-methyl-pyridin-3-yloxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 92; 50 mg, 0.12 mmol) in dichloromethane (2 mL). The solution was stirred at room temperature for 30 min and then the solvents were evaporated, first using house vacuum and then high vacuum. Dichloromethane (4 mL) was added to the residue, and then phenyl chloroformate (23 μL, 0.18 mmol) was added, followed by triethylamine (110 μL, 0.8 mmol). The mixture was stirred overnight at room temperature and then water was added. The layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water to give 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid phenyl ester (8 mg, 15%) as an oil that changed to a waxy solid on standing. 1H NMR (300 MHz, CDCl3) δ 2.08-2.17 (m, 2H), 2.34-2.52 (m, 5H), 3.06-3.34 (m, 2H), 4.42-4.58 (m, 2H), 5.02-5.10 (m, 1H), 7.14 (d, 2H, J=7.9 Hz), 7.22-7.25 (m, 1H), 7.28-7.31 (m, 1H), 7.38 (t, 2H, J=7.7 Hz), 7.52 (d, 1H, J=8.1 Hz), 8.10 (s, 1H), 8.48-8.53 (m, 2H). Mass spectrum MH+=431. HRMS Calcd. For C23H23N6O3 (MH+): 431.1826. Found: 431.1825.
Reaction SMILES: C([O-])(=O)C.[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.[Br:14]Br.[OH-].[Na+]>C(O)(=O)C.O>[NH2:6][C:7]1[C:12]([Br:14])=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1
Reactant: BrBr
Reactant: Nc1ccc(Cl)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(Cl)cc1Br
Temperature: 43 °C
Yield: 70.7 %

Procedure:
An acetic acid (400 mL) suspension of sodium acetate (57.1 g, 0.696 mol) and 2-amino-5-chloropyridine (89.5 g, 0.696 mol) was treated with a solution of bromine (35.9 mL, 0.696 mol) in acetic acid (15 mL) over a period of 1.25 hours with gentle warming to 43° C. The resulting orange slurry was then cooled to 15° C. and filtered to provide a solid which was subsequently dissolved in water, basified (pH 8.5) with 1N NaOH, and extracted with ethyl acetate (5×150 mL). The combined organic layers were washed with 10% sodium bisulfite (2×150 mL), dried over magnesium sulfate, and condensed to give 102.1 g (70.7%) of a yellow solid, m.p. 83-85° C.: IR(CHCl3) 3683, 3504, 3401, 2987, 2482, 2392, 1608, 1571, 1544, 1455, 1389, 1316, 1207, 1127, 1057, 1026, 895, 881, 650, 607, 249, 236 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 5.20 (br s, 2H), 7.70 (d, 1H), J=2.2 Hz), 8.0 (d, 1H, J=2.2 Hz); 13C NMR (CDCl3) δ 104.08, 120.33, 139.62, 145.24, 154.10; exact mass calculated for C5H4N2BrCl=205.9246. High resolution mass spec. 205.9246.
Reaction SMILES: CO.C(O)C.Cl.COC1C=CC=CC=1C[NH:12][C@H:13]1[CH2:18][CH2:17][CH2:16][NH:15][C@H:14]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.[C].[Pd]>[NH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][NH:15][C@H:14]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccccc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CO
Product: N[C@H]1CCCN[C@H]1c1ccccc1
Reaction time: 8 h

Procedure:
In a bottle were placed 9 g of 10% palladium-carbon, 180 ml of methanol, 275 ml of ethanol, 6.5 ml of concentrated hydrochloric acid and 9 g of the hydrochloride salt of (2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine. The mixture was shaken under hydrogen (40 p.s.i.) overnight, 9 g of additional catalyst were added to the system and the mixture was shaken under hydrogen for 1 day. The mixture was diluted with water (250 mL), filtered through diatomaceous earth (Celite (trademark)) and the Celite was rinsed well with water. The filtrate was concentrated to a volume of ca. 600-700 mL, made basic with concentrated aqueous sodium hydroxide and extracted with chloroform, and the chloroform extracts were dried (sodium sulfate) and concentrated to obtain 4.4 g of the title compound as a colorless oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:31]([N:38]([CH2:59][CH2:60][CH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([N+:69]([O-:71])=[O:70])=[CH:65][CH:64]=1)[CH2:39][CH2:40][C:41]1[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([NH2:50])[CH:48]=2)[NH:43][C:42]=1[C:51]1[CH:56]=[C:55]([CH3:57])[CH:54]=[C:53]([CH3:58])[CH:52]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:38]([CH2:59][CH2:60][CH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([N+:69]([O-:71])=[O:70])=[CH:65][CH:64]=1)[CH2:39][CH2:40][C:41]1[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([NH:50][C:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[O:8])[CH:48]=2)[NH:43][C:42]=1[C:51]1[CH:52]=[C:53]([CH3:58])[CH:54]=[C:55]([CH3:57])[CH:56]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2ccc([N+](=O)[O-])cc2)Cc2ccccc2)c1
Reactant: CC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CC(=O)NCC(=O)Nc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccc([N+](=O)[O-])cc3)Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 92.4 %

Procedure:
To a solution of acetylaminoacetic acid (32.2 mg in 6 mL dry methylene chloride) was added 48 mg 1-hydroxybenzotriazole followed by 50 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the mixture stirred at room temperature. After 50 minutes, a solution of 3-(2-{benzyl-[4-(4-nitrophenyl)butyl]amino}ethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-ylamine (120 mg in 2 mL methylene chloride) was added and stirring continued. After 4 hours (total), the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give the title compound (131 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]2[CH:13]=[N:14][NH:15][C:5]=2[CH:4]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>O1CCOCC1>[Cl:18][CH2:19][C:20]([NH:12][C:10]1[S:11][C:7]2[C:6]3[CH:13]=[N:14][N:15]([C:20](=[O:21])[CH2:19][Cl:18])[C:5]=3[CH:4]=[C:3]([C:2]([F:1])([F:16])[F:17])[C:8]=2[N:9]=1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: Nc1nc2c(C(F)(F)F)cc3[nH]ncc3c2s1
Solvent: C1COCCO1
Product: O=C(CCl)Nc1nc2c(C(F)(F)F)cc3c(cnn3C(=O)CCl)c2s1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A mixture of 0.26 g (1.00 mmol) of 4-trifluoromethyl-6H-pyrazolo[4′,3′:3,4]benzo[1,2-d]thiazol-2-ylamine, 1.0 ml (12.6 mmol) of chloroacetyl chloride and 4 ml of 1,4-dioxane was heated under reflux for 3 hours. After the completion of the reaction was confirmed by HPLC, the reaction mixture was cooled to room temperature and poured into ice-water. The precipitated solid was collected by filtration and was washed with water to give 0.34 g (yield: 77%) of 2-chloro-N-[6-(2-chloro-acetyl)-4-trifluoromethyl-6H-pyrazolo[4′,3′:3,4]benzo[1,2-d]thiazol-2-yl]-acetamide.
Reaction SMILES: [CH3:1][C@@:2]([S:20]([CH3:23])(=[O:22])=[O:21])([CH2:6][CH2:7][N:8]1[C:12]([CH3:13])=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=[N:9]1)[C:3](O)=[O:4].C[C@@](S(C)(=O)=O)(CCN1C(C2C=CC=CC=2)=C(C)N=N1)C(O)=O.CN1CCOCC1.O1CCCCC1[O:60][NH2:61].C(O)(C(F)(F)F)=O>C1COCC1>[OH:60][NH:61][C:3](=[O:4])[C@:2]([CH3:1])([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:6][CH2:7][N:8]1[C:12]([CH3:13])=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=[N:9]1
Reactant: NOC1CCCCO1
Reactant: Cc1c(-c2ccccc2)nnn1CC[C@](C)(C(=O)O)S(C)(=O)=O
Agent: Cc1nnn(CC[C@](C)(C(=O)O)S(C)(=O)=O)c1-c1ccccc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Product: Cc1c(-c2ccccc2)nnn1CC[C@](C)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2R)-2-methyl-4-(5-methyl-4-phenyl-1H-1,2,3-triazol-1-yl)-2-(methylsulfonyl)butanoic acid and (2R)-2-methyl-4-(4-methyl-5-phenyl-1H-1,2,3-triazol-1-yl)-2-(methylsulfonyl)butanoic acid (115 mg, 0.341 mmol, 1 eq) in THF (5 mL) was added N-methyl morpholine (65.5 mg, 0.341 mmol, 1 eq), and CDMT (59.9 mg, 0.341 mmol, 1 eq). The reaction mixture was allowed to stir at RT for 1 h then O-tetrahydro-2H-pyran-2-yl-hydroxylamine (39.9 mg 0.341 mmol, 1 eq) was added and the reaction mixture was allowed to stir at RT for 2 days. Upon completion of the coupling reaction (as observed by LC-MS monitoring), 1 mL of TFA was added and the mixture was allowed to stir at RT for 3 h. The reaction mixture was concentrated and purified by HPLC to give (2R)—N-hydroxy-2-methyl-4-(5-methyl-4-phenyl-1H-1,2,3-triazol-1-yl)-2-(methylsulfonyl)butanamide (14 mg) as a 10:1 mixture with the corresponding regioisomer (2R)—N-hydroxy-2-methyl-4-(4-methyl-5-phenyl-1H-1,2,3-triazol-1-yl)-2-(methylsulfonyl)butanamide. 1H NMR (400 MHz, METHANOL-d4) δ 7.61-7.67 (m, 2H), 7.43-7.50 (m, 2H), 7.38 (d, J=7.42 Hz, 1H), 4.51-4.63 (m, 1H), 4.36-4.48 (m, 1H), 3.06 (s, 3H), 2.85-2.93 (m, 1H), 2.51 (s, 3H), 2.43 (ddd, J=13.42, 10.10, 5.37 Hz, 1H), 1.72 (s, 3H). LC-MS M+H+353.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](O)=[CH:7][N:6]=1)=[O:4].O=P(Cl)(Cl)[Cl:14]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Cl:14])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(O)cn1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cnc(Cl)cn1
Yield: 55.1 %

Procedure:
A mixture of 5-hydroxy-pyrazine-2-carboxylic acid methyl ester (Preparation 40, 50 g, 324 mmol) and POCl3 (500 mL, 5.36 mol) was heated under reflux for 1.5 hours and then poured onto ice. The resulting mixture was extracted with ether (4×500 mL). The organic layers were concentrated in vacuo, and the residue was recrystallised from toluene to give the title compound (30.8 g) in a 55% yield.
Reaction SMILES: [NH:1]1CCN=[C:2]1[NH:6][N:7]=[C:8]([CH3:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C@@H:20]([C:32]([OH:34])=[O:33])[NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:13][CH:12]=1.C(NN)(N)=[NH:37].Cl>C(Cl)Cl.CO.O.CC(O)=O>[NH2:37][N:1]=[CH:2][NH:6][N:7]=[C:8]([CH3:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C@@H:20]([C:32]([OH:34])=[O:33])[NH:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])=[CH:13][CH:12]=1
Reactant: N=C(N)NN
Reactant: CC(CCc1ccc(OCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1)=NNC1=NCCN1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(CCc1ccc(OCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1)=NNC=NN
Yield: 91.3 %

Procedure:
The operation is carried out as in Example 1 Stages A, B and C but using 440 mg of ketone (obtained in Stage A of Example 1) and 342 mg of aminoguanidine hydrochloride. 380 mg of expected product is obtained after chromatography (eluent CH2Cl2/MeOH/H2O/AcOH 90/10/1/1) in the form of an E/Z mixture 85/15.
Reaction SMILES: [CH2:1]([CH:5]1[S:10][CH2:9][CH2:8][N:7]([CH:11]([P:16](=[O:19])([OH:18])[OH:17])[P:12](=[O:15])([OH:14])[OH:13])[CH:6]1C)[CH:2]([CH3:4])[CH3:3].[Na][Na]>>[CH2:1]([CH:5]1[S:10][CH2:9][CH2:8][N:7]([CH:11]([P:16](=[O:17])([OH:19])[OH:18])[P:12](=[O:13])([OH:15])[OH:14])[CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1SCCN(C(P(=O)(O)O)P(=O)(O)O)C1C
Agent: [Na][Na]
Product: CC(C)CC1CN(C(P(=O)(O)O)P(=O)(O)O)CCS1

Procedure:
(2-Isobutyl-3-methyl-4-thiomorpholinylmethylene)-bisphosphonic acid, disodium salt: NMR (D2O, TMS=0.0 ppm as reference): δ=0.93 (m, 6H); 1.1-2 (m, 6H) and 2.9-4.3 (m, 7H) ppm.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[N:5][CH:4]=1)#[CH:2].[BH4-].[Na+].O>CO>[C:1]([C:3]1[N:7]([CH3:8])[C:6]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[N:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1cnc(C(=O)c2ccccc2)n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C#Cc1cnc(C(O)c2ccccc2)n1C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
A solution of 200 mg (0.951 mmol) of (5-ethynyl-1-methyl-1H-imidazol-2-yl)-phenyl-methanone in 1 mL of MeOH was added dropwise to a 0° C. solution of 54 mg (1.43 mmol) of NaBH4 in 5 mL of MeOH. After stirring for 2 h, 10 mL of water was added and the mixture was extracted with CH2Cl2 (3×50 mL). The combined extracts were washed with brine, dried with MgSO4, filtered, concentrated, and chromatographed (0-80% EtOAc in hexanes) to give (5-ethynyl-1-methyl-1H-imidazol-2-yl)-phenyl-methanol as a white solid (75 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:10]2[C:6]([S:7][CH:8]=[CH:9]2)=[CH:5][N:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[N:10]2[C:6]([S:7][CH:8]=[CH:9]2)=[CH:5][N:4]=1)=[O:1]
Reactant: OCc1ncc2sccn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ncc2sccn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a solution of 480 mg (3.12 mmol) of 5-hydroxymethylimidazo[5,1-b]thiazole in 10 ml of methylene chloride was added 5 g of manganese dioxide, and the mixture was stirred vigorously at room temperature for 2 hours. The reaction solution was filtered through Celite to remove the manganese dioxide. The filtrate was concentrated under reduced pressure to give 442 mg (yield 93%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-:8][CH2:9][CH3:10].[Na+]>C(O)C>[CH2:9]([O:8][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:10]
Reactant: CCOC(=O)CCl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.8 %

Procedure:
A solution of ethyl chloracetate (100 g, 99% pure, 0.81 mol) in ethanol is treated with ethanolic sodium ethoxide (282.9 g, 20.6% solution, 0.86 mole NaOC2H5) over a 1 hr period at 20° C.-30° C., heated at 40° C.-45° C. for 0.5 hr, cooled to room temperature, treated with diatomaceous earth, stirred for 0.25 hr and filtered. The filtercake is washed with ethanol. The combined filtrates are distilled to obtain the title product as a colorless liquid 75.78 g, 98.8% pure (71% yield), bp 87° C.-88° C./59 mmHg, identified by 13CNMR, 1HNMR and mass spectral analyses.