Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[C:18]([Cu])#[N:19].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:18]#[N:19])=[CH:8][C:6]=2[N:7]=1
Reactant: N#C[Cu]
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.9 %

Procedure:
A solution of 2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 from Example 12 (0.2 g, 0.5 mmol) and CuCN (50 mg, 0.6 mmol) in pyridine (1 mL) was heated at 115° C. for 2 h then cooled to room temperature and stirred 18 h. The reaction was poured into 1 M HCl and ice and the aqueous layer was extracted with CH2Cl2. The product was purified by silica gel chromatography (0-75% EtOAc in hexane) to provide 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbonitrile (35 mg).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[Cl:15])(=O)C>N>[Cl:15][C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([OH:4])[CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Agent: N
Product: Oc1ccc2ncnc(Cl)c2c1
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A mixture of 4-chloroquinazolin-6-yl acetate (10.0 g, 44.9 mmol) and ammonia (200 mL of 7N solution in methanol) were stirred together for 1 hour. The reaction mixture was concentrated to about 3 mL and triturated with diethyl ether to provide the product (6.50 g, 80%) as tan solid.
Reaction SMILES: C([Mg]Br)C.C1COCC1.I[C:11]1[N:12]=[CH:13][N:14]2[CH:18]=[CH:17][S:16][C:15]=12.[C:19](=[O:21])=[O:20].[OH-].[Na+]>C1COCC1.CCOCC>[S:16]1[CH:17]=[CH:18][N:14]2[CH:13]=[N:12][C:11]([C:19]([OH:21])=[O:20])=[C:15]12
Reactant: O=C=O
Reactant: Ic1ncn2ccsc12
Agent: CC[Mg]Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1ncn2ccsc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A 0.95 M ethylmagnesium bromide/THF solution (12.6 ml) was added dropwise to a solution (50 ml) of 2.501 g of 7-iodoimidazo[5,1-b]thiazole in THF ac −70° C. The mixture was stirred for 30 min. Carbon dioxide (which had been evolved from about 5 g of dry ice and passed through a calcium chloride tube) was introduced into the reaction solution at the same temperature over a period of 40 min. The reaction solution was allowed to stand at −20° C. overnight, and then added to an ice cold mixed solution composed of an aqueous sodium hydroxide (0.41 g) solution (100 ml) and ether (200 ml) with stirring. The mixture was stirred for one hr. The organic layer was separated and concentrated under the reduced pressure by a minor amount, and the remaining organic solvent was removed by distillation. The residue was adjusted to pH 3.5 by the addition of 2 N hydrochloric acid under ice cooling. The resultant precipitate was washed with a minor amount of cold water, and then dried under the reduced pressure to give 1.407 g of imidazo[5,1-b]thiazole-7-carboxylic acid.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:13]([OH:16])([OH:15])=[O:14])([P:9]([OH:12])([OH:11])=[O:10])[OH:8])[CH:2]=1.CN(C=O)C.[OH-].[Na+:23].O>CO>[CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:9]([O-:12])([O-:11])=[O:10])([P:13]([O-:15])([OH:16])=[O:14])[OH:8])[CH:2]=1.[Na+:23].[Na+:23].[Na+:23]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: O=P([O-])([O-])C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C
Yield: 84 %

Procedure:
A 250 ml flask was loaded with Zoledronic acid form XII (5.0 g), Sodium hydroxide (1.4 g), Methanol (50 ml) and water (2.5 ml) [=5% v/v water in Methanol]. The reaction mixture was heated to reflux temperature for 22 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with Methanol (2×50 ml) and dried in a vacuum oven at 50° C. for 24 hours to give 5.4 g (84%) of Zoledronate trisodium crystal form XI in a mixture with crystal form IX (LOD by TGA=10.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][CH:4]=1.ClC1C=C[N:14]=[C:13](C#N)C=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:13]#[N:14])[CH:4]=1
Reactant: COc1cc[n+]([O-])cc1
Reactant: N#Cc1cc(Cl)ccn1
Product: COc1ccnc(C#N)c1

Procedure:
The title compound was prepared from 4-methoxypiridine-N-oxide by using the procedure described for the preparation of 4-chloro-2-pyridinecarbonitrile.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]2[C:13]3[C:18]([O:19][CH2:20][C:3]=12)=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=3.[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23]>>[C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=[C:4]3[C:13]4[C:18]([O:19][CH2:20][C:3]=23)=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=4)=[CH:26][CH:25]=1)#[N:23]
Reactant: Oc1ccc2c(c1)OCc1c-2nc2ccc(O)cc2c1Br
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2c3c(nc4ccc(O)cc24)-c2ccc(O)cc2OC3)cc1
Yield: 96 %

Procedure:
This compound was prepared from 7-bromo-3,9-dihydroxy-6H-chromeno[4,3-b]quinoline (7) using 4-cyanophenylboronic acid according to method M. Ivory powder; Yield: 96%; mp 295° C. (dec.); 1H-NMR (400 MHz, DMSOd-6) δ 4.99 (s, 2H), 6.36 (d, J=2.3 Hz, 1H), 6.53 (d, J=2.7 Hz, 1H), 6.61 (dd, J=8.7, 2.3 Hz, 1H), 7.27 (dd, J=9.1, 2.6 Hz, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.91 (d, J=9.0 Hz, 2H), 8.09 (d, J=8.3 Hz, 1H), 8.16 (d, J=8.6 Hz, 1H), 9.86 (s, 1H), 9.99 (s, 1H); MS (ESI) m/z 365 ([M−H]−), 367 ([M+H]+); HRMS (ESI+) calcd for C23H14N2O3 367.1077 ([M+H]30 ). Found: 367.1074.
Reaction SMILES: C(O)CCCCCCCO.FC1C(CBr)=C(F)C(F)=C(F)C=1F.[F:24][C:25]1[C:30]([CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:41])=[C:29]([F:42])[C:28]([F:43])=[C:27]([F:44])[C:26]=1[F:45].FC1C(COCCCCCCCC(O)=O)=C(F)C(F)=C(F)C=1F.Cl.Cl.[CH2:71]([O:78][C:79](=[O:87])[CH2:80][C@@H:81]([NH2:86])[CH2:82][N:83]([CH3:85])[CH3:84])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1>>[CH2:71]([O:78][C:79](=[O:87])[CH2:80][C@@H:81]([NH:86][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][O:32][CH2:31][C:30]1[C:25]([F:24])=[C:26]([F:45])[C:27]([F:44])=[C:28]([F:43])[C:29]=1[F:42])[CH2:82][N:83]([CH3:84])[CH3:85])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1
Reactant: OCCCCCCCCOCc1c(F)c(F)c(F)c(F)c1F
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Agent: Fc1c(F)c(F)c(CBr)c(F)c1F
Agent: O=C(O)CCCCCCCOCc1c(F)c(F)c(F)c(F)c1F
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1c(F)c(F)c(F)c(F)c1F

Procedure:
The title compound, m/e=467.5 ([M−H]−), was produced in analogy with intermediate 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated in step 1 with pentafluorobenzyl bromide, leading to 8-(pentafluoro-benzyloxy)-octan-1-ol, which was oxidized in step 2 to 8-(pentafluoro-benzyloxy)-octanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-3-[8-(pentafluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Br:25]Br>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:25][CH:9]([C:10](=[O:15])[C:11]([CH3:14])([CH3:12])[CH3:13])[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:18]
Reactant: CC(C)(C)C(=O)CC(c1ccc(Cl)cc1)S(=O)(=O)c1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)C(Br)C(c1ccc(Cl)cc1)S(=O)(=O)c1ccccc1
Reaction time: 3 h
Yield: 95.4 %

Procedure:
1-(4-Chlorophenyl)-4,4-dimethyl-1-phenylsulfonylpentan-3-one (5.0 g) was dissolved in a mixture of 100 ml of chloroform and 100 ml of acetic acid. To this solution, 2.2 g of bromine was added dropwise at 50° C. The mixture was kept at 50° C. for 3 hours and then washed with ice-water and an aqueous solution of sodium bicarbonate. The chloroform layer was evaporated and the solid residue was crystallized in a mixture of carbon tetrachloride and n-hexane. The crystals were collected by filtration and dried to give 5.8 g of the captioned compound. m.p. 167°-168° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[S:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)(=[O:9])=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C(Cl)Cl.[Cl:64][C:65]1[CH:66]=[C:67]([CH:70]=[CH:71][C:72]=1[Cl:73])[CH2:68][NH2:69]>>[Cl:64][C:65]1[CH:66]=[C:67]([CH:70]=[CH:71][C:72]=1[Cl:73])[CH2:68][NH:69][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([S:7]([NH:6][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)(=[O:8])=[O:9])=[CH:18][CH:17]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(C(=O)O)cc2)c(OC)c1
Reactant: NCc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reaction time: 8 h
Yield: 98.3 %

Procedure:
4-{[(2,4-Dimethoxybenzyl)(1,3-thiazol-2-yl)amino]sulfonyl}benzoic acid (Preparation 99, 1.30E3 mg, 0.00300 mol), HBTU (1400.8 mg, 0.0031671 mol) and Et3N (1.07 mL, 0.00766 mol) were mixed in methylene chloride (10 mL, 0.2 mol). 3,4-dichlorobenzylamine (457.3 mg, 0.002598 mol) was added and the reaction stirred overnight. The reaction was washed with saturated sodium bicarbonate (aq). The organic phase was separated and dried over magnesium sulfate, the solvent was removed in vacuo to give an oily residue. The residue was purified by column chromatography (40 g silica gel column, hexanes to 50% ethyl acetate-hexanes gradient elution). Product fractions were combined and evaporated to give 1.13 g of the protected benzamide intermediate. The residue was dissolved in DCM and TFA was added dropwise until wet pH paper turned acidic when held above the reaction. After 30 minutes of stirring at room temperature, the solid precipitate was collected by filtration. The solid was rinsed with DCM, then ethyl ether. The solid was dissolved in 0.5N NaOH (5 mL) and filtered. The filtrate was washed 2× with ethyl ether, then treated with activated carbon and filtered through Celite. The pale yellow filtrate was acidified to pH 2 with 6N HCl. The white precipitate was collected by filtration and rinsed with water then ethyl ether. Vacuum drying yielded 446 mg of product as a white powder.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:9])[CH2:8][O:7][CH2:6][O:5][CH2:4]1.[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][N+:16]([O-:19])=[C:15]([CH3:20])[C:14]=1[O:21][CH3:22]>C1COCC1>[CH3:22][O:21][C:14]1[C:15]([CH3:20])=[N+:16]([O-:19])[CH:17]=[CH:18][C:13]=1[O:1][CH2:2][C:3]1([CH3:9])[CH2:8][O:7][CH2:6][O:5][CH2:4]1
Reactant: COc1c(Cl)cc[n+]([O-])c1C
Reactant: CC1(CO)COCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(OCC2(C)COCOC2)cc[n+]([O-])c1C
Yield: 24.1 %

Procedure:
A deareated solution of 5-(hydroxymethyl)-5-methyl-1,3-dioxane (1.19 g, 9 mmol) in 125 ml dry THF was treated with NaH (0.79 g 55% dispersion in oil, 18 mmol) for 20 min. 4-Chloro-3-methoxy-2-methylpyridine-N-oxide (1.04 g, 6 mmol) was added and the mixture was refluxed for 26 h. Excess NaH was quenched with 10 ml of H2O and the solvent evaporated. The residue was partitioned between 150 ml CH2Cl2 and 50 ml 5% Na2CO3. The organic layer was passed through a phase separation paper and evaporated leaving 1.83 g enriched product. Chromatography (SiO2CH2Cl2 /MeOH, 95/5) afforded 0.39 g (24%) pure title compound as a tanned oil.
Reaction SMILES: [ClH:1].[CH:2]1([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[O:18][CH3:19])[C:11]([C:20]([N:22]3[CH2:27][CH:26](C)[NH:25][CH:24]([CH3:29])[CH2:23]3)=[O:21])=[CH:10]2)C[CH2:6][CH2:5][CH2:4][CH2:3]1.I[CH2:31][CH3:32]>>[ClH:1].[CH:2]1([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[O:18][CH3:19])[C:11]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH2:24][CH3:29])[C@H:31]([CH3:32])[CH2:23]3)=[O:21])=[CH:10]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCI
Reactant: COc1cccc2c(C(=O)N3CC(C)NC(C)C3)cn(CC3CCCCC3)c12
Agent: Cl
Product: CCN1CCN(C(=O)c2cn(CC3CCCC3)c3c(OC)cccc23)C[C@H]1C

Procedure:
(R)-1-{[1-(Cyclopentylmethyl)-7-methoxy-1H-indol-3-yl]carbonyl}-4-ethyl-3-methylpiperazine, hydrochloride salt was prepared using (R)-1-{[1-(cyclopentylmethyl)-7-methoxy-1H-indol-3-yl]carbonyl}-3-methylpiperazine (prepared as detailed in example 12) and iodoethane. 1H NMR (400 MHz, CD3OD) δH 1.24-1.42 (8H, m), 1.51-1.73 (6H, m), 2.43 (1H, heptet, J 7.6), 3.12-3.23 (2H, m), 3.47-3.71 (5H, br m), 3.95 (3H, s), 4.38 (2H, d, J 6.9), 4.51 (2H, br s), 6.77 (1H, d, J 8.2), 7.10 (1H, t, J 7.7), 7.26 (1H, d, J 8.1), 7.60 (1H, s). EIMS; m/z=384.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[CH:19]=[C:20]([C:22](Cl)=[O:23])[CH3:21].[CH2:25]([NH2:28])[CH2:26][CH3:27]>C(OCC)(=O)C>[CH2:25]([NH:28][C:12](=[O:13])[C:11]1[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:19]=[C:20]([C:22](=[O:23])[NH:8][CH2:5][CH2:4][CH3:3])[CH3:21])[CH:4]=1)=[O:18])[CH2:26][CH3:27]
Reactant: CC(=Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl)C(=O)Cl
Reactant: CCCN
Solvent: CCOC(C)=O
Product: CCCNC(=O)C(C)=Cc1cc(NC(=O)C2=C(C(=O)NCCC)CCCC2)ccc1Cl
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 10.9 g of N-[4-chloro-3-(2-chlorocarbonylprop-1-en-1-yl)-phenyl]-3,4,5,6-tetrahydrophthalimide in 200 ml of ethyl acetate was added dropwise to a solution of 5.9 g of n-propylamine in about 150 ml of ethyl acetate while cooling with ice. The mixture was stirred for 3 hours at about 20° C., after which the solid formed was separated off, washed twice with 5% by weight aqueous hydrochloric acid and then once with petroleum ether and then dried under reduced pressure at 40° C. The crude product was recrystallized from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[C:22]([CH2:25][OH:26])[N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:27]([NH2:29])=[O:28])[CH3:9].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>ClCCl>[CH3:30][S:31]([O:26][CH2:25][C:22]1[N:21]=[CH:20][C:19]2[N:18]=[CH:17][N:16]([C:14]3[S:13][C:12]([C:27](=[O:28])[NH2:29])=[C:11]([O:10][C@@H:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH3:9])[CH:15]=3)[C:24]=2[CH:23]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1F

Procedure:
In a similar manner as described for example 49 (step 1), 737 mg of 3-[(1R)-1-(2-fluorophenyl)ethoxy]-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 409 mg of methanesulfonyl chloride, and 362 mg of triethylamine in 18 ml dichloromethane give (1-{5-carbamoyl-4-[(1R)-1-(2-fluorophenyl)ethoxy]-2-thienyl}-1H-imidazo[4,5-c]pyridin-6-yl)methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12](OS(C)(=O)=O)[C:11]2=[O:20])[CH:7]=[CH:8][CH:9]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C=O)C>[N:23]([CH:12]1[CH2:13][CH2:14][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:22])([F:21])[F:1])[CH:5]=2)[C:11]1=[O:20])=[N+:24]=[N-:25]
Reactant: CS(=O)(=O)OC1CCN(c2cccc(OC(F)(F)F)c2)C1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC1CCN(c2cccc(OC(F)(F)F)c2)C1=O
Reaction time: 16 h
Yield: 104.6 %

Procedure:
A stirred solution of crude 1-(3-trifluoromethoxyphenyl)-3-methanesulfonyloxy-2-pyrrolidinone (4.00 g) in DMF (15 ml) was treated with sodium azide (0.76 g) and the mixture stirred for 16 hours. The mixture was poured into water and extracted with diethyl ether (x2). The combined ether extracts were washed with water (x3) and brine, then dried (MgSO4). Evaporation of the solvent under reduced pressure gave the crude sub-title compound (3.50 g), which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[C:8](=[O:23])[C:7]=1[CH2:24]Br)=[O:5])[CH3:2].[CH3:26][O:27][C:28](=[O:41])[CH2:29][NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)(=[O:33])=[O:32].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[C:8](=[O:23])[C:7]=1[CH2:24][N:30]([CH2:29][C:28]([O:27][CH3:26])=[O:41])[S:31]([C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=1)(=[O:33])=[O:32])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccn(Cc2ccc(OC)cc2OC)c(=O)c1CBr
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccn(Cc2ccc(OC)cc2OC)c(=O)c1CN(CC(=O)OC)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
A mixture of 3-bromomethyl-1-(2,4-dimethoxy-benzyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid ethyl ester (4.43 g, 10.8 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (2.89 mg, 11.9 mmol), sodium iodide (3.24 g, 21.6 mmol) and potassium carbonate (2.99 g, 21.6 mmol) in DMF (95 mL) was stirred at r.t. for 16 h. Brine (150 mL) was added, and the resulting suspension was extracted with EtOAc. The organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by chromatography (0-80% EtOAc/hexanes) to give 4.2 g of the title compound. MS: (+) m/z 595.32 (M+Na).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:16].[C:17]([C:20]1[C:21](F)=[N:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:16][C:21]1[C:20]([C:17](=[O:19])[CH3:18])=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: CC(=O)c1cccnc1F
Reactant: CC(C)(C)Cn1nnc2c(Br)c(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cccnc1Oc1ccc2c(nnn2CC(C)(C)C)c1Br

Procedure:
4-Bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (1-6) (1 g, 3.52 mmol, 1.0 equiv.), 3-acetyl-2-fluoropyridine (0.979 g, 7.04 mmol, 2.0 equiv.) and potassium carbonate (0.973 g, 7.04 mmol, 2.0 equiv.) were dissolved in acetonitrile (10 ml). The mixture was irradiated at 200° C. in microwave reactor until LCMS showed mostly desired product. The solvent was evaporated in vacuo, the mixture was neutralized with saturated aqueous NH4Cl, and then extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc/Hexane gradient from 0 to 100%) to obtain 2. 1H NMR (CDCl3) δ 8.30-8.24 (1H, m), 8.24 (1H, s), 7.83 (1H, d, J=2.06 Hz), 7.56 (1H, d, J=8.91 Hz), 7.29 (1H, dd, J=2.1, 8.9 Hz), 7.16-7.10 (1H, m), 4.42 (2H, s), 2.80 (3H, s), 1.09 (9H, s) ppm. LRMS m/z (M+H) 403.0 and 405.0 (intensity ratio ˜1:1) found, 403.1 and 405.1 required.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)(=[NH:4])[NH2:3].[CH3:20][S:21](O)(=[O:23])=[O:22].C(OCC)C>CO>[CH3:20][S:21]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:2](=[NH:3])[NH2:4])=[CH:6][C:7]=1[C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)O
Reactant: N=C(N)c1ccc(O)c(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CS(=O)(=O)Oc1ccc(C(=N)N)cc1C(=O)c1ccccc1

Procedure:
In 200 ml of methanol, was suspended the 4-amidino-2-benzoylphenol hydrochloride obtained above. To the suspension was added 60 g of methanesulfonic acid followed by ethyl ether. The precipitated pale yellow crystals were collected by filtration and dried to obtain 109 g of 4-amidino-2-benzoylphenol methanesulfonate.
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@:8]3([OH:24])[CH2:9][CH2:10][C@@H:11]2[C:12](=O)[CH3:13])[CH2:3]1.C(=O)(O)O.[NH2:29][NH:30][C:31]([NH2:33])=[NH:32].Cl>O1CCOCC1.O>[NH:30](/[N:29]=[C:12](/[C@@H:11]1[C@:15]2([CH3:23])[C@@:8]([OH:24])([C@H:7]3[C@H:18]([CH2:17][CH2:16]2)[C@:19]2([CH3:22])[C@@H:4]([CH2:3][C@@H:2]([OH:1])[CH2:21][CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1)\[CH3:13])[C:31]([NH2:33])=[NH:32]
Reactant: N=C(N)NN
Reactant: CC(=O)[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: O=C(O)O
Solvent: O
Solvent: C1COCCO1
Product: C/C(=N\NC(=N)N)[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.3 %

Procedure:
A mixture of 1.00 g of 3β,14β-dihydroxy-5β-pregnane-20-one (Templeton J. F. et al., J. Chem. Soc., Perkin Trans. 1, 1991, 823), 1.20 g of aminoguanidine hydrogencarbonate in 40 ml of dioxane and 10 ml of water acidified at pH 2.5 with 0.01M hydrochloric acid was stirred at room temperature for 3 days. The precipitate was collected by filtration and purified by flash-chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 78/20/2; the fractions containing the title compound were collected and evaporated to dryness. The crude product was ground with ethanol to give 0.40 g of the title compound (I-bk) as a white solid.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])[OH:3].[CH3:13][C:14]([CH3:16])=O>>[CH3:13][C:14]1([CH3:16])[O:9][CH:8]([CH:6]2[O:7][C:2]([CH3:4])([CH3:1])[O:5][CH:4]2[CH:2]2[O:3][C:8]([CH3:10])([CH3:6])[O:12][CH2:1]2)[CH2:10][O:11]1
Reactant: CC(C)=O
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC1(C)OCC(C2OC(C)(C)OC2C2COC(C)(C)O2)O1
Temperature: 58 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To 250 ml of acetone were added 10.0 g of D-mannitol and 125 mg of anhydrous cupric chloride, and the mixture was stirred for 8 hours under reflux in a warm-water bath at 58° C. The refluxing solvent was continuously dried with 20 g of molecular sieves 3A which was placed between the reaction vessel and the cooling tube. After the conclusion of the reaction, the acetone was distilled off under reduced pressure, and the residue was dissolved in chloroform. The chloroform solution was washed with aqueous sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. When the chloroform was distilled under reduced pressure, there was obtained 16.0 g (96.4%) of 1,2:3,4:5,6-tri-O-isopropylidene-D-mannitol (purity of not less than 92%). The compound, when recrystallized from 70% ethanol, showed a melting point of 68.5° to 70.5° C.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([NH:4][CH2:5]3)[CH2:2]1)[CH2:9]2.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>C(O)C>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([N:4]2[CH2:5][CH:6]3[CH2:11][CH:1]4[CH2:9][CH:8]([CH2:10][CH:3]2[CH2:2]4)[CH2:7]3)=[O:20])=[CH:22][CH:23]=1)([O-:14])=[O:13]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C1NC2CC3CC1CC(C3)C2
Solvent: CCO
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CC2CC3CC(C2)CC1C3
Yield: 83.2 %

Procedure:
A mixture of 4-azatricyclo[4.3.1.13,8 ]undecane (0.75 gram, 5 mmol) from Step B, and p-nitrobenzoyl chloride (0.93 gram, 5 mmol) in 40 ml anhydrous ethanol was refluxed for 4.5 hours. Following workup and recrystallization from isopropanol, 1.25 gram of compound 4b were obtained as white crystals (melting point 150° C.).