Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].O[CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][N:5]1[CH2:9][CH2:8][S:7][C:6]1=[NH:10].CC1C=CC(S(O)(=O)=O)=CC=1.[Cl-].[Na+].S(=O)(=O)(O)O.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O.C1(C)C=CC=CC=1>[CH2:9]1[N:5]2[C:6](=[N:10][CH:3]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4]2)[S:7][CH2:8]1.[ClH:1]
Reactant: N=C1SCCN1CC(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(C2CN3CCSC3=N2)cc1
Temperature: 50 °C
Yield: 92.5 %

Procedure:
A laboratory pressure bottle is charged with 92 ml. of 37% hydrochloric acid, cooled to 0°-5° C., and a mixture consisting of 79.0 g. (0.2 mole) of dl-3-(β-hydroxyphenethyl)-2-iminothiazolidine-p-toluene sulfonate and 40.4 g. (0.69 mole) of sodium chloride is added. The mixture is cooled to 0°-5° C., and 89.2 g. of 97% sulfuric acid (0.875 mole) is added. The pressure bottle is closed, and the contents heated at 50° C. for 20 hours. The reaction mixture is cooled and added to a mixture of 200 ml. water and 250 ml. of toluene. The mixture is agitated at 20°-30° C. and 50% sodium hydroxide solution is added thereto dropwise to adjust the pH to 6. The mixture is heated to 50°-55° C., 40.0 g. of anhydrous potassium carbonate is added quickly, and the mixture is stirred at 50°-55° C. for 2 hours. At the end of this time, an additional 100 ml. of water is added, the lower aqueous layer separated, and the organic layer clarified. The clarified organic layer is treated with a solution of isopropanolic hydrogen chloride below 40° C. to the point where Congo Red test paper changes from red to blue. The reaction mixture is then cooled to 10° C., the precipitate is separated by filtration, and filter cake washed with 100 ml. of ambient temperature isopropanol. The product is air dried to constant weight to obtain 44.4 g. (92.5% yield) of dl tetramisole hydrochloride, compound VII. The product contains less than 0.1% of the styryl impurity, VIII.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[F-:13].[K+]>>[F:13][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: [F-]
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Agent: [K+]
Product: O=C1OC(=O)c2c(F)cccc21
Temperature: 235 °C
Yield: 69 %

Procedure:
A mixture of 20 parts of 3-chlorophthalic anhydride, and 20 parts of anhydrous potassium fluoride was heated and maintained at about 235° C. for about 9 hours. The reaction mixture was then cooled and the crude product was removed by vacuum distillation and recrystallized from chloroform to yield 12.65 parts of purified 3-fluorophthalic anhydride (69% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)=[CH:2]1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])O.[Na+]>C1COCC1.CC(N(C)C)=O.CN(C)C=O>[Cl:32][C:29]1[CH:30]=[CH:31][C:22]([NH:21][C:9]([C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:7]=2)=[O:11])=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: O=C(O)c1cccc(-c2ccoc2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(-c2ccoc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
0.50 g (2.7 mmol) of 3-(furan-3-yl)benzoic acid, a catalytic amount of N,N-dimethylformamide (DMF), 0.78 g (3.7 mmol) of oxalyl chloride were stirred at 0° C. for 30 minutes in 10 mL of THF. Thereafter, the solvent was distilled off under reduced pressure. 0.49 g (2.7 mmol) of methyl 2-amino-5-chlorobenzoate and 5 mL of DMAc were added to the obtained residue at 0° C., and the mixture was stirred at room temperature for 0.5 hours. After the completion of the reaction, an aqueous sodium hydrogen carbonate solution was added. The precipitated solids were collected by filtration, followed by washing with water and IPE, thereby giving 0.63 g of methyl 5-chloro-2-({[3-(furan-3-yl)phenyl]carbonyl}amino)benzoate (yield: 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([C:13](O)=[O:14])=[N:9]2)=[CH:5][CH:4]=1.O=S(Cl)[Cl:20]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([C:13]([Cl:20])=[O:14])=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nnc(C(=O)O)n2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2nnc(C(=O)Cl)n2)cc1
Temperature: 80 °C

Procedure:
Next, to a mixture of 2-(4-methoxy-benzyl)-2H-tetrazole-5-carboxylic acid in Toluene (15 ml) at room temperature is added SOCl2 (1 ml, 13.70 mmol) and the mixture is heated at 80° C. for 3 hr. The reaction mixture is concentrated under reduced pressure to give the crude product, which is used without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH3:33])[CH:9]1[CH2:15][N:14]([C:16](OC(C)(C)C)=O)[CH2:13][CH2:12][N:11]2[C:23](=[O:32])[C:24]([OH:31])=[C:25]([C:27]([O:29][CH3:30])=[O:28])[N:26]=[C:10]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34](=O)C.C(N(CC)CC)C.[BH3-]C#N.[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(O)(=O)C>[CH2:1]([N:8]([CH3:33])[CH:9]1[CH2:15][N:14]([CH2:16][CH3:34])[CH2:13][CH2:12][N:11]2[C:23](=[O:32])[C:24]([OH:31])=[C:25]([C:27]([O:29][CH3:30])=[O:28])[N:26]=[C:10]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc2n(c(=O)c1O)CCN(C(=O)OC(C)(C)C)CC2N(C)Cc1ccccc1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCn2c(nc(C(=O)OC)c(O)c2=O)C(N(C)Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8-tert-butyl 2-methyl 10-[benzyl(methyl)amino]-3-hydroxy-4-oxo-6,7,9,10-tetrahydropyrimido[1,2-d][1,4]diazepine-2,8(4H)-dicarboxylate (prepared as described in Example 11, Step 1-4) was taken in CH2Cl2/TFA (8/2 v/v) and stirred at room temperature for 1 hour. Volatiles were evaporated and residue was triturated with diethyl ether. MS (ES) C18H22N4O4 requires 358. Found: 359 (M+H+). The crude organic product was dissolved in MeOH and treated with acetaldehyde (3 eq.) and triethylamine (3 eq.). Acetic acid was added until pH=5.5, followed by NaCNBH3 (2 eq.), and resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated to a residue which was purified on Cation Exchange Resin (Varian Mega Bond Elute SCX). After washing with MeOH, the product was collected eluting with 2N NH3 solution in MeOH. The fractions containing the desired material were concentrated under reduced pressure to yield the title compound as brown oil. MS (ES) C20H26N4O4 requires 386. Found: 387 (N+H+).
Reaction SMILES: C([O:3][C:4](=[O:16])[CH:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[CH3:6])C.[Li+].[OH-]>C1COCC1.CO.O>[Cl:15][C:10]1[CH:9]=[C:8]([NH:7][CH:5]([CH3:6])[C:4]([OH:16])=[O:3])[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: CCOC(=O)C(C)Nc1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Yield: 82.1 %

Procedure:
A mixture of 2-(3,4-dichloro-phenylamino)-propionic acid ethyl ester (10.0 g, 38.1 mmol) and LiOH (2.74 g, 114 mmol) in THF/MeOH/water 2:1:1 (100 mL) was heated at reflux for 3 h, then after cooling poured onto water and extracted with TBME. The organic phase was extracted twice with 1 M aq. sodium hydroxide solution. The aqueous phases were combined, acidified to pH 2-3 by addition of 37% aq. HCl solution, and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and evaporated to produce the title compound (7.32 g, 82%). Light yellow solid, MS: 233.9 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[NH:14][C:13]([C:15]([C:51]4[C:56]([CH3:57])=[CH:55][C:54]([CH3:58])=[CH:53][C:52]=4[CH3:59])=[C:16]4[N:50]=[C:19]([C:20]([C:41]5[C:46]([CH3:47])=[CH:45][C:44]([CH3:48])=[CH:43][C:42]=5[CH3:49])=[C:21]5[NH:40][C:24](=[C:25]([C:31]6[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][C:32]=6[CH3:39])[C:26]6[CH:27]=[CH:28][C:29]=2[N:30]=6)[CH:23]=[CH:22]5)[CH:18]=[CH:17]4)=[CH:12][CH:11]=3)=[CH:5][CH:4]=1.[CH3:60][O:61][P:62]([O:65]C)[O:63][CH3:64]>C1(C)C=CC=CC=1>[CH3:60][O:61][P:62]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[NH:14][C:13]([C:15]([C:51]4[C:56]([CH3:57])=[CH:55][C:54]([CH3:58])=[CH:53][C:52]=4[CH3:59])=[C:16]4[N:50]=[C:19]([C:20]([C:41]5[C:46]([CH3:47])=[CH:45][C:44]([CH3:48])=[CH:43][C:42]=5[CH3:49])=[C:21]5[NH:40][C:24](=[C:25]([C:31]6[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][C:32]=6[CH3:39])[C:26]6[CH:27]=[CH:28][C:29]=2[N:30]=6)[CH:23]=[CH:22]5)[CH:18]=[CH:17]4)=[CH:12][CH:11]=3)=[CH:5][CH:4]=1)([O:63][CH3:64])=[O:65]
Reactant: Cc1cc(C)c(-c2c3nc(c(-c4c(C)cc(C)cc4C)c4ccc([nH]4)c(-c4c(C)cc(C)cc4C)c4nc(c(-c5ccc(CBr)cc5)c5ccc2[nH]5)C=C4)C=C3)c(C)c1
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1ccc(-c2c3nc(c(-c4c(C)cc(C)cc4C)c4ccc([nH]4)c(-c4c(C)cc(C)cc4C)c4nc(c(-c5c(C)cc(C)cc5C)c5ccc2[nH]5)C=C4)C=C3)cc1)OC
Yield: 79 %

Procedure:
A solution of 26 (200 mg, 240 μmol) in trimethylphosphite (2.2 mL) and toluene (5 mL) was heated to 120° C. under argon for 17 h. The reaction mixture was cooled and concentrated under vacuum. The residue was chromatographed [silica, CHCl3→CHCl3/ethyl acetate (95:5)] to afford a purple solid (164 mg, 79%): 1H NMR δ −2.57 (br s, 2H), 1.84-1.85 (m, 18H), 2.62 (s, 9H), 3.50 (d, J=21.6 Hz, 2H), 3.87 (d, J=11.1 Hz, 6H), 7.27 (s, 6H), 7.67 (dd, J1=8.4 Hz, J2=1.8 Hz, 2H), 8.15 (d, J=7.8 Hz, 2H), 8.63 (s, 4H), 8.67 (d, J=4.8 Hz, 2H), 8.75 (d, J=4.8 Hz, 2H); 31P NMR δ 29.50; LDMS obsd 863.2; FABMS obsd 862.4045; calcd 862.4012 (C56H55N4O3P); λabs=421, 514, 547, 593, 649 nm.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[CH2:6][N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=3)[C:10]([OH:25])=[C:9]([C:26](OCC)=[O:27])[C:8]2=[O:31])[CH2:3][CH2:2]1.[CH2:33]([CH2:35][NH2:36])[OH:34]>>[CH:1]1([NH:4][C:5](=[O:32])[CH2:6][N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=3)[C:10]([OH:25])=[C:9]([C:26]([NH:36][CH2:35][CH2:33][OH:34])=[O:27])[C:8]2=[O:31])[CH2:2][CH2:3]1
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NC2CC2)c1=O
Product: O=C(Cn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21)NC1CC1

Procedure:
This compound was prepared from ethyl 1-[2-(cyclopropylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 245. The crude material was triturated with a mixture of MeOH and 1N HCl to afford the product as a white solid: 1H NMR (d6-DMSO) δ 10.25 (1H, t, J=5 Hz), 8.54 (1H, s), 8.25 (1H, d, J=4 Hz), 7.74 (1H, s), 7.32 (2H, dd, J=8.5, 5.7 Hz), 7.11 (2H, t, J˜9 Hz), 4.92 (1H, br m), 4.80 (2H, s), 4.11 (2H, s), 3.54 (2H, t, J=5 Hz), 3.42 (2H, q, J˜5 Hz), 2.57 (1H, m), 0.59 (2H, m), 0.35 (2H, m); HRMS calcd for C23H23FN4O5+H+: 455.1731. Found: 455.1728.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[CH:6]=[C:7]2[C:11]=1[C:10](=O)[CH2:9][CH2:8]2.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[CH:6]=[C:7]2[C:11]=1[C:10](=[N:15][OH:16])[CH2:9][CH2:8]2
Reactant: COc1cc(C)cc2c1C(=O)CC2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(C)cc2c1C(=NO)CC2
Yield: 98 %

Procedure:
7-Methoxy-5-methyl-1-indanon (CAS no: 62358-78-5) (7.70 g, 0.044 mol) was dissolved in ethanol (40 mL) and hydroxylamine hydrochloride (6.23 g, 0.09 mol) and sodium acetate (7.38 g, 0.09 mol) were added. The reaction mixture was heated to reflux for 3 h. Then water (100 mL) was added and a precipitation formed which was filtered. The precipitate was washed with water, isolated and dried under high vacuum to yield 7-methoxy-5-methyl-indan-1-one oxime (8.20 g, 98%) as a white solid; MS: m/e=192.4 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[CH:5][C:6]=1[C:7]([O:9]CC)=O.C(O)(=O)C.[CH:29](N)=[NH:30]>CN(C)C=O>[OH:9][C:7]1[C:6]2[CH:5]=[C:4]([CH2:12][CH2:13][N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[S:3][C:2]=2[N:1]=[CH:29][N:30]=1
Reactant: CCOC(=O)c1cc(CCN2C(=O)c3ccccc3C2=O)sc1N
Reactant: N=CN
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCc1cc2c(O)ncnc2s1
Temperature: 100 °C
Yield: 54.8 %

Procedure:
To a 250-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was added a solution of ethyl 2-amino-5-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)ethyl]thiophene-3-carboxylate (3.4 g, 9.87 mmol, 1.00 equiv) and formamidine acetate (1.5 g, 14.41 mmol, 1.46 equiv) dissolved in 50 mL of N,N-dimethylformamide. This solution was heated at 100° C. for 12 hrs. The reaction was cooled to room temperature and quenched with water. The resulting mixture was extracted with 3×100 mL of ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to yield 1.76 g (55%) of 2-(2-[4-hydroxythieno[2,3-d]pyrimidin-6-yl]ethyl)-2,3-dihydro-1H-isoindole-1,3-dione as an off-white solid. MS (ES): m/z 326 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:8])=[C:5]([OH:20])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:28]([CH3:32])[C:29](=[O:31])[CH3:30].O>CN(C=O)C.C(Cl)Cl>[ClH:19].[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])=[O:8])=[C:5]([O:20][CH:28]([CH3:32])[C:29](=[O:31])[CH3:30])[CH:4]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: CC(=O)C(C)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC(C)C(C)=O
Reaction time: 3 h
Yield: 119 %

Procedure:
To a stirred suspension of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (1.94 g, 6 mmoles) and potassium carbonate (4.16 g, 30 mmoles) in DMF (10 ml) was added 3-chloro-2-butanone (0.95 g, 8.9 mmoles) and the mixture stirred for 3 hours, followed by pouring into water and extraction with methylene chloride. The extract was washed well with water, dried and concentrated in vacuo. The residue was dissolved in 1-propanol and treated with 2N HCl followed by concentration to give an oily residue. This was crystallized from acetone and the product recrystallized from 2-propanol to give 1.4 g of the title compound mp 98° C. as the hemihydrate.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22](OCC)=[O:23])=[CH:16][CH:15]=2)=[N:12][CH:13]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][OH:23])=[CH:16][CH:15]=2)=[N:12][CH:13]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(C)cn2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(CCCO)cc2)nc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a suspension of lithium aluminum hydride (0.424 g) in tetrahydrofuran (20 mL), a solution of the compound obtained from step c above (2 g) in tetrahydrofuran (10 mL) was added at −20° C. The reaction mixture was stirred for 2 hours at 30° C. and a saturated solution of sodium sulphate was added at the same temperature. The reaction mixture was then filtered through a celite pad and the residue was washed with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography over silica gel using 50% ethyl acetate in hexane as eluant to afford the title compound (1.2 g).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[F:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27])=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([N+:26]([O-:28])=[O:27])[CH:24]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(F)cc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (8.00 g, 33.6 mmol) in CH2Cl2 (140 ml) was added drop wise, over a 30 minutes period, to a stirred solution of 1-fluoro-4-((E)-2-nitro-vinyl)-benzene (5.12 g, 30.6 mmol) and trifluoroacetic acid (0.23 ml, 3.1 mmol) in CH2Cl2 (200 ml) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:4) afforded 6.60 g (72%) of the title compound as a light yellow oil.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH2:20])[CH3:19])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24](Cl)[N:23]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24]([NH:20][C@H:18]([C:8]2[N:7]=[C:6]3[CH:5]=[CH:4][N:3]([CH3:2])[C:11]3=[CH:10][C:9]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:19])[N:23]=1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1-c1ccccn1
Temperature: 25 °C

Procedure:
A solution of (S)-1-(1-methyl-6-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (50 mg, 0.198 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (50.4 mg, 0.297 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.104 mL, 0.594 mmol) in acetonitrile (6 mL), was heated in a microwave reactor at 120° C. for 2 hours. After cooling to room temperature, the reaction mixture was concentrated, re-dissolved in DMF, and purified by preparative HPLC (basic mode) using a 20-30% CH3CN gradient in H2O. The desired fractions were combined and solvent was removed in vacuo. The residue was purified again by preparative HPLC (basic mode) using a 25-35% CH3CN gradient in H2O. The pure fractions were combined and the solvent was removed in vacuo to give the title compound as a colorless film (24 mg, 31%). 1H NMR (500 MHz, CD3OD) δ ppm 1.59 (d, J=7.32 Hz, 3 H), 4.04 (br s, 3 H), 5.84 (q, J=7.32 Hz, 1 H), 6.88 (d, J=3.42 Hz, 1 H), 7.62-7.68 (m, 1 H), 7.90 (d, J=7.81 Hz, 1 H), 8.08 (d, J=2.93 Hz, 1 H), 8.16 (td, J=7.81, 1.95 Hz, 1H), 8.66 (s, 1H), 8.83 (d, J=4.88 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C20H19N9, 386. found 386.
Reaction SMILES: CS(O[CH2:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]1[C:14]([C:19](=[O:27])[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[N:15][N:16]([CH3:18])[CH:17]=1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C)C=O>[N:28]([CH2:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]1[C:14]([C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:27])=[N:15][N:16]([CH3:18])[CH:17]=1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1noc(COS(C)(=O)=O)c1-c1cn(C)nc1C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(CN=[N+]=[N-])c1-c1cn(C)nc1C(=O)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 93.4 %

Procedure:
A mixture of (4-(3-(4-chlorobenzoyl)-1-methyl-1H-pyrazol-4-yl)-3-methylisoxazol-5-yl)methyl methanesulfonate (35 mg, 0.09 mmol), sodium azide (12 mg, 0.18 mmol) in N,N-dimethylformamide (10 mL) was heated to 80° C. and stirred for 10 h. After cooling to room temperature, the mixture was concentrated, and the residue was purified by flash chromatography eluting with petroleum ether/ethyl acetate=1:3 to give the titled product as a colorless oil (30 mg, 94%). LC/MS: m/z 356 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 8.16 (d, J=9 Hz, 2H), 7.50 (s, 1H), 7.46 (d, J=9 Hz, 2H), 4.37 (s, 2H), 4.09 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([N:11]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:12][CH2:13][N:14]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[C:20]([O:19][C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:10]2[CH:15]1[CH2:16][NH:8][CH2:9]2)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C2CN(Cc3ccccc3)CC21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C2CNCC21
Temperature: 70 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of 39 mg (0.093 mmol) of 8-benzyl-2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo-[4,3,0]nonane synthesized by the above process in methanol (1.5 ml) were added 40 mg (0.63 mmol) of ammonium formate and 40 mg of 10% palladium on carbon. The mixture was stirred for 1 hour at 70° C. under nitrogen, and the catalyst was removed from the reaction mixture by suction filtration through Celite. The filtrate was concentrated under reduced pressure, and the resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 29 mg (yield: 95%) of 2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo[4,3,0]nonane as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1.[OH-:17].[Na+].OO>C(O)C.O>[Cl:1][C:2]1[C:6]([C:7]([NH2:8])=[O:17])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: [OH-]
Reactant: COc1ccc(-c2snc(Cl)c2C#N)cc1
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2snc(Cl)c2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-chloro-5-(4-methoxyphenyl)-1,2-thiazole-4-carbonitrile (3.4 g, 13.56 mmol, 1.00 equiv) in ethanol/H2O (20/10 mL), sodium hydroxide (1 g, 25.00 mmol, 1.84 equiv), H2O2 (10 g). The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×80 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 680 mg (crude) of 3-chloro-5-(4-methoxyphenyl)-1,2-thiazole-4-carboxamide as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C11H9ClN2O2S, 269.0 (M+H). found 269.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-].S(OC)(OC)(=O)=O.C(OCC)C.[C-:22]#[N:23].[Na+]>O>[Cl:1][C:2]1[N:3]=[C:4]([C:22]#[N:23])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc[n+]([O-])c(Cl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Solvent: O
Product: Cc1cc(Cl)nc(C#N)c1
Reaction time: 8 h

Procedure:
2-chloro-4-methylpyridine 1-oxide (8.5 g, 59.2 mmol) from step 1 of this example was added to the dimethyl sulfate (9.0 g, 71 mmol) and the mixture stirred overnight. Diethyl ether (40 ml) was added, the mixture stirred, and ether decanted (2×). The volatiles were removed in vacuum. The residue was dissolved in water (50 ml) and the solution added drop wise to a −15° C. solution of sodium cyanide (11.3 g, 231 mmol) in water (50 ml) under N2. The mixture was stirred between −7 and −15° C. for 1.5 hours during which a solid precipitates. The crystals were filtered, washed with water followed by a small amount of cold ether to give the titled compound. LRMS calc: 152.01; obs: 153.56 (M+1).