Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)[C:3]1[CH:10]=[CH:9][C:6](CBr)=[CH:5][CH:4]=1.Cl.BrCC1C=[N:18]C=CC=1.[CH3:22][C:23]1[N:24]=[C:25]([N:33]2[CH2:37][CH2:36][NH:35][C:34]2=[O:38])[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH3:22][C:23]1[N:24]=[C:25]([N:33]2[CH2:37][CH2:36][N:35]([CH2:3][C:10]3[CH:9]=[CH:6][CH:5]=[CH:4][N:18]=3)[C:34]2=[O:38])[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: BrCc1cccnc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: Cl
Product: CCOC(=O)c1sc(N2CCN(Cc3ccccn3)C2=O)nc1C
Yield: 68 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 3-(bromomethyl)pyridine hydrochloride to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 68% yield: MS (ES+) m/z 347.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:11].COC[O:15][CH3:16]>OS(O)(=O)=O>[Cl:11][CH2:7][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:16]=1[OH:15]
Reactant: COCOC
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Cl
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(O)c(CCl)c1
Temperature: 70 °C
Yield: 76 %

Procedure:
A 5-necked flask equipped with mechanical overhead stirrer, gas inlet tube, reflux condenser and a thermometer was charged with 4-nitrophenol (100 g, 0.72 mol). Concentrated HCl 932%, 1.3 L), conc. H2SO4 (98%, 10 mL) and formaldehyde dimethylacetal (152.4 g, 2 moles) were added and the mixture was heated to 70° C. Gaseous HCl was bubbled through the mixture for 4 hours. During this time a thick white precipitate formed. The suspension was cooled to 0° C., the precipitate was isolated by vacuum filtration and the yellow powder was dried over night under vacuum to give 108.76 g of slightly impure 2-chloromethyl-4-nitrophenol (about 76% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6]Cl)[CH3:3].[Mg].Cl[CH:10]1[C:16]2[CH:17]=[C:18]([S:21][CH3:22])[CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13][C:12]2[CH:23]=[CH:24][CH:25]=[CH:26][C:11]1=2>O1CCCC1>[CH3:1][N:2]([CH3:3])[CH2:4][CH2:5][CH2:6][CH:10]1[C:16]2[CH:17]=[C:18]([S:21][CH3:22])[CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13][C:12]2[CH:23]=[CH:24][CH:25]=[CH:26][C:11]1=2
Reactant: CSc1ccc2c(c1)C(Cl)c1ccccc1C=C2
Reactant: CN(C)CCCCl
Agent: [Mg]
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)C(CCCN(C)C)c1ccccc1C=C2

Procedure:
The Grignard reagent is prepared from dimethylaminopropyl chloride (0.2 mole) and magnesium (0.2 g. atom) in 75 ml. of dry tetrahydrofuran following the method described in U.S. Pat. No. 2,996,503. A 15 ml. portion of this solution is cooled in an ice-bath and stirred while a solution of 4.7 g. (0.0172 mole) of 5-chloro-3-methylmercapto-5H-dibenzo[a,d]cycloheptene in 25 ml. of tetrahydrofuran is added dropwise. The usual precautions, such as careful drying of the apparatus and maintaining a nitrogen atmosphere, are observed. After stirring the mixture for 2 hours at room temperature, the bulk of the solvent is distilled at 30°C. under reduced pressure and the residue dissolved in benzene. The solution is cooled in an ice-bath and the excess Grignard reagent hydrolyzed by the dropwise addition of water. The benzene layer is decanted and the gelatinous precipitate washed with four 25 ml. portions of boiling benzene. After washing with water, the combined benzene solutions are extracted with 50 ml. of 0.5 M. citric acid. The acid extract is rendered alkaline with sodium hydroxide and the oily base extracted into benzene. Evaporation of the washed benzene extract under reduced pressure leaves 5-(3-dimethylaminopropyl)-3-methylmercapto-5H-dibenzo[a,d]cycloheptene as the oily residue weighing, typically, 4.2 g. (75%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][CH:22]=[C:21](C(O)=O)[CH:20]=1.[NH2:34][CH2:35][CH:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][CH:31]=[C:32]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][CH2:35][CH:36]([OH:37])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:18])=[O:7])[CH:33]=1
Reactant: NCC(O)c1ccccc1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2cccc(-c3ccccc3)c2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-3-carboxylic acid, and (1RS)-2-amino-1-phenylethanol, the title compound was obtained in 72% purity by HPLC. MS(ESI+): m/z=458.
Reaction SMILES: C[O:2]C(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[O:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH:22]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:18][CH2:17]1.[OH-:38].[K+].[CH2:40]([OH:42])C>O>[OH2:2].[F:36][C:33]1[CH:32]=[CH:31][C:30]([CH:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH2:13][O:12][C:5]3[CH:4]=[CH:9][C:8]([C:40]([OH:42])=[O:38])=[CH:7][C:6]=3[O:10][CH3:11])[CH2:21][CH2:20]2)=[CH:35][CH:34]=1
Reactant: CCO
Reactant: COC(=O)c1cccc(OC)c1OCCCN1CCC(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: COc1cc(C(=O)O)ccc1OCCCN1CCC(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Yield: 61.8 %

Procedure:
A solution of 4-[3-[4-[bis(4-fluorophenyl)methyl]-1-piperidinyl]-propoxy-3-methoxybenzoic acid methyl ester (18.58 g, 0.0365 mole) in 400 ml of ethanol was heated for 6 hr at reflux with potassium hydroxide (16.8 g) in 50 ml of water. The ethanol was removed by rotary evaporation. Next, 1N sulfuric acid (~200 ml) was added. The aqueous phase was made neutral to litmus paper by the addition of 5% sodium hydroxide. The neutral aqueous layer was extracted several times with chloroform. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a white solid. The white solid was triturated with ethyl ether and cooled to about 0° C. The white solid was then collected by filtration and dried in vacuo overnight at 80° C. to give 11.38 g (61.8% yield) of white, crystalline product, the title compound, mp 123°-126° C.
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C=O)C.C(Cl)(=O)C([Cl:25])=O>C1(C)C=CC=CC=1>[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([Cl:25])=[O:16])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ncoc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of commercially available 5-phenyl-oxazole-4-carboxylic acid (67 mg, 0.35 mmol) in toluene (1.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.08 mL, 0.91 mmol) and the resulting yellow solution was stirred at rt for 1 h. The solvent was then removed under reduced pressure (co-evaporation with toluene) to give 5-phenyl-oxazole-4-carbonyl chloride as a brown oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Cl)[CH3:2].[C:10]([O-:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[K+].[Br-].[K+].CN(C=O)C>C(OCC)(=O)C.O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:18][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC(CCl)OCC
Reactant: O=C([O-])c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COC(=O)c1ccccc1)OCC
Temperature: 25 °C
Yield: 34.1 %

Procedure:
Chloroacetaldehyde diethyl acetal (2.00 g), potassium benzoate (1.91 g), potassium bromide (0.30 g) and DMF (20 mL) were placed in a three-neck flask, followed by refluxing. Twenty hours later, the reaction mixture was cooled to room temperature, and water (30 mL) and ethyl acetate (80 mL) were added thereto, followed by stirring. After filtration, the organic layer was washed with water (30 mL) and was dried over anhydrous sodium sulfate. Subsequent filtration and vacuum concentration yielded the target compound (0.97 g) in a yield of 31%.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.OO.NC(N)=[O:14].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:9])=[N+:4]([O-:14])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: NC(N)=O
Reactant: Cc1ccc(Br)c(Cl)n1
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc(Br)c(Cl)[n+]1[O-]
Temperature: 25 °C
Yield: 102.2 %

Procedure:
To a solution of 3-bromo-2-chloro-6-methylpyridine (1 g, 4.84 mmol) and urea hydrogen peroxide (911 mg, 9.69 mmol) in DCM (24 mL) at 0° C. was added trifluoroacetic anhydride (1.4 mL, 9.69 mmol). After warming to 25° C. over 12 h, the solution was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 1% MeOH in DCM) yielding the title compound (1.1 g, quant.) as a white solid: LCMS (ES) m/z=223 (M+H)+.
Reaction SMILES: [NH2:1][C:2](=[N:5][C:6](=[O:9])[O:7][CH3:8])[O:3][CH3:4].NC(=NC(=O)OC)SC.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:28])[NH:1][C:2](=[N:5][C:6]([O:7][CH3:8])=[O:9])[O:3][CH3:4])=[CH:22][CH:21]=1
Reactant: COC(=O)N=C(N)OC
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: COC(=O)N=C(N)SC
Solvent: ClCCl
Product: COC(=O)N=C(NC(=O)Nc1ccc(Cl)cc1)OC
Reaction time: 8 h

Procedure:
To 13 parts of methyl N-(1-amino-1-methoxymethylene)-carbamate, m.p. 36°-39.5°, prepared similar to the procedure in Example 3 for methyl N-(1-amino-1-methylthiomethylene)-carbamate in 140 parts of methylene chloride is added 15 parts of p-chlorophenyl isocyanate. The reaction mixture is stirred overnight and the solution filtered to give 10 parts of methyl 4-(p-chlorophenyl)-N-methoxycarbonylallophanimidate melting at 170° dec.
Reaction SMILES: Br[C:2]1C=CC(C2C3C=C(OC)C(OC)=CC=3NC(=O)CN=2)=CC=1.[CH2:24]([O:26][C:27]1[C:28]([O:45][CH2:46][CH3:47])=[CH:29][C:30]2[NH:36][C:35](=[O:37])[CH2:34][N:33]=[C:32]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:31]=2[CH:44]=1)[CH3:25]>>[CH2:24]([O:26][C:27]1[C:28]([O:45][CH2:46][CH3:47])=[CH:29][C:30]2[N:36]([CH3:2])[C:35](=[O:37])[CH2:34][N:33]=[C:32]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:31]=2[CH:44]=1)[CH3:25]
Reactant: COc1cc2c(cc1OC)C(c1ccc(Br)cc1)=NCC(=O)N2
Reactant: CCOc1cc2c(cc1OCC)C(c1ccccc1)=NCC(=O)N2
Product: CCOc1cc2c(cc1OCC)N(C)C(=O)CN=C2c1ccccc1
Yield: 28 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 7,8-diethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIag) and proceeding in the same manner, the abovenamed product is obtained. Yield: 28%. M: 116–118° C. 1H-NMR (CDCl3, 200 MHz): d 1.40 (t, 3H, CH3), 1.56 (t, 3H, CH3), 3.42 (s, 3H, NCH3), 3.97 (q, 2H, OCH2), 4.21 (q, 2H, OCH2), 4.33 (AB system, ? d=0.98 JAB=10.5, 2H, CH2), 6.74 (s, 1H Ar), 6.81 (s, 1H Ar), 7.42–7.70 (m, 5H Ar).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].O=[C:7]1CCC[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]1.O>O1CCCC1.CCCCCC>[CH2:4]=[C:3]1[CH2:7][CH2:8][CH2:9][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:1][CH2:2]1
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon 12.56 g methyltriphenylphosphonium bromide are dissolved in 100 ml of tetrahydrofuran, cooled to −14° C. and within 45 minutes a 2 M solution of 17.58 ml n-butyllithium in hexane is added dropwise. The mixture is stirred for another 1 hour and then a solution of 5 g tert-butyl 4-oxo-azepan-1-carboxylate in 20 ml of tetrahydrofuran is added dropwise. Then the mixture is heated to ambient temperature and stirred for 12 hours. It is then divided between water and hexane and the aqueous phase is extracted twice with hexane. The combined organic phases are washed with saturated aqueous sodium chloride solution and dried on magnesium sulphate. The solvents are eliminated in vacuo and the residue is stirred with petroleum ether/tert.-butyl-methyl-ether. The solid is suction filtered and the mother liquor is evaporated down in vacuo. The residue is chromatographed on silica gel (petroleum ether/ethyl acetate 100:0, then 95:5).
Reaction SMILES: C(O[CH:4]([O:13]CC)[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)C.[CH2:16]([Mg]Br)[CH2:17][CH2:18][CH2:19][CH3:20].[NH4+].[Cl-]>C1COCC1>[OH:13][CH:4]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC[Mg]Br
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC(O)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 369.2 %

Procedure:
A solution of 4-diethoxymethyl-benzaldehyde (0.300 mL, 1.51 mmol) in THF (3 mL) was cooled to 0° C. Pentylmagnesium bromide (3.0 mL, 2.0 M in THF, 6 mmol) was added dropwise. The reaction was stirred at 0° C. for 1 h and was warmed to room temperature. Aqueous NH4Cl (satd) was added and the aqueous solution was extracted with EtOAc. The organic solution was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was dissolved in 10% aqueous acetone (50 mL) and wet Amberlyst-15 resin (1.5 g) was added. The mixture was stirred for 24 h and the resin was filtered off through Celite. The solution was concentrated in vacuo. Purification via flash chromatography (4:1 hexanes:EtOAc) provided the title compound (1.15 g). 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 7.86 (d, 2H), 7.51 (d, 2H), 4.77 (m, 1H), 1.89 (m, 1H), 1.74 (m, 2H), 1.48-1.28 (m, 6H), 0.87 (m, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][S:5](=[O:8])[CH2:4][CH2:3]1.[CH3:9][C:10]1[CH:11]=[C:12]([O:28][C:29]2[CH:30]=[N:31][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][CH:34]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25](O)=[O:26])[CH2:22][N:23]=1)=[CH:15]2.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[CH3:9][C:10]1[CH:11]=[C:12]([O:28][C:29]2[CH:30]=[N:31][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][CH:34]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([N:2]3[CH2:7][CH2:6][S:5](=[O:8])[CH2:4][CH2:3]3)=[O:26])[CH2:22][N:23]=1)=[CH:15]2
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: O=S1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)N4CCS(=O)CC4)S3)[nH]c12
Reaction time: 15 h
Yield: 42.4 %

Procedure:
To a solution of thiomorpholine 1-oxide hydrochloride (140 mg) and triethylamine (0.125 mL) in N,N-dimethylformamide (15 mL) were added [2-(7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (200 mg), 1-hydroxybenzotriazole (121 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (172 mg) under ice-cooling, and the mixture was stirred under ice-cooling and then at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0 to 75:25, volume ratio), and the obtained pale-yellow crystals were recrystallized from ethyl acetate-hexane to give the title compound (104 mg, yield 42%) as colorless crystals.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH3:13][CH:14]([NH2:33])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:23]=2)[NH:18][CH:17]=1>C(O)C>[CH3:13][C@@H:14]([NH:33][CH2:12][C@@H:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[N:2][N:1]=2)[CH:9]=1)[OH:11])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:23]=2)[NH:18][CH:17]=1.[CH3:13][C@H:14]([NH:33][CH2:12][C@@H:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[N:2][N:1]=2)[CH:9]=1)[OH:11])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:23]=2)[NH:18][CH:17]=1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Reactant: CC(N)Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Solvent: CCO
Product: C[C@@H](Cc1c[nH]c2ccc(OCc3ccccc3)cc12)NC[C@H](O)c1ccc2nnnn2c1
Product: C[C@H](Cc1c[nH]c2ccc(OCc3ccccc3)cc12)NC[C@H](O)c1ccc2nnnn2c1

Procedure:
A solution of 3.24 g of (R)-2-(tetrazolo-[1,5-a]pyrid-6-yl)oxirane and 5.89 g of 1-methyl-2-(5-benzyloxy-1H-indol-3-yl)ethyl amine in 84 ml of absolute ethanol was heated at reflux under nitrogen for 24 hours. The reaction mixture was concentrated and the residue purified by preparative TLC on silica gel (95:5:0.5 CH2Cl2 :MeOH:NH4OH) to give 1.29 g of (R)-α-[[(1(R)-methyl-2-(5-benzyloxy-1H-indol-3-yl)ethyl)amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol and 1.46 g of (R)-α-[[(1(S)-methyl-2-(5-benzyloxy-1H-indol-3-yl)ethyl)-amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)(Cl)Cl>[CH2:14]([N:16]([CH2:17][CH3:18])[C:7](=[O:9])[C:6]1[CH:10]=[C:2]([CH3:1])[N:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH3:15]
Reactant: CCNCC
Reactant: Cc1cc(C(=O)O)cc([N+](=O)[O-])n1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1cc(C)nc([N+](=O)[O-])c1

Procedure:
To a mixture of 1.0 g. of 6-methyl-2-nitroisonicotinic acid, 20 ml. of chloroform and 3 ml. of diethylamine was added 7.0 g. of phosphorus pentoxide with stirring. The resulting mixture was refluxed for 1 hour. After cooling, the chloroform layer was separated and poured into 20 ml. of water. The resulting mixture was neutralized with sodium hydrogencarbonate and the chloroform layer was separated, dried ever anhydrous sodium sulfate and the chloroform was distilled off in vacuo. The residual oil was gradually crystallized and then recrystallized from ethyl acetate - n-hexane to give 0.6 g. of the desired product.
Reaction SMILES: O.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:15]2[CH:16]=[C:17]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36](/[CH:40]=[CH:41]/[C:42]5[S:43][CH:44]=[C:45]([CH:47]6[CH2:50][CH2:49][CH2:48]6)[N:46]=5)[CH:35]=4)=[O:32])=[C:25]([CH:29]=3)[C:26](O)=[O:27])[S:18][C:14]=2[N:13]2[C:51]([CH3:54])=[N:52][N:53]=[C:12]2[CH2:11][N:10]=1.Cl.C(N=C=[N:60][CH2:61][CH2:62][CH2:63]N(C)C)C.C(N)C=C>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:15]2[CH:16]=[C:17]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36](/[CH:40]=[CH:41]/[C:42]5[S:43][CH:44]=[C:45]([CH:47]6[CH2:48][CH2:49][CH2:50]6)[N:46]=5)[CH:35]=4)=[O:32])=[C:25]([C:26]([NH:60][CH2:61][CH:62]=[CH2:63])=[O:27])[CH:29]=3)[S:18][C:14]=2[N:13]2[C:51]([CH3:54])=[N:52][N:53]=[C:12]2[CH2:11][N:10]=1
Reactant: Cc1nnc2n1-c1sc(CCc3ccc(CC(=O)Nc4cccc(/C=C/c5nc(C6CCC6)cs5)c4)c(C(=O)O)c3)cc1C(c1ccccc1Cl)=NC2
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C=CCN
Solvent: ClCCl
Product: C=CCNC(=O)c1cc(CCc2cc3c(s2)-n2c(C)nnc2CN=C3c2ccccc2Cl)ccc1CC(=O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.8 %

Procedure:
A mixture of 0.1 g (0.13 mmol) of (E)-5-[2-[4-(2-chlorophenyl)-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]ethyl]-2-[2-[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenylamino]-2-oxoethyl]-benzoic acid monohydrate, 0.03 g (0.16 mmol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride, 0.02 mL (4 mmol) of allylamine and 15 mL of dry CH2Cl2 was stirred at room temperature under nitrogen for 18 hours and concentrated to dryness. The residue was purified by thick layer chromatography using ethyl acetate/CH3OH (5:1) as the eluent. The product was isolated and partitioned between CH2Cl2 and dilute NH4OH. The organic phases were concentrated and the residue triturated with hot ethyl acetate and filtered. The filtrates were concentrated and the solid triturated with diethyl ether and filtered to give 60 mg (57%) of (E)-4-[ 2-[4-(2-Chlorophenyl)-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepin-2-yl]ethyl]-N-[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]-phenyl]-2-[(2-propenylamino)carbonyl]benzeneacetamide as a tan powder: mp 127°-132° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Si](Cl)(Cl)(Cl)Cl.[C:10]([C:12]1[C:13]([CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[C:14]([C:23]([NH2:25])=O)[S:15][C:16]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)#[N:11].O>C(#N)C.CCOC(C)=O>[N:17]1([C:16]2[S:15][C:14]([C:23]3[NH:25][N:3]=[N:2][N:1]=3)=[C:13]([CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[C:12]=2[C:10]#[N:11])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: N#Cc1c(N2CCOCC2)sc(C(N)=O)c1Cc1ccc2ccccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1c(N2CCOCC2)sc(-c2nnn[nH]2)c1Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20.9 %

Procedure:
To a mixture of sodium azide (153 mg, 2.35 mmol) in acetonitrile (2.50 mL) in a 20 mL microwave tube was added silicon(IV) chloride (89.9 uL, 0.783 mmol). The mixture was stirred at rt under an atmosphere of Nitrogen for 20 min, then 4-cyano-5-(morpholin-4-yl)-3-(2-naphthylmethyl)thiophene-2-carboxamide (197 mg, 0.522 mmol) was added. The tube was sealed and the reaction was heated to 90° C. for 12 hrs. The mixture was cooled and distributed between water and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layer was washed with brine, dried, and concentrated to provide a purple syrup. Purification on HPLC (reverse phase, AA) provided 2-(morpholin-4-yl)-4-(2-naphthylmethyl)-5-(1H-tetrazol-5-yl)thiophene-3-carbonitrile as a yellow solid (44 mg, 20.9% yield). LCMS: (AA) ES+ 403; 1H NMR (400 MHz, MeOD) δ 7.78-7.73 (m, 1H), 7.73-7.67 (d, J=7.8 Hz, 2H), 7.67-7.61 (s, 1H), 7.42-7.36 (m, 2H), 7.36-7.30 (m, 1H), 4.63-4.57 (s, 2H), 3.85-3.76 (t, J=4.9 Hz, 4H), 3.57-3.48 (t, J=4.8 Hz, 4H).