Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.CN1CCNCC1.N1C=CN=C1.C([O:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[C:27]([CH3:32])[CH:26]=2)=[O:22])C.C(CNC([C@@H]1CCCC[C@@H]1NC(C1NC2C(C=1)=CC=C(CN1C=CC=N1)C=2)=O)=O)#N.C(CNC([C@@H]1CCCC[C@@H]1NC(C1NC2C(C=1)=CC=C(CN1CCN(C)CC1)C=2)=O)=O)#N>>[N:1]1([CH2:32][C:27]2[CH:26]=[C:25]3[C:30]([CH:31]=[C:23]([C:21]([OH:22])=[O:20])[NH:24]3)=[CH:29][CH:28]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCOC(=O)c1cc2ccc(C)cc2[nH]1
Reactant: c1cn[nH]c1
Agent: CN1CCN(Cc2ccc3cc(C(=O)N[C@H]4CCCC[C@H]4C(=O)NCC#N)[nH]c3c2)CC1
Agent: CN1CCNCC1
Agent: N#CCNC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccc(Cn3cccn3)cc2[nH]1
Product: O=C(O)c1cc2ccc(Cn3cccn3)cc2[nH]1

Procedure:
Similarly, using pyrazole and 1-methyl-piperazine respectively in place of imidazole in reaction with 6-methyl-1H-indole-2-carboxylic acid ethyl ester, the compounds 6-pyrazol-1-ylmethyl-1H-indole-2-carboxylic acid and 6-(4-methyl-piperazin)-1-ylmethyl-1H-indole-2-carboxylic acid were prepared. These acids in turn were used to make 6-pyrazol-1-ylmethyl-1H-indole-2-carboxylic acid [(1S,2R)-2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide and 6-(4-methyl-piperazin-1-ylmethyl)-1H-indole-2-carboxylic acid [(1S,2R)-2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide using the coupling procedure of Example 10.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3]1.Cl[C:12]([S:14]Cl)=[O:13]>>[F:1][C:2]1([F:10])[CH2:6][CH2:5][CH:4]([C:7]2[O:8][C:12](=[O:13])[S:14][N:9]=2)[CH2:3]1
Reactant: NC(=O)C1CCC(F)(F)C1
Reactant: O=C(Cl)SCl
Product: O=c1oc(C2CCC(F)(F)C2)ns1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed 3,3-difluorocyclopentane-1-carboxamide (1.5 g, 10.06 mmol, 1.00 equiv), tol (30 mL), chloro(chlorosulfanyl)methanone (2.6 g, 19.85 mmol, 1.97 equiv). The resulting solution was stirred for overnight at 100° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10-1/30). This resulted in 300 mg of 5-(3,3-difluorocyclopentyl)-2H-1,3,4-oxathiazol-2-one as brown oil.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5](Cl)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.CC[O:24]CC>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH:4]([CH:1]([CH3:3])[CH3:2])[C:5]([OH:24])=[O:6])=[CH:9][CH:10]=1
Reactant: CCOCC
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution was prepared by admixing 3.0 grams (0.014 mole) of 6-(phenoxy)picolinalcohol, 3.5 grams (0.015 mole) of 2-isopropyl-2-(4-chlorophenyl)acetic acid chloride 10 milliliters of triethylamine and 100 milliliters of dry ether. The reaction mixture was agitated at room temperature for 1 hour. The resulting reaction product mixture was successively washed with dilute hydrochloric acid, dilute sodium hydroxide, dried over anhydrous magnesium sulfate, filtered through silica gel and concentrated to give 5.3 grams of the desired 4-chloro-α-(1-methylethyl)benzeneacetic acid:(6-phenoxy-2-pyridinyl)methyl ester. The product, a viscous yellow oil, had a refractive index of 1.5664 and the structure of the product was confirmed by NMR. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 68.83, 5.19 and 3.10 percent, respectively, as compared with the theoretical contents of 69.78, 5.60 and 3.54 percent, respectively, as calculated for the above named compounds (Compound No. 2).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1cccc(Cl)c1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cccc(Cl)c1Cl)C2
Yield: 213.3 %

Procedure:
A mixture of 7-(2,3-dichlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (306 mg), aminoguanidine hydrochloride (122 mg) and concentrated hydrochloric acid (0.2 ml) in ethanol (4 ml) was refluxed for 1 hour. The reaction solution was cooled, and precipitated crystals were filtered, washed with ethanol and dried to give 7-(2,3-dichlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 62) (425 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH2:13][CH2:14][C:15]#[N:16]>>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:16][CH2:15][CH2:14][C:13]#[N:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: N#CCCN
Product: N#CCCNS(=O)(=O)c1cccc(Br)c1
Yield: 55.9 %

Procedure:
Prepared by general procedure III from 3-Bromobenzenesulfonyl chloride (10.0 g, 38 mmol) and 3-aminopropanonitrile (2.96 g, 42 mmol) to give the title compound (6.14 g, 55%) of an off-white solid. MS (ISP) 308.1 [(M+NH4)+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[C:34]([CH3:35])=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][N:27]=4)[CH2:22][C@H:21]3[CH3:36])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:37]O>OS(O)(=O)=O>[CH3:37][O:31][C:30](=[O:32])[C:29]1[CH:33]=[C:34]([CH3:35])[C:26]([N:23]2[CH2:24][CH2:25][N:20]([C:10]3[CH:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:13]=[C:12]([N:14]4[CH2:18][CH2:17][CH2:16][CH:15]4[CH3:19])[N:11]=3)[C@H:21]([CH3:36])[CH2:22]2)=[N:27][CH:28]=1
Reactant: Cc1cc(C(=O)O)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCCC3C)n2)[C@H](C)C1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCCC4C)n3)[C@H](C)C2)c(C)c1
Temperature: 25 °C

Procedure:
Reflux a solution of 6-{4-[6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-nicotinic acid (120 mg, 0.245 mmol) and 2 drops of concentrated H2SO4 in MeOH for 4 h. Cool to room temperature, concentrate, and partition between saturated NaHCO3 and EtOAc. Dry the solution (Na2SO4), concentrate under reduced pressure. Purify the residue by flash column chromatography eluting with EtOAc-Hexanes (1:4) to afford the title ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C@@H:8]2[O:30][C@H:29]([CH2:31][O:32]C(=O)C3C=CC=CC=3)[C@@H:19]([O:20]C(=O)C3C=CC=CC=3)[C@H:9]2[O:10]C(=O)C2C=CC=CC=2)[C:4](=[O:41])[C:3]=1[Br:42].C[O-].[Na+]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C@@H:8]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:19]([OH:20])[C@H:9]2[OH:10])[C:4](=[O:41])[C:3]=1[Br:42]
Reactant: Nc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)c1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)c1Br
Reaction time: 1 h

Procedure:
A solution of 3.52 g (5.6 mmol) of 4-amino-3-bromo-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2(1H)-pyridinone and 0.556 mmol of sodium methoxide in 50 ml of methanol was stirred at room temperature for 24 hours. At the end of this time, 0.88 g of methanol-washed IRC-50 ion exchange resin (Dow Chemical Co., Midland, Mich., USA) in the hydrogen ion form were added to the solution, and the resulting mixture was stirred for one hour.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[C:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][N:26]1[C:30]([CH3:31])=[C:29]([S:32](Cl)(=[O:34])=[O:33])[C:28]([CH3:36])=[N:27]1.C(N(CC)CC)C>>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:20][CH2:21][N:22]([S:32]([C:29]3[C:28]([CH3:36])=[N:27][N:26]([CH3:25])[C:30]=3[CH3:31])(=[O:33])=[O:34])[CH2:23][CH2:24]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1nn(C)c(C)c1S(=O)(=O)Cl
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3=CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(C)c1S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1

Procedure:
Following the general procedure in example 267, 5-phenyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole-7-carboxamide (32 mg, 0.1 mmol), 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride (24.4 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.3 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (9 mg, 18%).
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[N+:9]([C:12]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:35])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])([O-:11])=[O:10]>CN(C)C=O>[N+:9]([C:12]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])=[CH:24][C:23]=2[Cl:35])=[CH:17][C:13]=1[C:14]([O:16][CH3:3])=[O:15])([O-:11])=[O:10]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
390 mg (2.76 mmol) of methyl iodide and 320 mg (2.3 mmol) of powdered potassium carbonate were added to 940 mg (2.3 mmol) of 2-nitro-5-(2-chloro-4-pentafluoroethylphenoxy)benzoic acid in 30 ml of dimethylforamide (freshly eluted through neutral alumina). After 1 hour, the mixture was poured into 300 ml of water, extracted with ether, the ether layer was washed with saturated sodium chloride solution, then dried and evaporated to 820 mg of light yellow oil (84%) diphenyl ether methyl benzoate having the following elemental analysis, calculated (found): C: 45.14 (47.54); H: 2.13 (2.69); Cl: 8.33 (6.19); F: 22.31 (21.26); N: 3.29 (2.72); O: 18.79.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>[Cl-].[NH4+].C(Cl)Cl>[N:9]1([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: C1COCCN1
Reactant: Nc1cccc(Cl)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Nc1cccc(N2CCOCC2)n1
Temperature: 200 °C

Procedure:
6-Chloropyridin-2-amine (244 mg, 1.90 mmol) and morpholine (0.827 mL, 9.49 mmol) were combined and heated for 2 hr at 200° C. via microwave irradiation. The reaction mixture was diluted with saturated aqueous ammonium chloride and DCM. The organics were separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-80% acetone/hexanes, linear gradient) to afford 6-(morpholin-4-yl)pyridin-2-amine. MS ESI calc'd. for C9H14N3O [M+H]+ 180. found 180. 1H NMR (500 MHz, CDCl3) δ 7.29 (t, J=7.9 Hz, 1H), 5.99 (d, J=8.1 Hz, 1H), 5.91 (d, J=7.8 Hz, 1H), 3.82-3.75 (m, 4H), 3.46-3.38 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C@H:6]([CH3:13])[CH2:5]2.[H-].[Na+].[CH3:16]I.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:16])[C@H:6]([CH3:13])[CH2:5]2
Reactant: CI
Reactant: C[C@@H]1Cc2cc(Br)ccc2C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1Cc2cc(Br)ccc2C(=O)N1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
426 mg (1.7 mmol) (R)-6-bromo-3-methyl-3,4-dihydro-2H-isoquinolin-1-one are dissolved in 3 ml DMF and at 0° C. combined with 80 mg (2 mmol) sodium hydride (60% in mineral oildispersion). After 10 minutes 122 μl (1.9 mmol) methyl iodide are added dropwise, and the mixture is stirred for 16 hours at RT. Then the reaction mixture is mixed with water and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. The residue is purified by flash chromatography on silica gel (eluant DCM/MeOH 20:1).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:58]/[O:59][CH2:60][C:61]([O:63][CH:64]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[O:62])/[C:27]([NH:29][C@@H:30]2[C:56](=[O:57])[N:32]3[C:33]([C:44]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=4)=[S:45])=[C:34]([CH2:37][CH2:38][O:39]C(=O)CCl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC(N)=S>CN(C)C(=O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:58]/[O:59][CH2:60][C:61]([O:63][CH:64]([C:71]2[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=2)[C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[O:62])/[C:27]([NH:29][C@@H:30]2[C:56](=[O:57])[N:32]3[C:33]([C:44]([O:46][CH2:47][C:48]4[CH:49]=[CH:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=4)=[S:45])=[C:34]([CH2:37][CH2:38][OH:39])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(COC(=S)C2=C(CCOC(=O)CCl)CS[C@@H]3[C@H](NC(=O)/C(=N\OCC(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Agent: NC(N)=S
Solvent: CC(=O)N(C)C
Product: COc1ccc(COC(=S)C2=C(CCO)CS[C@@H]3[C@H](NC(=O)/C(=N\OCC(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 67.6 %

Procedure:
(d-1) To a solution of 1.24 g (1.12 mM) of p-methoxybenzyl 7β-{α-(2-tritylaminothiazole-4-yl)-α-[(Z)-benzhydryloxycarbonylmethoxyimino]acetamido}-3-(2-chloroacetyloxy)ethylthio-3-cephem-4-carboxylate, in 7 ml of N,N-dimethylacetamide was added 171 mg (2.24 mM) of thiourea, and the mixture was stirred at 20° C. for 16 hours. Then, the reaction mixture was poured into 20 ml of ice-water and extracted with 30 ml of ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution (10 ml×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent; benzene:acetone=5:1), and then crystallized from diethyl ether to give 780 mg of p-methoxybenzyl 7β-{α-(2-tritylaminothiazole-4-yl)-α-[(Z)-benzhydryloxycarbonylmethoxyimino]acetamido}-3-(2-hydroxy)ethylthio-3-cephem-4-carboxylate
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: CC#N
Solvent: O
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).
Reaction SMILES: [C:1](O)(=[O:5])[CH2:2][CH2:3][CH3:4].ClCC(OC(=O)CCl)=O.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>ClCC(Cl)(Cl)Cl>[C:1]([C:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][CH:23]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O
Reactant: c1ccc2ccccc2c1
Agent: ClCC(Cl)(Cl)Cl
Agent: O=C(CCl)OC(=O)CCl
Product: CCCC(=O)c1cccc2ccccc12
Temperature: 115 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
In 50 ml of tetrachloroethane were dissolved 4.41 g (0.05 mole) of butyric acid and 9.83 g (0.0575 mole) of monochloroacetic anhydride. To the resulting solution were added 7.69 g (0.06 mole) of naphthalene and 0.9 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 115° C. for 8 hours. After completion of the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 4.26 g of butyrylnaphthalene.
Reaction SMILES: [CH:1]([P:4]1(=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]1[Si](C)(C)C)([CH3:3])[CH3:2]>CO>[CH:1]([P:4]1(=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)P1(=O)c2ccccc2CN1[Si](C)(C)C
Solvent: CO
Product: CC(C)P1(=O)NCc2ccccc21
Reaction time: 40 h

Procedure:
The 1-isopropyl-2-trimethylsilyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide was added to 50 ml. of methanol and allowed to stand for 40 hours. The methanol was removed under vacuum and the resulting residue was slurried in ether to yield 1-isopropyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide as a white solid. A second crop was obtained to give a total yield of 2.35 g (20% yield) of 1-isopropyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide having a melting point of 149°-151° C. and the following analysis:
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Br:12]Br.O>C(O)(=O)C>[Br:12][C:7]1[CH:6]=[CH:5][C:4]([O:8][CH3:9])=[CH:3][C:2]=1[C:1]([OH:11])=[O:10]
Reactant: BrBr
Reactant: COc1cccc(C(=O)O)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Br)c(C(=O)O)c1
Yield: 79 %

Procedure:
To a mixture of m-anisic acid (250 g, 1.67 mol) in acetic acid (1 L) was added bromine (85 mL) and then water (1 L). The mixture was heated to reflux, cooled in an ice bath and the product which precipitated was collected by filtration and washed with water to afford 305.7 g (79%) of 2-bromo-5-methoxybenzoic acid, m.p. 154°-156° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH2:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:33]([N:40]=[C:41]=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH:25][C:41](=[O:42])[NH:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)NCc1ccccc1
Yield: 48 %

Procedure:
A solution of 0.28 g of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester, and 0.083 g of benzyl isocyanate in 5 ml of dichloromethane was stirred at 20° C. for 2 hours. The solvent was then removed by evaporation and the residue was triturated with diethyl ether to give 0.174 g of N-[3(S)-[[N-(benzylcarbamoyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester as a white solid; MS: m/e 582 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:11]([O:13][C:14](=O)[CH3:15])=[CH2:12]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:12]=[CH:11][O:13][CH:14]=[CH:15][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C=COC(C)=O
Product: O=[N+]([O-])c1ccc(C=COC=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
104 g (0.75 Mol) of 4-nitrophenol are dissolved in 420 ml (4.5 Mol) acetic acid vinyl ester. After washing with nitrogen, successively 3.0 g mercury acetate and 0.2 ml BF3 -etherate are added. The reaction mixture is stirred for 4 hours at 50° C. After cooling, 2 g sodium acetate are added, evaporated, and the residue then dissolved in ether. There follows washing three times with 2 n-caustic soda, three times with water, drying and evaporation. The residue is recrystallized from ether. 65 g (52% of theoretical amount) of 4-nitrophenylvinylether are obtained, with a melting point of 59°-61° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1>N1C=CC=CC=1>[C:15]1([CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([NH:7][C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH2:9][CH2:10]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)NC1CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 62.1 %

Procedure:
Ethyl chloroformate (30 g, 0.276 mol) was added at 0° C. to 4-amino-1-phenylmethylpiperidine (50 g, 0.262 mol) in pyridine (600 mL). After the addition, the mixture was kept at room temperature overnight, and the pyridine was then evaporated. The residue was extracted with methylene chloride; and the resulting solution washed with water, dried over sodium sulfate, and the methylene chloride evaporated to dryness. The residue was dissolved in diisopropyl ether. A white product precipitated, which was isolated by filtration to yield 42.71 g (62%) of ethyl (1-phenylmethyl-4-piperidyl)-carbamate, m.p. 100° C.