Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:18][CH3:19])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13](OCC)=[O:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].O.[NH2:21][NH2:22]>C(O)C>[CH2:1]([C:3]1[C:4]([O:18][CH3:19])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]([NH:21][NH2:22])=[O:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: CCOC(=O)c1cn2c(C)c(CC)c(OC)nc2n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCc1c(OC)nc2nc(C(=O)NN)cn2c1C
Yield: 86 %

Procedure:
A solution of 10.0 g of ethyl 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carboxylate (published UK Patent Application No. 2,128,989) and 20 ml of hydrazine hydrate in 150 ml of ethanol was refluxed for 4 hours. Most of the ethanol was evaporated and 100 ml of water were added. The resulting precipitate was filtered, washed with water, then ether and dried under vacuum over P2O5 to obtain 8.15 g of 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carbohydrazide (86% yield) as an off-white solid.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][C:3]([OH:5])=O.[C:8](=[O:13])([O:10][CH2:11][CH3:12])[NH2:9].P(Cl)(Cl)(Cl)=O>O>[C:3]([NH:9][C:8]([O:10][CH2:11][CH3:12])=[O:13])(=[O:5])[CH2:2][C:1]([NH:9][C:8]([O:10][CH2:11][CH3:12])=[O:13])=[O:7]
Reactant: O=C(O)CC(=O)O
Reactant: CCOC(N)=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)NC(=O)CC(=O)NC(=O)OCC
Temperature: 80 °C
Yield: 43.1 %

Procedure:
With a mortar and pestle 10.40 g (0.100 mole) of malonic acid and 18.00 g (0.210 mole) of ethyl carbamate were ground to a fine powder. This powder was placed in a flask, and 16.0 mL (0.167 mole) of phosphorus oxychloride was added. This mixture was heated at 80° C. until the evolution of gas ceased. After this reaction mixture had cooled to ambient temperature, 210 mL of water was added. When the stiff glassy mixture became fluid, it was extracted with ethyl acetate. The combined extracts were washed in succession with saturated aqueous solutions of sodium bicarbonate and sodium chloride and were then dried over anhydrous magnesium sulfate and filtered. The solution was filtered through a short column of silica gel, which was eluted with ethyl acetate. The solvent was then evaporated under reduced pressure, leaving a crystalline mass of malonyidiurethane weighing 10.62 g. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[C:9]([CH2:12][O:13][CH3:14])[NH:10][CH:11]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:14][O:13][CH2:12][C:9]1[N:8]2[C:3](=[S:2])[NH:4][N:5]=[CH:6][C:7]2=[CH:11][N:10]=1
Reactant: COCc1nc(C=NNC(=S)SC)c[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COCc1ncc2cn[nH]c(=S)n12

Procedure:
A miture of 62.4 gm. of 3-[2-(methoxymethyl)-4-imidazolyl]methylene dithiocarbazic acid methyl ester and 250 ml. of diphenyl ether is reacted as described in Example 58 giving the desired product, m.p. 219.5°-223° C.
Reaction SMILES: [OH-].[Na+].Cl.[O:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16]Cl)[C:11]=2[Cl:18])[CH2:6][CH2:5]1.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]2[N:25]=[C:26]([SH:28])[NH:27][C:23]=2[CH:22]=1>>[O:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:28][C:26]3[NH:25][C:24]4[CH:29]=[CH:30][C:21]([O:20][CH3:19])=[CH:22][C:23]=4[N:27]=3)[C:11]=2[Cl:18])[CH2:6][CH2:5]1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: ClCc1nccc(N2CCOCC2)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2[nH]c(SCc3nccc(N4CCOCC4)c3Cl)nc2c1
Reaction time: 8 h

Procedure:
5 N Sodium hydroxide (5.68 ml) was added dropwise to a stirred solution of 4 -morpholino-3 -chloro-2 -chloromethylpyridine hydrochloride (3.66 g) and 5 -methoxy-2 -mercaptobenzimidazole (2.33 g). After standing overnight the solution was evaporated under reduced pressure and the residue triturated with water. The solid thus obtained was recrystallised from ethanol to give 2 -(4 -morpholino-3 -chloro-2 -pyridyl-methylthio)-5 -methoxy-(1H)-benzimidazole, 4.38 g, m.p. 124°-25°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl[CH2:11][CH2:12][CH2:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl.CCN(C(C)C)C(C)C>[O:15]=[S:14]1(=[O:16])[CH2:13][CH2:12][CH2:11][N:1]1[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: N#Cc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cccc(N2CCCS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 g of 3-Aminobenzonitril were dissolved in 10 ml DCM and 2.2 ml of DIPEA. 1.3 ml of 3-Chloro-propane-1-sulfonyl chloride were added and the reaction mixture stirred at rt overnight. The organic layer was evaporated, the crude taken up in DMF and 1.5 ml DBU added. The reaction mixture was stirred at rt overnight. DCM was added and the organic phase washed with water. The organic layer was separated, dried over Na2SO4 and evaporated. MS(ISO): 232.2 (MH+)
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=O)[C:7](=[O:14])[N:8]3[CH3:13])[CH2:3][CH2:2]1.O.NN>ClCCl.O>[CH:1]1([C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[CH2:6][C:7](=[O:14])[N:8]3[CH3:13])[CH2:3][CH2:2]1
Reactant: CN1C(=O)C(=O)c2c(C3CC3)cccc21
Agent: NN
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)Cc2c(C3CC3)cccc21
Temperature: 130 °C
Reaction time: 4 h

Procedure:
4-Cyclopropyl-1-methyl-1H-indole-2,3-dione (1.0 g, 4.2 mmol) was treated with hydrazine hydrate (7.0 mL, 225 mmol). The reaction was heated to 130° C. and stirred for 4 hours, at which time the reaction temperature was elevated to 150° C. for another 1.5 hours. The reaction was then placed at room temperature and cooled by the addition of ice. Once the reaction was cooled to room temperature it was diluted with dichloromethane and water and the layers were separated. The aqueous layer was extracted an additional two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 0 to 60%) to afford 4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) ink 188.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:32]=[C:31]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:28]=[C:27]([C:26]2[CH:29]=[CH:30][C:31]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:32][C:25]=2[Cl:24])[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Reactant: N#Cc1ccc(Oc2ccccc2)cc1Cl
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Oc2ccccc2)cc1Cl
Temperature: 140 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (3.30 g), 2-chloro-4-phenoxybenzonitrile (2.30 g), anhydrous iron (III) chloride (1.60 g) and o-dichlorobenzene (10 ml) is stirred at an oil bath temperature of 140° C. for 1 hour. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochrolic acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.15 g of desired compound (melting point: 135.0°-140.0° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C1COCC1.[C:14]1(C)[CH:19]=[CH:18]C=[CH:16][CH:15]=1>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:18][CH2:19][C:14]#[C:15][CH3:16])=[CH:3][CH:4]=1
Reactant: Cc1ccccc1
Reactant: Brc1ccc(Br)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC#CCCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
This reagent was gradually (for about one hour), dropwise added to a mixture consisting of p-dibromobenzene (150 mmol), bis(triphenylphosphine) Ni(II) dichloride (7.5 mmol) and THF (150 ml), at 0° C. or lower, followed by heating the mixture under reflux with stirring, allowing the mixture to cool down to room temperature, adding toluene (200 ml) and water (200 ml) to the reaction solution, sufficiently stirring the mixture, three times washing the organic layer with a brine (200 ml), drying over anhydrous magnesium sulfate, distilling off the solvent under reduced pressure at 30° C. or lower, purifying the residue subjecting to silica gel column chromatography (eluent solvent: heptane/toluene mixture) and further distilling under reduced pressure to obtain oily 4-bromo-1-(3pentynyl)benzene (61 mmol).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]2)[N:6]=1.[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1B(O)O>>[NH2:33][C:4]1[S:3][C:2]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[C:42]([F:53])([F:52])[F:41])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]1)=[O:32]
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4ccccc4C(F)(F)F)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-(trifluoromethyl)phenyl)boronic acid gave 220. 1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 7.93-7.86 (m, 2H), 7.81-7.63 (m, 3H), 7.44 (s, 2H), 5.04 (t, J=5.1 Hz, 1H), 3.73-3.57 (m, 5H), 3.29-3.15 (m, 2H), 2.74 (s, 3H), 2.48-2.35 (m, 1H), 1.65-1.47 (m, 3H), 1.41 (br, 2H). LCMS (ES+) m/z 511 (M+1).
Reaction SMILES: O[C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][C:5]1[C:6]([CH:16]([OH:32])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=2)=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([OH:15])[CH:9]=[CH:8]2>Cl.C(Cl)Cl>[N:26]1([CH2:25][CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:17]([CH:16]3[C:6]4[C:7]5[CH:8]=[CH:9][C:10]([OH:15])=[CH:11][C:12]=5[CH:13]=[CH:14][C:5]=4[CH2:4][C:3]4[CH:2]=[CH:36][CH:35]=[CH:34][C:33]=4[O:32]3)=[CH:18][CH:19]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Oc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(Cc3ccccc3O)ccc2c1
Agent: Cl
Solvent: ClCCl
Product: Oc1ccc2c3c(ccc2c1)Cc1ccccc1OC3c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
Dissolve 6-(2-hydroxy-benzyl)-5-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-naphthalen-2-ol (80 mg, 0.17 mmol) in HCl solution (20% 1M aq. HCl in THF). Stir at r.t. for 2 h and warm gently for 10 min. Dilute with CH2Cl2, wash with sat. NaHCO3, water and brine, dry over MgSO4, filter and concentrate. Purify the crude product by flash chromatography (0–5% (2M NH3 in MeOH)/CH2Cl2) to afford 13-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-7,13-dihydro-12-oxa-benzo[4,5]cyclohepta[1,2-a]naphthalen-3-ol (43 mg, 56%).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12.[CH3:25][S:26]SC>CCCCCC.O1CCCC1>[CH3:25][S:26][CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12
Reactant: CSSC
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(C)=C21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(CSC)=C21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The starting material is prepared as follows: 36.4 ml of 2.5 M n-butyl lithium in hexane are added dropwise under nitrogen and at room temperature to the stirred suspension of 7.8 g of 1-methyl-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]-azepin-2-one in 70 ml of anhydrous tetrahydrofuran. The mixture is stirred at room temperature for 45 minutes and cooled in a dry ice-acetone bath. The solution of 5.45 ml of dimethyl disulfide in 60 ml of tetrahydrofuran is added dropwise and the mixture stirred with said cooling for 2 hours. It is quenched by the slow addition of 150 ml of water, the mixture is extracted with chloroform, the extract is dried and evaporated. The residue is crystallized from diethyl ether and recrystallized from ethyl acetate, to give the 1-methylthiomethyl-3,4,5,5a,6,7-hexahydro9-methoxy-2H-naphth[1,2-d]azepin-2-one melting at 182°-184°.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][N:7]=1.[C:12]([O:15][CH2:16][C:17]1[CH2:24][S:23][CH:22]2[N:19]([C:20](=[O:26])[CH:21]2[NH2:25])[C:18]=1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:14])[CH3:13].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:12]([O:15][CH2:16][C:17]1[CH2:24][S:23][CH:22]2[N:19]([C:20](=[O:26])[CH:21]2[NH:25][C:9](=[O:11])[CH2:8][N:4]2[CH:5]=[CH:6][N:7]=[C:3]2[S:2][CH3:1])[C:18]=1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:14])[CH3:13]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)C2SC1
Reactant: CSc1nccn1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CSc1nccn1CC(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CSC12
Temperature: 50 °C
Reaction time: 18 h
Yield: 42.6 %

Procedure:
(2-methylthio-imidazol-1-yl)-acetic acid (10.3 g.) is dissolved in dimethylformamide (360 cc.), by heating to 50° C. After cooling, 3-acetoxymethyl-7-amino-2-(tertiary butoxycarbonyl)-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (21.4 g.) and dicyclohexylcarbodiimide (13.5 g.) are added. The reagents are contacted for 18 hours, with stirring, at a temperature of about 20° C., and then the solid is filtered off. The filtrate is taken up in ethyl acetate (2.5 liters) and is washed with a saturated aqueous solution of sodium bicarbonate and then with water. Extraction is then effected using N hydrochloric acid (400 cc.), and the acid aqueous phase is washed with ethyl ether and then brought to pH 8 by adding a 4 N solution of sodium hydroxide. The oil which separates out is extracted with methylene chloride (500 cc.). The methylene chloride extracts are washed with water, dried over sodium sulphate, treated with decolorising charcoal and concentrated to dryness under reduced pressure (20 mm.Hg.). An orange-yellow oily residue (30.2 g.) is obtained and is purified by crystallisation from a mixture of methanol (32 cc.) and isopropyl ether (210 cc.) to give 3-actoxymethyl-2-(tertiary butoxycarbonyl)-7-[(2-methylthio-imidazol-1-yl)-acetamido]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (12.3 g.), m.p. 170° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[C-:17]#[N:18].[Na+]>>[C:9]([C:5]1[CH:4]=[C:3]([CH2:2][C:17]#[N:18])[CH:8]=[CH:7][CH:6]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Product: N#CCc1cccc(C(=O)c2ccccc2)c1

Procedure:
m-(Bromomethyl)benzophenone is reacted with sodium cyanide to form (m-benzoylphenyl)acetonitrile which is reacted with diethyl carbonate in the presence of sodium ethoxide to form sodium salt of ethyl alpha-cyano(m-benzoylphenyl)acetate. The sodium salt is reacted with methyl iodide to obtain ethyl alpha-cyano-alpha-(m-benzoylphenyl)propionate. The resulting ester is hydrolyzed and then subjected to decarboxylation to form alpha-(m-benzoylphenyl)propionitrile. Alkaline hydrolysis of alpha-(m-benzoylphenyl)propionitrile affords alpha-(m-benzoylphenyl)propionic acid. (For details, see British Patent No. 1,164,585).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].Cl[C:7]1(Cl)[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:1][S:2]([N:5]=[C:7]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1)(=[O:4])=[O:3]
Reactant: CS(N)(=O)=O
Reactant: ClC1(Cl)Oc2ccccc2O1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N=c1oc2ccccc2o1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
53.4 g of methanesulfonamide and 89.4 g of 2,2-dichloro-1,3-benzodioxole were heated under reflux with 400 ml of anhydrous ethyl acetate for 7 hours. After cooling, the solvent was removed by distillation under reduced pressure. To the residue thus obtained was added 200 ml of benzene, and the mixture was refluxed for 10 minutes and then cooled slowly to room temperature with stirring. The crystals deposited were collected by filtration and washed with benzene, water and 2-propanol in this order to obtain 83 g (yield: 83%) of 2-methanesulfonylimino-1,3-benzodioxole.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[NH2:11][C@@H:12]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14]>>[N:2]1([CH2:7][C:8]([NH:11][C@@H:12]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)=[O:14])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccccc2)cc1
Agent: Cl
Product: O=C(Cn1cncn1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccccc2)cc1
Yield: 82 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1,2,4)-triazol-1-ylacetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-phenoxyphenyl)propanamide, gave Compound 146, (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-3-(benzyloxy)-N-(4-phenoxyphenyl)propanamide (106 mg, 82%). 1H-NMR (400 MHz, CDCl3): σ 8.69 (s, 1H), 8.41 (br s, 1H), 7.64 (d, 1H), 7.58 (d, 1H), 7.44 (d, 2H), 7.39-7.25 (m, 6H), 7.10-7.06 (m, 2H), 6.99-6.97 (m, 4), 5.03-4.99 (m, 1H), 4.76 (d, 1H), 4.65 (d, 1H), 4.25 (dd, 1H), 3.78 (dd, 1H). MS (EI) for C26H25N5O4. found 472.1 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[C:28](O)(=[O:32])[CH:29]([CH3:31])[CH3:30]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: CC(C)C(=O)O
Product: CC(C)C(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F) and isobutyric acid followed by deprotection of the intermediate yielded the title compound as a colorless oil. MS (ESI): m/z=349.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)=[CH:28][CH:27]=1)[C:20](=O)[CH:21]([CH3:23])[CH3:22])C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]3[CH:36]=[CH:35][CH:34]=[N:33]3)=[CH:28][CH:27]=1)=[C:20]([CH:21]([CH3:23])[CH3:22])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCOC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)C(C)C
Product: COC(=O)COc1ccc(F)c2[nH]c(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(=O)c12

Procedure:
The title compound was prepared by the method of Preparation 1c using (3-amino-4-fluorophenoxy)acetic acid methyl ester and 4-methyl-3-oxo-2-(4-pyrazol-1-ylbenzyl)pentanoic acid ethyl ester.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[F:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>C(OC(C)C)(=O)C>[F:29][C:30]1[CH:31]=[C:32]([NH:33][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:34]=[CH:35][CH:36]=1
Reactant: Nc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(F)c2)CC1
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (NaBH(OAc)3 74 g, 0.35 mol) was added to a stirred solution of 1,1-Dimethylethyl 4-oxo-1-piperidinecarboxylate (50 g, 0.25 mol) and 3-Fluoroaniline (24 ml, 0.25 mol) in isopropyl acetate (1-PrOAc, 500 ml) and the slurry stirred overnight.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[C:18]1([CH3:26])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][NH2:25].[OH-].[Na+].C(OCC)(=O)C>CCCCCC>[NH2:2][C:1]1[N:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH3:26])[N:25]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Reactant: Cc1ccccc1NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(-c2nn(-c3ccccc3C)c(N)c2C(N)=O)cc1
Yield: 4.9 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl) acrylamide (464 mg, 2.0 mmol), 2-tolylhydrazine hydrochloride (350 mg, 2.2 mmol) and sodium hydroxide (88 mg, 2.2 mmol) following the procedure used for the compound of Example 12. The crude product was subjected to column chromatography (SiO2, 75% ethyl acetate in hexane) to give the title compound as a yellow solid (30 mg) m.p. 133-135°. δH (CDCl3) 7.52 (2H, d, J 8.1 Hz), 7.38 (4H, m), 7.28 (2H, d, J 7.4 Hz), 5.40 (4H, m), 2.40 (3H, s) and 2.23 (3H, s).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[S:8](Cl)(Cl)=[O:9].O>C(OCC)C>[CH3:1][C:2]1([CH3:7])[CH2:5][O:6][S:8](=[O:9])[O:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(CO)CO
Solvent: CCOCC
Solvent: O
Product: CC1(C)COS(=O)OC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
Step A A mixture of 2,2-dimethyl-propane-1,3-diol (Aldrich) (5 g, 48 mmol) in anhydrous ethyl ether (100 mL) at 0° C. was added thionyl chloride (8.7 mL, 120 mmol). The reaction mixture was stirred at 0° C. for 2 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with ethyl ether. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, concentrated to give 5,5-dimethyl-[1,3,2]dioxathiane 2-oxide as a light pink oil (4.8 g, 82%).
Reaction SMILES: C(S[C:6](=[O:19])[CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)[C:8](=[O:10])[CH3:9])(C)(C)C.[NH2:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=1[Cl:27]>>[Br:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH:7]([C:8](=[O:10])[CH3:9])[C:6]([NH:20][C:21]2[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=2[Cl:27])=[O:19])=[CH:17][CH:16]=1
Reactant: CC(=O)C(Cc1ccc(Br)cc1)C(=O)SC(C)(C)C
Reactant: Nc1cc(O)ccc1Cl
Product: CC(=O)C(Cc1ccc(Br)cc1)C(=O)Nc1cc(O)ccc1Cl

Procedure:
The title compound was prepared by the method of Preparation 11b using 2-(4-bromobenzyl)-3-oxothiobutyric acid S-tert-butyl ester and 3-amino-4-chlorophenol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:22]2[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)cn1

Procedure:
A mixture of 17 mmol methyl-5-chloropyrazine-2-carboxylate, 18 mmol of N-BOC-piperazine and 20 mmol of K2CO3 in 20 ml of acetonitrile was heated under reflux for 3 hours. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The title compound was recrystallized from ethyl acetate to yield a colorless solid. MS (m/e): 323.4 (MH+, 100%)