Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:42]([C:43]([O:45]C)=[O:44])=[C:11]3[CH:12]=[C:13]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:41])[NH:31][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)([CH3:34])[CH3:33])[CH:25]=4)[C:14]([N:16]([CH2:21][CH2:22][OH:23])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C1COCC1.[OH-].[Li+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:42]([C:43]([OH:45])=[O:44])=[C:11]3[CH:12]=[C:13]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:41])[NH:31][C:32]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)([CH3:34])[CH3:33])[CH:25]=4)[C:14]([N:16]([CH2:21][CH2:22][OH:23])[S:17]([CH3:20])(=[O:18])=[O:19])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(CCO)S(C)(=O)=O)c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1cccc(-c2cc3c(C(=O)O)c(-c4ccc(F)cc4)nn3cc2N(CCO)S(C)(=O)=O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution containing methyl 2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.021 g, 0.33 mmol), THF (0.20 mL) and methanol (0.13 mL) was added aqueous lithium hydroxide (0.081 mL, 2.0 M). The solution was maintained at room temperature for 20 h, then at 45° C. for 8 h. The solution was adjusted to below pH 4 with aqueous HCl (0.21 mL, 1.0 N) and extracted with ethyl acetate (2×0.50 mL). The combined organic portions were washed with brine (0.50 mL) and concentrated to afford 2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid as a light yellow residue which was used without further purification. LCMS: retention time: 1.778 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 u, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% methanol/90% H2O/10 mM TFA and solvent B was 10% H2O/90% methanol/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 631 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.F[C:12]1[CH:20]=[N:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:17]2[CH:18]=[N:19][CH:20]=[CH:12][C:13]=2[C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccncc1F
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2cnccc2C(=O)O)cc1
Yield: 26 %

Procedure:
The title compound was prepared in 26% yield from 4-methoxybenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1H), 7.81 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.29 (d, 2H, J=8.5 Hz), 6.91 (d, 2H, J=8.5 Hz), 4.47 (s, 2H), 3.73 (s, 3H). [M+H] calc'd for C14H14N2O3, 259; found 259.
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].[P:10](=[O:14])([OH:13])([OH:12])[OH:11].C(=O)=O>O>[P:10]([O-:14])([O-:13])([O-:12])=[O:11].[NH2:5][NH:6][C:7]([NH2:9])=[NH2+:8].[NH2:5][NH:6][C:7]([NH2:9])=[NH2+:8].[NH2:5][NH:6][C:7]([NH2:9])=[NH2+:8]
Reactant: O=P(O)(O)O
Reactant: N=C(N)NN
Agent: O=C(O)O
Agent: O=C=O
Solvent: O
Product: NNC(N)=[NH2+]
Product: O=P([O-])([O-])[O-]
Yield: 143 %

Procedure:
Aminoguanidine bicarbonate (38 g, 0.5 mole) was slurried in 150 ml of water and phosphoric acid (59.5 g of 85% H3PO4, 0.5 mole) dropped in causing the evolution of carbon dioxide. After stirring about a half hour a clear solution resulted. Approximately one half the solvent was vacuum stripped and the remaining solution cooled to precipitate the product. The solids were filtered, ethanol washed and vacuum dried to give 76.3 g of product melting 140.5°-142.5° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[O:11][C:12]([CH:27]([CH3:29])[CH3:28])=[C:13]([CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=2)=[O:18])[N:14]=1.B(Cl)(Cl)Cl.C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[O:11][C:12]([CH:27]([CH3:29])[CH3:28])=[C:13]([CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=2)=[O:18])[N:14]=1
Reactant: COc1cc(Cl)ccc1-c1nc(CCC(=O)c2ccc(O)c(C)c2)c(C(C)C)o1
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C(=O)CCc2nc(-c3ccc(Cl)cc3O)oc2C(C)C)ccc1O
Temperature: 0 °C
Reaction time: 72 h
Yield: 64.2 %

Procedure:
The obtained 3-[2-(2-methoxy-4-chlorophenyl)-5-isopropyl-4-oxazolyl]-1-(3-methyl-4-hydroxyphenyl)propan-1-one (621 mg, 1.50 mmol) was suspended in methylene chloride (30 mL) and cooled with ice. To the suspension, a 1M methylene chloride solution of boron trichloride (BCl3) (3.0 mL, 3.00 mmol) was dropwise added for 1 minute. The mixture was allowed to room temperature, stirred for 72 hours, and poured into ice water. Chloroform and saturated sodium hydrogen carbonate were added to the mixture. The organic layer was washed with water, and a saline, dried over anhydrous sodium sulfate. The chloroform was removed under reduced pressure. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (3/1) to give the desired compound (385 mg) as colorless oil (yield 64%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:17][OH:18].C(N(CC)CC)C>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:17][OH:18])[C:5]([O:9][CH3:10])=[C:6]([Cl:8])[N:7]=1
Reactant: OC[C@@H]1CCCN1
Reactant: COc1c(Cl)nc(Cl)nc1Cl
Solvent: CCN(CC)CC
Product: COc1c(Cl)nc(Cl)nc1N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 0.1 %

Procedure:
A mixture of 2,4,6-trichloro-5-methoxy-pyrimidine (1.2 g, 5.62 mmol), (S)-1-pyrrolidin-2-yl-methanol (1.1 mL, 11.3 mmol) and triethylamine (1.08 mL, 7.75 mmol) in IMS (36 mL) was stirred at RT for 20 mins, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 50% ethyl acetate in cyclohexane) affording [(S)-1-(2,6-Dichloro-5-methoxy-pyrimidin-4-yl)-pyrrolidin-2-yl]-methanol (1.08 mg, 70%). LCMS (method A): RT=2.98 min, [M+H]+=278/280.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[C:15]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=3[S:17][CH:18]=2)[C:5]1=[O:24].C(N(CC)CC)C.[C:32]1([S:38]([N:41]=[C:42]=[O:43])(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>O.C(Cl)Cl>[CH3:23][C:22]1[C:15]2[C:14]([CH2:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]([CH2:3][CH2:2][NH:1][C:42]([NH:41][S:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)(=[O:40])=[O:39])=[O:43])[C:5]3=[O:24])=[CH:18][S:17][C:16]=2[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cccc2scc(Cn3c(=O)n(CCN)c4ccccc43)c12
Reactant: O=C=NS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc2scc(Cn3c(=O)n(CCNC(=O)NS(=O)(=O)c4ccccc4)c4ccccc43)c12
Reaction time: 2 h
Yield: 76.4 %

Procedure:
1-(2-Amino-ethyl)-3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (28 mg, 0.083 mmol) is added into DCM (1.0 mL) at room temperature and triethylamine (0.014 mL, 0.10 mmol) is added. Then Benzenesulfonyl isocyanate (0.014 mL, 0.10 mmol) is added into the above reaction mixture. After stirring for 2 hr, another 0.014 mL of Benzenesulfonyl isocyanate is added and the mixture is further stirred for 30 min. Then 1.0 mL of 1.0M HCl is added along with 5 mL of water. The mixture is extracted with EtOAc (3×20 mL) and the organic layers are combined, dried (Na2SO4) and concentrated to give crude product. Purification by preparative TLC affords 33 mg (76%) of the title compound. LCMS (ESMS): m/z 521.17 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH3:19]O>>[OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:19])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(O)c1[N+](=O)[O-]

Procedure:
A solution of 3-hydroxy-2-nitrobenzoic acid (51 g) and con.H2SO4 (5 mL) in anhydrous methanol (450 mL) was heated to reflux for 48 hr. The mixture was concentrated to remove methanol, and the residue was partitioned between water (500 mL) and ethyl acetate (800 mL). The organic layer was washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated to give crude compound. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=40:1 to 5:1) to give methyl 3-hydroxy-2-nitrobenzoate (28 g) 1H-NMR (400 MHz, CDCl3) δ 3.8 (s, 3H), 7.32-7.34 (d, J=8.4 Hz, 1H), 7.39-7.41 (d, J=8.0 Hz, 1H), 7.48-7.52 (t, J=8.0 Hz, 1H), 11.37 (s, 1H); LC-MS (m/z) 198 [M+1]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:27]>CN(C=O)C.O>[C:3]([O:7][C:8]([N:10]([CH3:27])[C@H:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a suspension of 60% dispersion of sodium hydride in mineral oil (1.5 g, 37.5 mmol) in anhydrous DMF (20 mL) cooled on an ice-bath to 0° C. was added dropwise a solution of (S)-benzyl 3-(tert-butoxycarbonylamino)pyrrolidine-1-carboxylate (10 g, 31.2 mmol) in anhydrous DMF (100 mL). The resulting mixture was stirred at 0° C. for 1 hour then at ambient temperature for 2 hours. The mixture was subsequently cooled to 0° C. and treated dropwise with iodomethane (2.1 mL, 34.3 mmol), and the mixture stirred at 0° C. for 1 hour then warmed to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with water (300 mL) and the mixture extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residual oil was purified by column chromatography (Biotage, 65M; 10-20% ethyl acetate:hexanes) to afford (S)-benzyl 3-(tert-butoxycarbonyl(methyl)amino)pyrrolidine-1-carboxylate (7.2 g, 69%).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=O)[C:4]([CH3:7])([CH3:6])[CH3:5].P(Cl)(Cl)(Cl)=O.[NH2:15][C:16]1[N:17]=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:9])[C:3](=[N:15][C:16]1[N:17]=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: Nc1ccc(Cl)nn1
Reactant: CN(C)C(=O)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C(=Nc1ccc(Cl)nn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.6 %

Procedure:
36 g of N,N-dimethylpivalamide was dissolved in 85 ml of toluene; under ice cooling conditions, 11.3 ml of phosphorus oxychloride was added drop by drop, followed by stirring at room temperature for 24 hours. To this solution, 12.0 g of 3-amino-6-chloropyridazine was added, followed by stirring at 60-70° C. for 24 hours. After cooling, ethyl acetate was added; the mixture was washed with a 2 N aqueous solution of sodium hydroxide and saline and dried with sodium sulfate. After the dry product was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate:triethylamine (50:50:2). The desired fraction was collected to yield 6.38 g of N,N-dimethyl-N′-(6-chloropyridazin-3-yl)pivalamidine. The mother liquor was purified by silica gel column chromatography to yield 6.07 g of the amidine. 12.45 g of the amidine derivative obtained was dissolved in 100 ml of methanol; a solution of 4.31 g of hydroxylamine hydrochloride in methanol was added, followed by stirring at room temperature for 2 hours. The methanol was concentrated to half volume under reduced pressure; the crystal precipitated was collected by filtration, washed with water and ethyl ether and dried to yield 10.44 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:18][O:19][C:20]([NH:22][C:23](=NC(OC)=O)OC)=[O:21].C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:16][C:14]([CH3:17])([CH3:15])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:23]1[NH:22][C:20](=[O:21])[O:19][CH3:18]
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Reactant: COC(=O)N=C(NC(=O)OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Nc1nc2cnc3ccccc3c2n1CC(C)(C)O

Procedure:
A mixture of 1-[(3-amino-4-quinolinyl)amino]-2-methyl-2-propanol (1.0 g, 4.3 mmol), 1,3-dimethoxycarbonyl-O-methylisourea (prepared according to the general method of Viswanathan, N. Indian Patent No. 168,784, 1.64 g, 8.64 mmol), acetic acid (1.3 g, 22 mmol), and p-toluenesulfonic acid (0.82 g, 4.3 mmol) in methanol (20 mL) was heated at reflux for 16 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in chloroform (100 mL). The solution was washed sequentially with water (100 mL), aqueous sodium carbonate (100 mL of 4% w/w), water (100 mL), and brine (100 mL) and then concentrated under reduced pressure. The residue was purified by automated flash chromatography (40+M silica cartridge, eluting with 0% to 25% CMA in chloroform) followed by recrystallization from acetonitrile to provide 0.64 g of methyl [1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]carbamate as a white solid, mp 225° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH2:11]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:25])[C@H:19]([CH2:21][CH:22]([CH3:24])[CH3:23])[NH2:20])[CH3:12].C(N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C>[CH2:11]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:25])[CH:19]([NH:20][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([Cl:1])[N:7]=1)[CH2:21][CH:22]([CH3:23])[CH3:24])[CH3:12]
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CCOCCCNC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOCCCNC(=O)C(CC(C)C)Nc1cc(Cl)nc(Cl)n1
Temperature: 25 °C

Procedure:
2,4,6-trichloropyrimidine (1.0 g), L-leucine-3-ethoxypropylamide hydrochloride (17 mL of a 0.32 M solution in DMSO), and N,N-diisopropylethylamine (3.0 mL) were stirred for 24 h in 20 mL methyl sulfoxide at 60 C. The solution was cooled to room temperature and diluted with ethyl acetate (100 mL), then washed 4 times with 100 mL aliquots of a saturated aqueous solution of sodium chloride. Silica gel chromatography (gradient: 20–40–50–100% ethyl acetate in hexanes) followed by semi-preparative HPLC purification of mixed fractions provided 1.06 g of 2-(2,6-dichloropyrimidin-4-ylamino)-4-methylpentanoic acid (3-ethoxypropyl)amide as a colorless oil
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([N:19]1[CH2:33][CH2:32][CH2:31][C@H:20]1[C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([OH:27])=O)=[O:22])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.[NH3:42]>O1CCCC1.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([N:19]1[CH2:33][CH2:32][CH2:31][C@H:20]1[C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([NH2:42])=[O:27])=[O:22])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Benzyloxycarbonyl-isoleucyl-prolyl-proline (4.5 g) is dissolved in a mixture of tetrahydrofuran (30 ml) and triethylamine (1.4 ml). The solution is chilled in a -5° cooling bath and isobutyl chloroformate (1.6 ml) is added. The solution is allowed to warm to room temperature (10 minutes) and concentrated aqueous ammonia (10 ml) is added. After four hours stirring at room temperature, the reaction is concentrated in vacuo, diluted with ethyl acetate and washed sequentially with saturated sodium bicarbonate, water, 0.1 N hydrochloric acid and water. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo to give the title compound.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].[CH2:5]([Mg]Br)[CH:6]=[CH2:7].[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13](/[CH:17]=[N:18]/[S@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[CH:12]=1>O1CCCC1.C(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C@@H:17]([NH:18][S@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[CH2:7][CH:6]=[CH2:5])[CH:12]=1
Reactant: CC(C)(C)[S@](=O)/N=C/c1cc(Cl)ccn1
Reactant: C=CC[Mg]Br
Agent: [Cl-]
Agent: [In+3]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CC[C@H](N[S@@](=O)C(C)(C)C)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 115.1 %

Procedure:
To a cooled (0-5° C.) mixture of indium(III) chloride (13.56 g, 61.3 mmol) in tetrahydrofuran (170 mL) was added dropwise over 30 min. allylmagnesium bromide (1M in diethylether) (62 mL, 61.3 mmol). The reaction was allowed to warm to rt. After 1 h at rt, a solution of 1A (10 g, 40.9 mmol) in ethanol (170 mL) was added. After 2-3 h, the reaction was concentrated under vacuum at 50-55° C. The crude material was partitioned between ethyl acetate (200 ml) and water (1×50 ml) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×50 ml). The organic layers were combined and washed with brine (1×100 ml), dried over sodium sulfate, filtered and concentrated to give 1B (13.5 g, 106%) as a yellow oil. MS (ESI) m/z: 287.2 (M+H)+. This material was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([N:6]1[C:10](CNCC)=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].Cl[C:17]1[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=1.[CH:25]([N:28](CC)[CH:29](C)C)(C)[CH3:26].C(OCC)(=O)C>C(O)(C)C>[CH3:15][N:2]([CH3:1])[S:3]([N:6]1[CH:10]=[C:9]([CH2:29][N:28]([CH2:25][CH3:26])[C:17]2[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=2)[N:8]=[CH:7]1)(=[O:4])=[O:5]
Reactant: COc1ccnc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCNCc1cncn1S(=O)(=O)N(C)C
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCN(Cc1cn(S(=O)(=O)N(C)C)cn1)c1nccc(OC)n1

Procedure:
A solution of 5-ethylaminomethyl-imidazole-1-sulfonic acid dimethylamide (0.527 g, 2.25 mmol), 2-chloro-4-methoxy-pyrimidine (0.217 g; 1.5 mmol) and N,N-diisopropyl ethyl amine (0.51 ml, 3.0 mmol) in isopropanol (2 ml) was heated in a sealed vessel in a microwave oven for 20 min at 160° C. Ethyl acetate (20 ml) and silica gel (1 g) was added and the mixture was evaporated. The residue was purified by flash chromatography, column: Isolute® Flash-NH2 (Separtis); eluent: heptane/ethyl acetate=8:2) to yield a white solid, (0.265 g, 52%); MS (ISP): 341.0 ((M+H)+.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.F[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C(N(CC)CC)C>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCN(CC)CC
Product: Cc1ccc(Nc2ccc3[nH]ccc3c2)c([N+](=O)[O-])c1
Temperature: 225 °C
Yield: 90 %

Procedure:
5-Aminoindole (0.264 g, 2.00 mmoles) and 4-fluoro-3-nitrotoluene (0.465 g, 3.00 mmoles) were combined with triethylamine (0.42 ml, 3.01 mmoles) in which 4-fluoro-3-nitrotoluene was the only solvent and the reaction was heated at 225° C. under nitrogen for 18 hours. Chromatography using ether/hexanes [1:1 ] afforded the title compound (90%) as a red amorphous solid. Mp, decomposes 94° C.; Rf =0.55 in ethyl acetate/hexanes [1:1]; 13C NMR (CDCl3) δ143.4, 137.3, 134.2, 131.8, 131.1, 128.7, 126.1, 125.6, 120.8, 117.9, 116.2, 112.1, 102.8, 20.1; LRMS (m/z, relative intensity) 267 (M+, 45), 250 (5), 233 (20), 220 (13). HRMS calculated for C15H13N3O2 : 267.1005. Found: 267.0993.
Reaction SMILES: I.CS[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]=1.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.CCOCC>C(O)C>[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][CH2:6][N:5]=2)=[CH:17][CH:16]=1
Reactant: CSC1=NCCc2ccccc21
Reactant: NCc1ccc(O)cc1
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: Oc1ccc(CNC2=NCCc3ccccc32)cc1
Yield: 22.4 %

Procedure:
1-Methylthio-3,4-dihydroisoquinoline hydroiodide (0.6 g, 0.00197 mol) and 4-hydroxybenzylamine (0.24 g, 0.00195 mol) were heated together at reflux temperature in ethanol (25 ml) for five hours. Effluent gases were passed through a CHLOROS trap. The mixture was then cooled and the ethanol evaporated off at reduced pressure. The tacky residue was dissolved in dilute HCl and the solution extracted with ethyl acetate. The clear aqueous solution was basified with 6N. NaOH and re-extracted with ethyl acetate. The latter organic extract was washed with water, dried and evaporated to dryness to give a white sticky solid. This was treated with ether and the ether decanted off. The residual solid was crystallised from absolute ethanol to give the title compound (0.11 g) as white crystals, m.p. 177°-179°.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28](OC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH3:32][O:33][CH:34]1[CH2:37][NH:36][CH2:35]1.C[Al](C)C.C(O)(=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28]([N:36]3[CH2:37][CH:34]([O:33][CH3:32])[CH2:35]3)=[O:29])[N:27]=2)[CH2:22]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC1CNC1
Reactant: COC(=O)c1coc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC1CN(C(=O)c2coc(N3CC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C3)n2)C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-methoxycarbonyl-1,3-oxazol-2-yl)azetidine (1.57 g, 3.60 mmol) (obtained as described in Reference Example 70(8)) in toluene (80 ml) was added a solution of 0.67 M 3-methoxyazetidine (obtained as described in Reference Example 31(2))-trimethylaluminium in toluene (10.8 ml) at room temperature under an atmosphere of nitrogen and the mixture was stirred in an oil bath (60° C.) for 30 minutes. After checking the completion of the reaction, to the reaction mixture were added 10% aqueous acetic acid (100 ml) and ethyl acetate (200 ml) in an ice bath and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethyl acetate. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]azetidine (1.50 g, yield 90%) as a pale brown solid.