Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:3].[C:12]1([O:19][CH2:20][CH:21]2[O:23][CH2:22]2)[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1>C(OCCO)C.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[C:2]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:22][CH:21]([OH:23])[CH2:20][O:19][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])(=[O:3])[CH3:1]
Reactant: Cc1ccccc1OCC1CO1
Reactant: CC(=O)c1c(O)cccc1O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCOCCO
Product: CC(=O)c1c(O)cccc1OCC(O)COc1ccccc1C
Yield: 60.8 %

Procedure:
A solution of 2,6-dihydroxyacetophenone (15.2 g) and o-cresylglycidyl ether (16.4 g) in 2-ethoxyethanol (75 ml) containing benzyltrimethylammonium hydroxide solution (10 drops; 40%) was heated under reflux for 48 hours. Following removal of the 2-ethoxyethanol under reduced pressure, the resulting solid was washed with ether to give 1-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-o-cresyloxypropane (19.2 g) as a cream solid, m.p. 101°-102.5° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:75][CH:76]1[CH2:81][CH2:80][N:79]([CH3:82])[CH2:78][CH2:77]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:75][CH:76]5[CH2:81][CH2:80][N:79]([CH3:82])[CH2:78][CH2:77]5)=[O:28])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h

Procedure:
To a mixture of 0.050 g (0.116 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-184) and 5 mL of dimethylformamide was added 0.0235 g (0.174 mmole) of 1-hydroxybenzotriazole, 0.0659 g (0.174 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.060 g (0.463 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0198 g (0.174 mmole) of 4-amino-1-methylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0536 g) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-N-(1-methyl-piperidin-4-yl)-benzamide (I-185) as a white solid.
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1.[N-:11]=[N+:12]=[N-:13].[Na+].CCOCC.O>CN(C)C=O>[N:11]([C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1)=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1nc(F)cnc1F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: N#Cc1nc(F)cnc1N=[N+]=[N-]
Reaction time: 0.17 h
Yield: 107.5 %

Procedure:
In 2.0 mL of N,N-dimethylformamide was dissolved 0.20 g of 3,6-difluoro-2-pyrazinecarbonitrile. At 5° C., 0.11 g of sodium azide was added and stirred at the same temperature as above for 10 minutes. The reaction mixture was added to a mixture of 20 mL of ether and 20 mL of water, and the organic layer was separated. The organic layer thus obtained was washed successively with 20 mL of water and 20 mL of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 0.25 g of 3-azido-6-fluoro-2-pyrazinecarbonitrile was obtained as a yellow-colored oily product.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[N:3]=1.[C:17]([CH2:19][C:20]1([N:31]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[N:32]2)[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1)#[N:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([CH2:19][C:20]1([N:31]2[CH:35]=[C:34]([C:2]3[N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[CH:5]=[C:4]([C:11]4[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=4)[N:3]=3)[CH:33]=[N:32]2)[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1)#[N:18]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: Cn1cc(-c2cc3nccn3c(Cl)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(C(=O)OC(C)(C)C)C4)c3)n2)cn1
Temperature: 70 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
In a 5 L 4-necked flask with an overhead mechanical stirrer was added 5-chloro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation J; 34.83 g, 149.1 mmol), tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-Pyrazol-1-yl)azetidine-1-carboxylate (Preparation F; 86.82 g, 223.6 mmol), and K3PO4 (94.92 g, 447.2 mmol) by powder funnel. Dioxane (745.3 mL, 149.1 mmol) was added to rinse down funnel. Pd(PPh3)4 (17.23 g, 14.91 mmol) was added, followed by 74.5 mL of water. The reaction mixture was slowly heated to 70° C. as measured by an internal temperature probe. After heating for 6 hours, the reaction mixture was cooled to ambient temperature. The reaction mixture was diluted in EtOAc (500 mL) and water (100 mL), and then the resultant solids were filtered out. The solids were washed with EtOAc (2×500 mL) to afford a grey-white solid, which was re-introduced back to the 5 L 4-neck flask and diluted with 1 L of water and 300 mL of EtOAc. This was stirred for 3 hours, and then the solids were isolated by filtration. After washing with EtOAc (2×500 mL), the solids were dried to afford tert-butyl 3-(cyanomethyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (60.83 g, 132.4 mmol, 88.81% yield). MS (apci) m/z=460.1 (M+H).
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]([N:13]1[CH2:16][CH:15]([C:17]2[C:22]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:14]1)=[O:12].CCN(CC)CC.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]([N:13]1[CH2:14][CH:15]([C:17]2[C:22]([C:23]3[CH2:24][CH2:25][N:26]([C:36](=[O:38])[CH3:37])[CH2:27][CH:28]=3)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:16]1)=[O:12]
Reactant: CC(=O)Cl
Reactant: O=C(c1nc2ccccc2[nH]1)N1CC(c2nccnc2C2=CCNCC2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC=C(c2nccnc2C2CN(C(=O)c3nc4ccccc4[nH]3)C2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of (1H-benzoimidazol-2-yl)-{3-[3-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone hydrochloride (187 mg, 0.47 mmol) in dry CH2Cl2 (10 mL) was added Et3N (1 mL). The reaction mixture was cooled to 0° C. with an ice bath, and acetyl chloride (39 mg, 0.50 mmol) was added dropwise. After 1 h, the reaction mixture was warmed to RT, and stirred overnight. Then the reaction mixture was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product (170 mg, 0.42 mmol, 90% yield). ESI-MS (M+1): 403 calc. for C22H22N6O2 402.
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC=CC=2N=1.[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25]C)=O.[O-:27][C:28]#[N:29].[K+]>C(O)(=O)C.O>[NH:17]1[C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23](=[O:25])[NH:29][C:28]1=[O:27]
Reactant: N#C[O-]
Reactant: COC(=O)c1sccc1N
Agent: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2sccc2[nH]1

Procedure:
Scheme 1 shows the synthesis of 4-(2-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine 4 starting by cyclization of methyl 3-amino-thiophenecarboxylate 1 and potassium cyanate in acetic acid and water at room temperature to give thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione 2. This is an improvement over cyclization of 1 with urea which requires high temperature and evolution of ammonia gas. Thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione 2 was converted to 2,4-dichlorothieno[3,2-d]pyrimidine 3 with phosphorous oxychloride and a catalytic amount of N,N-dimethylaniline (0.75 equiv.) in acetonitrile. Selective substitution at the 4-position with morpholine gave 4.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([SH:6])[CH3:5].C([C:9]1[CH:10]=[C:11]([C:16]([NH:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=2[CH3:28])=O)C=[CH:13][C:14]=1F)#N.O.[CH3:31][N:32](C=O)C>>[C:31]([C:14]1[CH:13]=[C:16]([NH:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=2[CH3:28])[CH:11]=[CH:10][C:9]=1[S:6][CH:4]([CH3:5])[CH3:3])#[N:32]
Reactant: Cc1cc(Br)ccc1C(=O)NNC(=O)c1ccc(F)c(C#N)c1
Reactant: CN(C)C=O
Reactant: CC(C)S
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)ccc1C(=O)NNc1ccc(SC(C)C)c(C#N)c1
Temperature: 100 °C
Yield: 44 %

Procedure:
Sodium hydride (95%) (0.8 mmol, 0.025 g) was added to a solution of 2-propanethiol (0.8 mmol, 0.09 mL) in DMF (4 mL) in an oven dried high pressure tube. This reaction mixture was stirred for 10 minutes at room temperature after which N′-(3-cyano-4-fluorophenylcarbonyl)-4-bromo-2-methylbenzhydrazide (0.53 mmol, 0.2 g) was added. The reaction mixture was heated at 100° C. for 16 h, cooled to room temperature, and combined with water. The resulting precipitate was collected by filtration and washed with water to yield 0.1 g (44%) of the title compound. 1H NMR (500 MHZ, DMSO) δ 8.28 (s, 1H), 8.14 (d, J=8.0, 1H), 7.76 (d, J=8.2, H), 7.55 (s, 1H), 7.49 (d, J=7.8, 1H), 7.36 (d, J=8.0, 1H), 3.80-3.90 (m, 1H), 2.40 (s, 3H), 1.34 (d, J=6.2, 6H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:32]1[CH:33]=[C:34]([CH:45]=[CH:46][CH:47]=1)[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:21][C:22]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][N:26]3[C:32]2[CH:33]=[C:34]([CH:45]=[CH:46][CH:47]=2)[C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: Cc1cc(N)c2cnn(-c3cccc(C(=O)OCc4ccccc4)c3)c2c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)OCc2ccccc2)c1)C(F)(F)F
Temperature: 85 °C
Reaction time: 21 h
Yield: 65.3 %

Procedure:
A mixture of racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (which may be prepared according to WO 04/063163, 350 mg, 1.2 mmol), phenylmethyl 3-(4-amino-6-methyl-1H-indazol-1-yl)benzoate (Intermediate 29, 357 mg, 1.0 mmol) and ytterbium(III) triflate (124 mg, 0.2 mmol) in acetonitrile (2 mL) was heated at 85° C. for 18 hours when the temperature was raised to reflux temperature and heating continued for a further 21 hours. The mixture was cooled to room temperature and partitioned between dichloromethane (50 mL) and aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted again with dichloromethane (50 mL) and the combined organic extracts were dried over anhydrous sodium sulphate and evaporated. The residue was purified by silica gel chromatography using the Flashmaster II (50 g cartridge) eluting with a 1:1 cyclohexane:ethyl acetate gradient over 40 minutes to give the title compound as a white solid (424 mg).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]12[CH2:24][O:23][CH:22]([OH:25])[CH:9]1[C:10](=[O:21])[N:11]([C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.C(O)C>[C:1]([O:5][C:6]([C@@:8]1([CH2:24][OH:23])[CH:9]([CH2:22][OH:25])[C:10](=[O:21])[N:11]([C@@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)COC(O)C2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@@](CO)(C(=O)OC(C)(C)C)C(CO)C1=O
Reaction time: 5.5 h
Yield: 43.4 %

Procedure:
To a cooled solution (−20° C.) of (3aS)-1-hydroxy-6-oxo-5-[(R)-1-phenylethyl]tetrahydrofuro[3,4-c]pyrrole-3a-carboxylic acid tert-butyl ester (350 mg, 1.01 mmol) in tetrahydrofuran and ethanol (10 mL; 4:1), sodium borohydride (38.0 mg, 1.00 mmol) was added portionwise, and the mixture was stirred at the same temperature for 5.5 h. The reaction mixture was concentrated in vacuo and taken up in AcOEt and water. The layers were separated and the aqueous layer extracted with AcOEt. The combined extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 90% AcOEt in hexane to afford the title compound (153 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].C(C1C=C[N:20]=[C:19](CN)C=1)(C)C>>[CH3:1][C:2]1[N:3]=[C:4]([C:19]#[N:20])[CH:5]=[CH:6][C:7]=1[CH2:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(C)c1ccnc(CN)c1
Reactant: Cc1c(CS(C)(=O)=O)ccc[n+]1[O-]
Product: Cc1nc(C#N)ccc1CS(C)(=O)=O

Procedure:
6-methyl-5-(methylsulfonylmethyl)picolinonitrile was synthesized from 2-methyl-3-(methylsulfonylmethyl)pyridine N-oxide following the general procedure as described for the 4-isopropyl-2-pyridylmethylamine.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].[O:21]=[S:22]1(=[O:38])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=2[C:24](=[O:32])[N:23]1[CH2:33][CH2:34][CH2:35][CH2:36]Br>>[O:38]=[S:22]1(=[O:21])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=2[C:24](=[O:32])[N:23]1[CH2:33][CH2:34][CH2:35][CH2:36][N:17]1[CH2:18][CH2:19][CH:14]([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]2=[O:20])[CH2:15][CH2:16]1
Reactant: CCCCn1c(=O)n(C2CCNCC2)c2ccccc21
Reactant: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCBr
Product: CCCCn1c(=O)n(C2CCN(CCCCN3C(=O)c4cc(Cl)ccc4S3(=O)=O)CC2)c2ccccc21

Procedure:
From 4-(3-butyl-2-oxo-1-benzimidazolinyl)piperidine and 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one using the procedures described in Example 1 there was obtained a white solid upon formation of the HCl salt (from methanol), melting point 192-195° C. Analysis calculated for C27H334N4O4S.HCl.0.8 H2O: C, 54.41; H, 6.02; N, 9.40; found: C, 54.41; H, 5.82; N, 9.34. The NMR was consistent with the structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:12])[CH2:10]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(=O)[NH:17]C(=O)C2=CC=CC=C12.O.NN.Cl[C:28]1[S:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.C(N(CC)CC)C>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][NH:17][C:28]1[S:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: Clc1nc2ccccc2s1
Reactant: O=C1NC(=O)c2ccccc21
Agent: NN
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@H](CNc1nc2ccccc2s1)NC(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 10 %

Procedure:
2-[(R)-N-tert-butyloxycarbonylamino]-1-propylamine was prepared by standard synthetic steps from (R)-2-(N-tert-butyloxycarbonylamino)-1-propanol by Mitsunobu reaction with phthalimide followed by reaction with hydrazine hydrate. This amine (0.52 g, 3.0 mmol) and 2-chlorobenzothiazole (0.76 g, 4.5 mmol) were dissolved in dioxan (20 ml) and triethylamine (0.83 ml, 6.0 mmol) was introduced. The reaction mixture was heated at 50° C. for 18 h, evaporated and purified by "flash" column chromatography, eluting with heptane/ethyl acetate (10:3) to provide the 2-[(R)-2-(N-tert-butyloxycarbonylamino)-1-propylamino]benzothiazole (0.09 g, 10%) as an oil, TLC Rf 0.31 [SiO2 ; hexane/ethyl acetate (10:3)].
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH:25]3[CH2:27][CH2:26]3)CC3C=CC(OC)=CC=3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][C@@H:38]([NH:41][C:42](=[O:45])[O:43][CH3:44])[C@H:37]([O:46][P:47]([OH:50])([OH:49])=[O:48])[CH2:36]1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH:25]3[CH2:27][CH2:26]3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][C@@H:38]([NH:41][C:42](=[O:45])[O:43][CH3:44])[C@H:37]([O:46][P:47]([OH:50])([OH:49])=[O:48])[CH2:36]1
Reactant: COC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(N(Cc4ccc(OC)cc4)C4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1OP(=O)(O)O
Solvent: COc1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1OP(=O)(O)O
Yield: 55.2 %

Procedure:
To a solution of methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-(phosphonooxy)piperidin-4 yl)carbamate (0.007 g, 0.009 mmol) in DCE (1 mL) was added anisole (0.006 mL, 0.055 mmol) followed by TFA (25% in DCE) (1.1 mL, 3.57 mmol) and at 35° C. for overnight. After completion of starting material (by LCMS), reaction mixture was concentrated and residue was taken in DCM (5 mL) concentrated under vacuum, the same thing was repeated one more time with 5 mL DCM. The resultant mixture was purified by reverse phase preparative HPLC and collected fractions were lyophilized to give methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4 (cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-(phosphonooxy)piperidin-4 yl)carbamate (0.003 g, 4.97 μmol, 51.28% yield) as white solid.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([CH2:6][O:7][C:8](=[O:10])[NH2:9])[N:4]([S:11]([OH:14])(=[O:13])=[O:12])[C:3]1=[O:15].[Na:16].S1C2C=CC=CC=2N=C1S[O:27][C:28](=O)/[C:29](/[C:42]1[N:43]=[C:44]([NH2:47])[S:45][CH:46]=1)=[N:30]\[O:31][C:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:34])[CH3:33]>CC(C)=O.O>[NH2:47][C:44]1[S:45][CH:46]=[C:42](/[C:29](=[N:30]/[O:31][C:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:34])[CH3:33])/[C:28]([NH:1][C@H:2]2[C@@H:5]([CH2:6][O:7][C:8](=[O:10])[NH2:9])[N:4]([S:11]([OH:14])(=[O:12])=[O:13])[C:3]2=[O:15])=[O:27])[N:43]=1.[Na:16]
Reactant: NC(=O)OC[C@@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)OSc1nc2ccccc2s1)c1csc(N)n1
Agent: [Na]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1COC(N)=O)c1csc(N)n1

Procedure:
1.62 g of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidine-sulfonic acid-sodium salt in 180 ml of acetone-water (2:1) are stirred with 3.87 g of (Z)-2-(2-amino-4-thiazolyl)-2-[[1-(t-butoxycarbonyl)-1-methylethoxy]imino]-acetic acid 2-benzthiazolyl-thioester at room temperature for 15 hours. After removal of the acetone in vacuo and the addition of 50 ml of water, crystals are obtained which are washed with water. The mother liquor is evaporated under reduced pressure at 37° C. and chromatographed (MCI Gel, water as eluting agent). After lyophilization (3S,4S)-3-[(2-amino-4-thiazolyl)-2-(Z)-[[1-(t-butoxycarbonyl)-1-methylethoxy]imino]-acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulfonic acid-sodium salt is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13](=[O:15])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][C:13](=[O:15])[NH:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: O=c1[nH]nc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2n[nH]c(=O)o2)cc1

Procedure:
5-(4-nitrophenyl)-1,3,4-oxadiazol-2(3H)-one, (0.65 g) in ethanol (100 ml) was hydrogenated at 276 kPa (40 p.s.i.) in the presence of palladium on carbon ar room temperature for one hour. The reaction mixture was filtered, the filtrate was evaporated to dryness and the resultant yellow solid was recrystallised from ethanol to afford (5-(4-aminophenyl)-1,3,4-oxadiazol-2(3H)-one, 0.46 g, m.p. 172-173° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClCCl.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][CH:15]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)CCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 500 ml three-necked flask provided with a mechanical agitator and a thermometer were added a solution of 22.4 g (133.2 mmol) in theoretical amount of 3-phenylpropionyl chloride which was prepared in the step 1, dissolved in 100 ml dichloromethane, 14.4 g (205.9 mmol) methylphenyl ether and 150 ml dichloromethane, the mixture was cooled in an ice salt bath to lower than −5° C., while maintaining the inside temperature at −5° C. to −10° C., 17.8 g (133.2 mmol) anhydrous AlCl3 was added portionwise, upon the completion of addition. The mixture was stirred at this temperature for 1 hour and then at room temperature for 1 hour, the resultant was poured under stirring into a mixture of 100 g ice, 100 g water and 40 ml concentrated hydrochloric acid, the organic layer was separated, and the aqueous layer was extracted with dichloromethane twice ×20 ml, the organic layers were combined and washed with saturated brine, then with saturated aqueous sodium bicarbonate solution, and then with saturated brine until neutrality, dried over anhydrous magnesium sulfate, filtrated and concentrated under a reduced pressure to obtain a crude product, which was recrystallized with petroleum ether and ethyl acetate (2:1) to obtain a 23.5 g product, the mother liquid was concentrated and recrystallized to obtain a 3.3 g product in a yield of 83.7% in total, mp: 96-97□. 1H-NMR (CDCl3, 400 MHz) δ: 3.05 (2H, t, J=8.16 Hz), 3.25 (2H, t, J=8.16 Hz), 3.86 (3H, s, OCH3), 6.92 (2H, d, J=9.00 Hz, ArH), 7.18˜7.32 (5H, m, ArH), 7.94 (2H, d, J=9.00 Hz, ArH); EI-MS m/e (%): 240.1 (M+, 37), 135 (100).