Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[NH2:11][C:12]1[N:17]([CH3:18])[C:16](=[O:19])[NH:15][C:14](=[O:20])[CH:13]=1.[OH-].[Na+]>C(O)C>[NH2:11][C:12]1[N:17]([CH3:18])[C:16](=[O:19])[N:15]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)[C:14](=[O:20])[CH:13]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(N)cc(=O)n(Cc2ccc(C#N)cc2)c1=O
Reaction time: 1.75 h
Yield: 12.2 %

Procedure:
α-Bromo-p-tolunitrile (5.41 g, 27.6 mmol) was added at once with stirring to a solution of 6-amino-1-methyluracil (V. Papesch and E. F. Schroeder. J. Org. Chem. (1951), 16, 1879) (3.90 g, 27.6 mmol) in 1:1 ethanol: 1N sodium hydroxide (56 ml) at 42° C. After 1.75 hours, the mixture was cooled, filtered and washed with water. The resulting solid and second crop obtained by evaporation of the filtrate were combined (5.80 g) and partially purified by silica gel chromatography followed by repeated trituration with 1:2 methanol; ether to give crude 4-[(6-Amino-1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-3-pyrimidinyl)methyl]benzonitrile (0.86 g), indentified by NMR.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[O:12]1[C:16]2[CH:17]=[CH:18]C=CC=2N=C1>>[O:12]1[CH2:16][CH:17]1[CH2:18][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Oc1ccnc2ccccc12
Reactant: c1ccc2ocnc2c1
Product: c1ccc2c(OCC3CO3)ccnc2c1

Procedure:
Compound 75 was prepared in the manner of compound 6 substituting 4-hydroxy-quinoline for compound 8 in part C-5 of Example 1.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12]/[C:11](=[CH:14]\[C:15]([O:17][CH2:18][CH3:19])=[O:16])/[CH:10]([CH3:20])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[CH3:20][CH:10]1[CH2:9][NH:8][CH2:13][CH2:12]/[C:11]/1=[CH:14]\[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)/C=C1\CCN(Cc2ccccc2)CC1C
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CCOC(=O)/C=C1\CCNCC1C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl (2E)-(1-benzyl-3-methylpiperidin-4-ylidene)acetate, 1-chloroethyl chloroformate, and 1,2-dichloroethane was heated under reflux with stirring for 30 minutes and then concentrated under reduced pressure. The residue was dissolved in EtOH and the solution was heated under reflux with stirring for 10 minutes to yield ethyl (2E)-(3-methylpiperidin-4-ylidene)acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21]([NH:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5])(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: COC(=O)c1ccc(Br)cc1N
Product: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1c(F)cccc1F

Procedure:
Methyl 2-amino-4-bromobenzoate was sulfonylated with 2,6-difluorobenzenesulfonyl chloride and hydrolyzed as in EXAMPLE 1, Part B. 1H NMR (400 MHz, acetone-d6): 11.65 (s, 1H), 8.02 (d, J=8.5, 1H), 7.93 (d, J=1.8, 1H), 7.74-7.82 (m, 1H), 7.38 (dd, J=8.5, 1.9, 1H), 7.28-7.23 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27].C(Cl)Cl>>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCC(=O)c2ccc(F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCCC1CCNCC1)c1ccc(F)cc1

Procedure:
A solution of 4-(4-(4-fluorophenyl)-4-oxo-butyl)-1-tert-butoxycarbonyl-piperidine (184 mg, 0.52 mmol, from Step C) in 30% TFA/CH2Cl2 was stirred for 30 min, then concentrated and dried under vacuum to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[C:4]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:3]=1.[F:27][C:28]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]2[C:29]=1[CH:30](O)[CH2:31][CH2:32][O:33]2.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[F:27][C:28]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]2[C:29]=1[C@@H:30]([O:1][C:2]1[C:10]3[N:9]=[C:8]([CH3:11])[N:7]([S:12]([C:15]4[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=4)(=[O:14])=[O:13])[C:6]=3[CH:5]=[C:4]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:3]=1)[CH2:31][CH2:32][O:33]2
Reactant: OC1CCOc2cc(F)cc(F)c21
Reactant: Cc1ccc(S(=O)(=O)n2c(C)nc3c(O)cc(C(=O)N(C)C)cc32)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c(C)nc3c(O[C@H]4CCOc5cc(F)cc(F)c54)cc(C(=O)N(C)C)cc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a stirred mixture of 4-hydroxy-N,N,2-trimethyl-1-[(4-methylphenyl)sulfonyl]-1H-benzimidazole-6-carboxamide (21.2 g, 56.8 mmol, STEP 4), (+)-5,7-difluoro-3,4-dihydro-2H-chromen-4-ol (15.86 g, 85.1 mmol, STEP 8) and tributylphosphine (22.9 g, 113 mmol) in toluene (840 mL) was added 1,1′-(azodicarbonyl)dipiperidine (ADDP) (19.3 g, 76.5 mmol) at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was filtered through a pad of Celite and washed with ethyl acetate (300 mL). The filtrate was concentrated in vacuum. The residue was purified by column chromatography on silica get (ethyl acetate:hexane gradient elution from 1:20 to 20:1) to afford crude solids (27.0 g). The solids were recrystallized from 2-propanol (130 mL) to give the title compound as a colorless crystal (23.2 g, 75%, >99% ee)
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[C:8]([C:14](=O)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].[NH:19]1[C:23]([NH2:24])=[N:22][C:21]([NH2:25])=[N:20]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:24][C:23]1[N:22]=[C:21]2[NH:25][C:14]([CH3:15])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]([C:6]3[CH:17]=[CH:18][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:20]2[N:19]=1
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Reactant: Nc1n[nH]c(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2nc(N)nn2C1c1ccc(C#N)cc1
Temperature: 63 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, ethyl 2-(4-cyanobenzylidene)-3-oxobutanoate (12.2 g, 50.1 mmol; preparation see WO 2004/020410-A2, Example 32A) and 1H-1,2,4-triazole-3,5-diamine (6.0 g, 60.5 mmol, 1.2 eq.) were dissolved in DMF (150 ml). Solid sodium bicarbonate (30.7 g, 365.6 mmol, 6 eq.) was added, and the mixture was stirred at 63° C. for 12 h. The mixture was then filtered and the DMF was distilled off from the filtrate under reduced pressure. The residue was suspended in ethanol and stirred, and the product was then filtered off and dried under high vacuum. This gave 12.45 g (76% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(C(C)C)C(C)C)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.CCOC(C)=O.CN(C=O)C.[CH3:51][S:52]([NH2:55])(=[O:54])=[O:53]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH:55][S:52]([CH3:51])(=[O:54])=[O:53])=[O:5]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Yield: 71.6 %

Procedure:
2,4,5-Trifluorobenzoic acid (3.00 g, 17.0 mmol), N-ethyl-N-isopropylpropan-2-amine (8.9 mL, 6.6 g, 51.1 mmol), 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide 50% solution in EtOAc/DMF (12.7 mL, 13.6 g, 42.6 mmol) and methanesulfonamide (3.24 g, 34.1 mmol) were suspended in THF (40 mL) and stirred under a nitrogen atmosphere at reflux for 18 hours. The reaction mixture was cooled, concentrated in vacuo and the residue suspended in water (pH=4). The mixture was acidified to pH=2 with an aqueous solution of potassium hydrogen sulfate (0.5 M). The mixture was extracted with EtOAc (1×100 mL). The organic layer was washed with brine (2×50 mL), dried over sodium sulfate, filtered and evaporated to yield the crude solid. The crude solid was triturated with hexane to yield the title compound as an off-white crystalline solid (3.08 g, 72%):
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[CH:5][C:4]([CH3:8])=[N:3]1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[N:11]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[CH3:1][N:2]1[C:6]([O:7][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[N:11]=2)=[CH:5][C:4]([CH3:8])=[N:3]1
Reactant: N#Cc1cccc(Cl)n1
Reactant: Cc1cc(O)n(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cccc(C#N)n2)n(C)n1
Reaction time: 5 h

Procedure:
5.6 g of 1,3-dimethyl-5-hydroxypyrazole (50 mmol) was added to a suspension of 7.7 g 2-chloro-6-cyanopyridine (55 mmol) and 7.6 g K2CO3 (55 mmol) in 50 ml N,N-dimethylformamide and heated to reflux with vigorous stirring for 5 hours. After cooling, the mixture was poured into water (100 ml) and the aqueous layer extracted 3 times with each 100 ml ethyl acetate. The combined extracts were dried with anhydrous magnesium sulphate and the solvent was removed in vacuo. The residue was purified by flash silica gel column chromatography using hexane/ethyl acetate 7/3. The title compound was obtained after recrystallisation from isopropanol as 5.9 g (55%) of white crystals of m.p. 95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].CCN=C=NCCCN(C)C.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]([O:15][CH3:16])[CH3:13])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(Cl)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution 4-chloro-2-fluorobenzoic acid (1 eq) in CH2Cl2 (1.6 M) was added N,O-dimethylhydroxylamine hydrochloride (1.5 eq), EDCI (1.5 eq) and triethylamine (4 eq). The reaction mixture was stirred at rt for 16 hrs, concentrated and 0.5M aqueous citric acid was added. The mixture was extracted with 1:1 EtOAc:Et2O. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give 4-chloro-2-fluoro-N-methoxy-N-methylbenzamide, which was used as such for the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]([C:8]1[O:12][N:11]=[C:10]([CH:13]([NH:18]C(OC(C)(C)C)=O)[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:9]=1)=[O:7])[CH3:2].[ClH:27]>O1CCOCC1>[ClH:27].[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]([C:8]1[O:12][N:11]=[C:10]([CH:13]([NH2:18])[CH2:14][CH:15]([CH3:16])[CH3:17])[CH:9]=1)=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1cc(C(CC(C)C)NC(=O)OC(C)(C)C)no1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CC(=O)c1cc(C(N)CC(C)C)no1

Procedure:
A solution of 3-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-yl]-3-oxo-propionic acid ethyl ester (1.4 g, 3.9 mmol) in 4M HCl in dioxane (5 ml) was stirred at room temperature. After 3 h the mixture was concentrated under reduced pressure to give the title compound as a pale yellow solid. MS [M+1]+269.0.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([CH:6]=[CH2:7])=[CH2:5].[CH2:10]([NH:12][CH2:13][CH2:14][CH3:15])[CH3:11].B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH2:10]([N:12]1[CH2:7][CH2:6][C:4](=[O:5])[CH2:3][CH:13]1[CH2:14][CH3:15])[CH3:11]
Reactant: CCCNCC
Reactant: C=CC(=C)O[Si](C)(C)C
Agent: Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCC1CC(=O)CCN1CC

Procedure:
To 100 mL of methylene chloride cooled to 0° C. is added 2-(trimethylsilyloxy)-1,3-butadiene (14.2 g, 0.1 mol), 8.5 g (0.1 mol) of N-ethyl-propanamine, and 14.2 g (0.1 mol) of borontrifluoride etherate. Monitor the reaction by thinlayer chromatography. Upon completion add 1N HCl until gas evolution ceases. Separate the aqueous layer and make it alkaline with 1N NaOH. Extract twice with 100 mL ether and dry over Na2SO4. Filter the drying agent and evaporated the solvent in vacuo to obtain the title compound.
Reaction SMILES: Br[C:2]1[C:3](=[O:18])[N:4]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[N:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Li])CCC.[Cl-].[NH4+]>C1COCC1>[Cl:17][C:12]1[CH:11]=[C:10]([N:4]2[C:3](=[O:18])[CH:2]=[C:7]([O:8][CH3:9])[CH:6]=[N:5]2)[CH:15]=[C:14]([Cl:16])[CH:13]=1
Reactant: COc1cnn(-c2cc(Cl)cc(Cl)c2)c(=O)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cnn(-c2cc(Cl)cc(Cl)c2)c(=O)c1

Procedure:
4-Bromo-2-(3,5-dichlorophenyl)-5-methoxypyridazin-3-one (2.5 g, 0.0071 moles) was dissolved in THF (250 ml) and cooled to −50° under nitrogen. 1.6M n-Butyl lithium (6.7 ml, 0.011 moles) was added dropwise with stirring. Allowed to warm to −20° over 1 hour. Added 1 equivalent of 1.6M n-Butyl lithium (4.4 ml, 0.0071 moles) dropwise. Stirred at −20° for 30 minutes. Poured into ammonium chloride solution and stirred for 15 minutes. Extracted with EtOAc (×2) and washed with water. Dried over anhydrous magnesium sulphate, filtered and evaporated to give a brown solid. (3.0 g) Purified using MPLC (silica, eluted with dichloromethane: EtOAc 9:1) to give a yellow solid. (0.25 g, 13%) Not pure used directly in the next reaction.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[NH2:21][C@H:22]1[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1>>[N:24]12[CH2:23][C@@H:22]([NH:21][C:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:9]4[O:8][C:7]([N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[N:11][C:10]=34)=[O:18])[CH:27]([CH2:28][CH2:29]1)[CH2:26][CH2:25]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)c1cccc2oc(N3CCCCC3)nc12
Agent: Cl
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(N3CCCCC3)nc12

Procedure:
Following general procedure GP-C1, a mixture of 2-(piperidin-1-yl)benzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-2-(piperidin-1-yl)benzoxazole-4-carboxamide which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: C([N:5]1[C:9]([NH:10][C:11]([C:13]2[CH:28]=[CH:27][C:16]3[N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)[CH:18]=[N:19][C:15]=3[CH:14]=2)=[O:12])=[CH:8][C:7]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[N:6]1)(C)(C)C>C(O)=O>[C:31]1([CH3:35])[CH:32]=[CH:33][CH:34]=[C:29]([C:7]2[CH:8]=[C:9]([NH:10][C:11]([C:13]3[CH:28]=[CH:27][C:16]4[N:17]([C:20]5[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=5)[CH:18]=[N:19][C:15]=4[CH:14]=3)=[O:12])[NH:5][N:6]=2)[CH:30]=1
Reactant: Cc1cccc(-c2cc(NC(=O)c3ccc4c(c3)ncn4-c3cccc(F)c3)n(C(C)(C)C)n2)c1
Solvent: O=CO
Product: Cc1cccc(-c2cc(NC(=O)c3ccc4c(c3)ncn4-c3cccc(F)c3)[nH]n2)c1

Procedure:
General procedure for t-butyl cleavage: N-(2-tert-butyl-5-m-tolyl-2H-pyrazol-3-yl) 1-(3-Fluoro-phenyl)-1H-benzimidazole-5-carboxamide (110 mg, 0.235 mmol) was dissolved in formic acid (3 mL) and the mixture stirred at reflux for 30 min. The solvent was then evaporated and chased with CHCl3 and Et2O and the residue triturated with MeOH. The resulting precipitate was filtered off and washed with MeOH and CHCl3 to give N-(5-m-tolyl-2H-pyrazol-3-yl) 1-(3-fluorophenyl)-1H-benzimidazole-5-carboxamide: 1H NMR (400 MHz, CDCl3) δ 2.55 (s, 3H), 7.05 (br.s, 1H), 7.18 (br.d, J=8.4 Hz, 1H), 7.33-7.43 (m, 2H), 7.57 (br.d, J=7.6 Hz, 1H), 7.62 (br.d, J=8.0 Hz, 2H), 7.70-7.74 (m, 2H), 7.78 (d, J=8.4 Hz, 1H), 8.07 (dd, J=8.0 Hz, J=2.0 Hz, 1H), 8.54 (s, 1H), 8.75 (s, 1H); MS (ES+): m/z 412 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH2:12])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.[H-].[Na+].C(N(CC)C(C)C)(C)C.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37](Cl)=[O:38])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>O1CCCC1>[C:24]([O:28][C:29]([N:31]1[CH2:32][CH2:33][N:34]([C:37](=[O:38])[NH:12][C:10]2[S:9][C:5]3[N:6]=[CH:7][N:8]=[C:3]([O:2][CH3:1])[C:4]=3[N:11]=2)[CH2:35][CH2:36]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: COc1ncnc2sc(N)nc12
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncnc2sc(NC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)nc12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
A solution of 7-methoxy-thiazolo[5,4-d]pyrimidin-2-ylamine (3.5 g, 19.2 mmol) in tetrahydrofuran (100 mL) was treated with sodium hydride (60% in mineral oil, 2.3 g, 57 mmol) at 25° C. A slight evolution of gas was observed. The resulting purple slurry was warmed to 50° C. for 1 h. At this time, the reaction was cooled to 25° C. and was treated with N,N-diisopropylethylamine (10 mL, 57 mmol). The resulting mixture was stirred at 25° C. for 30 min. The mixture was then treated with a solution of 4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester (4.73 g, 19 mmol) in tetrahydrofuran (20 mL) over a 10 min period. The reaction was stirred at 50° C. overnight. At this time, the reaction was concentrated in vacuo, diluted with methanol (100 mL) and absorbed onto silica gel (6 g). The silica gel was divided into two equal lots. ISCO chromatography (330 g, Silica, gradient elution 5/95 methanol/methylene chloride) afforded 4-(7-methoxy-thiazolo[5,4-d]pyrimidin-2-ylcarbamoyl)-piperazine-1-carboxylic acid tert-butyl ester (5.58 g, 74%) as an off-white solid; LRMS for C16H22N6O4S (M+H)+ at m/z=395. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C(C)=O)cc1
Yield: 50.8 %

Procedure:
A solution of 0.90 g (6.61 mmol) of 4'-hydroxyacetophenone, and 1.93 g (9.92 mmol) of ethyl 4-bromobutyrate in 1.80 mL of N,N-dimethylformamide is stirred for 48 hours, under dry conditions with 2.74 g (19.8 mmol) of potassium carbonate and 0.110 g (0.66 mmol) of potassium iodide. The reaction mixture is then evaporated under vacuum, and the residue partitioned between ether and water. The organic phase is separated, washed thrice with water, dried with magnesium sulfate, filtered, and evaporated under vacuum to give a brown solid. This is recrystallized from a warm ether-hexane mixture. The beige crystals are air dried, leaving 0.84 g (51%) of 4-(4-acetylphenoxy)butanoic acid, ethyl ester: m.p. 59°-61° C.; IR (KBr) 1740, 1670 cm-1 ; 1H-NMR (CDCl3) is consistent with the desired product; MS (FAB) m/e 251.1285 Δ=-0.2 mmμ (M+ +H). Analysis calculated for C14 H18O4 : C, 67.18; H, 7.25; O, 25.57. Found: C, 67.16; H, 7.16; O, 25.68.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH3:30][C:31]1(O)[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([O:9][C:31]2([CH3:30])[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(O)CCCC1
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Product: CC1(OC(=O)C#C[C@H]2[C@@H](C(=O)O[C@H](C#N)c3cccc(Oc4ccccc4)c3)C2(C)C)CCCC1
Yield: 55.1 %

Procedure:
Using the procedure of Step A of Example 15, 3 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[2-carboxyethynyl]-cyclopropane-carboxylate and 3 g of 1-methylcyclopentanol were reacted. The residue was chromatographed over silica gel and was eluted with an 8-2 n-hexane-ethyl acetate mixture to obtain 2 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[2-(1-methylcyclopentyloxycarbonyl)ethynyl]-cyclopropane-carboxylate.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[CH3:17][Si:18]([CH3:33])([CH3:32])[CH2:19][CH2:20][O:21][C:22](=O)[O:23]N1C(=O)CCC1=O>ClCCl>[CH3:2][O:3][C:4](=[O:9])[CH:5]([NH:6][C:22]([O:21][CH2:20][CH2:19][Si:18]([CH3:33])([CH3:32])[CH3:17])=[O:23])[CH2:7][OH:8]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NC(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 108.2 %

Procedure:
To a mixture of 1.25 g serine methyl ester hydrochloride, 2.25 ml triethylamine and 10 ml dichloromethane was added at 0° C. a solution of 2.22 g carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 2-trimethylsilanyl-ethyl ester [R. E. Shute, D. H. Rich, Synthesis, 1987, 346]. After stirring for 24 h at rt the reaction mixture was washed two times with 1N potassium hydrogen sulfate, once with saturated sodium bicarbonate solution and once with brine. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 2.29 g of a colorless liquid.
Reaction SMILES: [N:1]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]([CH:12]([C:14]([O:16]C)=[O:15])[CH3:13])[C:5]1=[O:18])=[N+:2]=[N-:3].[OH-].[Na+]>>[N:1]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]([CH:12]([C:14]([OH:16])=[O:15])[CH3:13])[C:5]1=[O:18])=[N+:2]=[N-:3]
Reactant: COC(=O)C(C)N1CCCCCC(N=[N+]=[N-])C1=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)N1CCCCCC(N=[N+]=[N-])C1=O

Procedure:
Saponify this ester with dilute NaOH, acidify the reaction mixture and extract with methylene chloride. After drying and concentration of the extracts, isolate 3-azido-1-(1-carboxyethyl)-perhydroazocin-2-one. Fractionally crystallize this material from acetonitrile as the dicyclohexylamine salt to obtain the desired diastereomer.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:5]=1[O:6][CH:7]([CH3:13])[C:8]([O:10]CC)=[O:9]>CCO>[Cl:3][C:4]1[CH:17]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:15]=[CH:14][C:5]=1[O:6][CH:7]([CH3:13])[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C(C)Oc1ccc(C(F)(F)F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(Oc1ccc(C(F)(F)F)cc1Cl)C(=O)O

Procedure:
50 mL (0.100 mol) of 2 M aqueous NaOH solution was added to a solution of 14.00 g (0.047 mol) of ethyl 2-(2-chloro-4-trifluoromethyl-phenoxy)-propionate in 100 mL EtOH and the mixture was refluxed for 1 hour. EtOH was evaporated off i. vac., the residue was diluted with ice water and acidified with 2 M aqueous HCl. The precipitate formed was filtered off, washed with water and dried at 70° C. i. vac.
Reaction SMILES: Cl.O1CCOCC1.[C:8]([C:10]1[C:11]([O-])=[N:12][CH:13]=[C:14]([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]2)[CH:15]=1)#[N:9].[Na+].P(Cl)(Cl)([Cl:30])=O.[OH-].[Na+]>C(#N)C.O.C(O)(C)C>[Cl:30][C:11]1[N:12]=[CH:13][C:14]([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]2)=[CH:15][C:10]=1[C:8]#[N:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)N1CCN(Cc2cnc([O-])c(C#N)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CC(C)N1CCN(Cc2cnc(Cl)c(C#N)c2)CC1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
A 4.0 M solution of hydrogen chloride in dioxane (1.33 ml, 5.31 mmol) was added to a stirred suspension of sodium 3-cyano-5-[(4-isopropylpiperazin-1-yl)methyl]pyridin-2-olate (1.5 g, 5.31 mmol; see Method 21) in acetonitrile (15 ml). The mixture was heated to 40° C. and phosphorous oxychloride (2.48 ml, 26.6 mmol) added then the mixture was heated at 80° C. for 18 hours. After cooling to room temperature, isopropyl alcohol (8 ml) was added and the mixture stirred for 10 minutes. The mixture was diluted with water (50 ml) and basified with a solution of sodium hydroxide (1M) to pH 8. The product was extracted with dichloromethane (2×100 ml), the extracts dried over magnesium sulfate, filtered and concentrated to yield the title compound as a brown oil (1.2 g, 81%).