Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([N:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])=[C:3]([C:6]#[N:7])[C:4]#[N:5].C(N(CC)CC)C.[SH2:22]>N1C=CC=CC=1>[NH2:1][C:2]([N:8]([CH2:9][CH2:10][CH3:11])[CH2:12][CH2:13][CH3:14])=[C:3]([C:4]#[N:5])[C:6](=[S:22])[NH2:7]
Reactant: S
Reactant: CCCN(CCC)C(N)=C(C#N)C#N
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(N)=C(C#N)C(N)=S
Reaction time: 48 h
Yield: 29.1 %

Procedure:
An attempt at conversion by the method of Example IV, part D, was unsuccessful. Thus a mixture of 28 g of 3-amino-2-cyano-3-(dipropylamino)propenenitrile, 14.7 g of triethylamine and 100 ml of pyridine in a pressure bottle was cooled to -70° and 10 g of hydrogen sulfide were added. The bottle was capped and allowed to stand at ambient temperature during two days, then heated at 80° for about 16 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in a minimum of toluene containing a trace of ethanol. The solid which separated on cooling was collected to obtain 9.6 g of 3-amino-2-cyano-3-(dipropylamino)propenethioamide, m.p. 141°-144°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]([F:21])([F:20])[CH:17]([OH:19])[CH3:18]>>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([O:19][CH:17]([CH3:18])[C:16]([F:21])([F:20])[F:15])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CC(O)C(F)(F)F
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F

Procedure:
Prepared in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1(a)) and rac-1,1,1-trifluoro-propan-2-ol. The crude material was purified by preparative HPLC to yield the title compound as a white solid. MS (m/e): 311.3 ([M−H]−, 100%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[Br:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:17][CH:16]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 90 °C
Reaction time: 20 h
Yield: 67 %

Procedure:
Under an argon gas atmosphere, 70.0 g (407 mmol) of 2-naphthaleneboronic acid, 115.10 g (407 mmol) of 4-bromoiodobenzene, 9.40 g (8.14 mmol) of tetrakis(triphenylphosphine)palladium(0), 1.2 L of toluene and 600 mL of aqueous solution of 2M sodium carbonate were added together, and stirred at 90 degrees C. for 20 hours. After the reaction was over, toluene was distilled away and methanol was added. Then, the precipitated solid was separated by filtration. The obtained solid was recrystallized with acetic ether and methanol and dried. 77.2 g of 2-(4-bromophenyl)naphthalene was obtained at an yield of 67%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][CH:21]([CH3:41])[CH2:22][CH:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[OH:24].O[C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][N:44]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:20][CH:21]([CH3:41])[CH2:22][CH:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[O:24][C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][N:44]=1
Reactant: CC(C)CC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)c1ccc(O)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
A mixture of triphenylphosphine (1.34 g, 5.09 mmol), 3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-ol (942 mg, 3.06 mmol), and methyl 6-hydroxynicotinate (0.390 g, 2.55 mmol) in tetrahydrofuran (30 mL) was stirred at room temperature for 0.5 hours. Diisopropyl azodicarboxylate (1.02 g, 5.09 mmol) was added dropwise. After consumption of the starting material, as indicated by TLC, the mixture was concentrated. Purification by column chromatography gave methyl 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butoxy)nicotinate (400.0 mg, 36%). 1H NMR (400 MHz, CDCl3, δ): 8.69 (d, 1H), 8.04-8.06 (m, 1H), 7.56-7.61 (m, 4H), 7.42-7.48 (m, 4H), 6.72 (d, 1H), 6.20-6.24 (m, 1H), 3.78 (s, 3H), 1.94-2.01 (m, 1H), 1.58-1.72 9 (m, 2H), 0.89-0.94 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: C1CCNCC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and piperidine in DMSO at ambient temperature.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Li]CCCC.CN([CH:29]=[O:30])C>>[CH3:1][C:2]1[N:3]=[C:4]([CH:29]=[O:30])[N:5]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ncn(COCC[Si](C)(C)C)c1-c1ccccc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: Cc1nc(C=O)n(COCC[Si](C)(C)C)c1-c1ccccc1
Yield: 96.7 %

Procedure:
Reaction of 4-methyl-5-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (187 mg, 0.65 mmol), 2.5 M n-BuLi (338 uL, 0.84 mmol), and DMF (151 uL, 1.95 mmol) for 2 h at −40° C. gave the title compound (199 mg, 99%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.94 (t, 2H, J=7.5 Hz), 2.54 (s, 3H), 3.61 (t, 2H, J=7.5 Hz), 5.88 (s, 2H), 7.33-7.38 (m, 1H), 7.46 (dd, 2H, J=7.5, 7.5 Hz), 7.68 (d, 2H, J=6.0 Hz), 9.82 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:33](Cl)(=[O:35])[CH3:34].O>C1COCC1>[C:33]([N:31]([CH3:32])[C:27]1[CH:26]=[C:25]([O:24][C:18]2[CH:17]=[C:16]3[C:21]([CH2:22][CH2:23][CH:14]([C:12]([NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=4)=[O:13])[CH2:15]3)=[CH:20][CH:19]=2)[CH:30]=[CH:29][N:28]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CNc1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cccc(C(C)(C)C)c2)CC3)ccn1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(C)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cccc(C(C)(C)C)c2)CC3)ccn1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of N-(3-tert-butylphenyl)-7-{[2-(methylamino)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide (337 mg, 0.78 mmol) in THF (8 mL) was added TEA (0.219 mL, 1.57 mmol). The reaction mixture was cooled to 0° C. and acetyl chloride (0.062 mL, 0.86 mmol) was added dropwise. The reaction mixture was allowed to stir at 0° C. for 5 hr. during which time further portions of TEA (0.219 mL, 1.57 mmol) and acetyl chloride (0.62 mL, 0.86 mmol) were added. Water was added and the mixture was extracted with EtOAc. The organic solutions were combined, washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography. The product was further purified by HPLC (250 mm C18 column) eluting with 40% A/60% B to 100%/0% B (25 min gradient) (A=99/1 H2O in AcCN, 0.1% FA, B=95/5 AcCN/H2O, 0.1% FA). The product was dissolved in DCM and MeOH and 2M HCl-Et2O solution was added. The solvents were evaporated to provide 7-({2-[acetyl(methyl)amino]pyridin-4-yl}oxy)-N-(3-tert-butylphenyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-395 as the HCl salt (22 mg, 5.4%). 1H NMR (300 MHz, d6-DMSO, HCOOH Salt) δ: 9.94 (s, 1H), 8.31 (d, 1H), 7.63 (t, 1H), 7.50 (d, 1H), 7.24-7.18 (m, 2H), 7.10-7.05 (m, 2H), 6.76 (dd, 3H), 3.24 (s, 3H), 2.95-2.71 (m, 5H), 2.13-1.99 (m, 4H), 1.85-1.72 (m, 1H), and 1.26 (s, 9H). LCMS: (FA) ES+470.2, ES−472.9
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:21])[CH2:16][C:15]3[C:10](=[C:11]([Cl:19])[C:12]([Cl:18])=[C:13]([OH:17])[CH:14]=3)[C:9]2=[O:20])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32]CC)=[O:31].[OH-].[Na+].Cl>CN(C)C=O.O>[O:20]=[C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:17][CH2:29][C:30]([OH:32])=[O:31])=[C:12]([Cl:18])[C:11]=2[Cl:19])[CH2:16][C:8]1([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:21]
Reactant: CC1(c2ccc(Br)cc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2ccc(Br)cc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 100 °C

Procedure:
A stirred mixture of 2-(4-bromophenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (4.48 g., 0.0116 mole), potassium carbonate (3.88 g., 0.0232 mole) and ethyl bromoacetate (3.21 g., 0.0232 mole) in dimethylformamide (100 ml.) is warmed at 55°-60° C. for 3 hours, then treated with water (100 ml.)-10 N sodium hydroxide solution (5 ml., 0.05 mole) and heated at 100° C. for 2 hours. The reaction mixture is added slowly to crushed ice-water (1500 ml.)-12 N hydrochloric acid (50 ml.) to precipitate 3.24 g. of [1-oxo-2-(4-bromophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid which melts at 171°-172° C. after crystallization from nitromethane followed by acetic acid: water, 3:2.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([S:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:10]=[C:9]1[CH2:25]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:34]1C(SC2C=C(Cl)C=C(Cl)C=2)=C(C(C)C)N=C1CO)C1C=CC=CC=1>>[NH2:34][CH2:25][C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]([S:13][C:14]2[CH:15]=[C:16]([Cl:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[C:11]([CH:22]([CH3:23])[CH3:24])[N:10]=1
Reactant: CC(C)c1nc(CO)n(Cc2ccccc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CC(C)c1nc(CCl)n(Cc2ccccc2)c1Sc1cc(Cl)cc(Cl)c1
Product: CC(C)c1nc(CN)n(Cc2ccccc2)c1Sc1cc(Cl)cc(Cl)c1

Procedure:
1-Benzyl-2-chloromethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-imidazole (28e)was synthesized from [1-benzyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-imidazol-2-yl]methanol by the same synthetic process as that for (28a)in Example 66, and without purification of this compound, 2-azidomethyl-1-benzyl-5-(3,5-dichlorophenylthio)-4-isopropylimidazole (29e)was obtained by the same synthetic process as that for (29a)in Example 66. Oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:13][CH:14]([C:16]#[C:17][CH3:18])[CH3:15])[CH:3]=1.O.Cl>CO.[OH-].[Na+]>[NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:13][CH:14]([C:16]#[C:17][CH3:18])[CH3:15])[CH:3]=1
Reactant: CC#CC(C)Oc1cc(N)c(Cl)cc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC#CC(C)Oc1cc(N)c(Cl)cc1C(=O)O
Yield: 97 %

Procedure:
To the suspension of methyl 4-amino-5-chloro-2-{(3-pentyn-2-yl)oxy}benzoate (56.0 g) in methanol (1.3 l), aqueous sodium hydroxide (5N) solution (140 ml) was added. The resultant mixture was stirred for 6 hours at 50° C., and then 3 days at room temperature. To the obtained mixture, water (1 l) was added, followed by acidification with 2N hydrochloric acid. Crystal thus precipitated was recovered by filtration, washed with water and dried to obtain 51.5 g of the title compound as colorless crystal.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([OH:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][N:24]=[C:25]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[CH2:37]Br)[C:26]([O:28][CH3:29])=[O:27]>CN(C)C=O>[CH3:22][O:23][N:24]=[C:25]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[CH2:37][O:11][C:9]1[CH:8]=[C:7]([C:12]([F:14])([F:15])[F:13])[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[N:10]=1)[C:26]([O:28][CH3:29])=[O:27]
Reactant: CC(C)Oc1nc(O)cc(C(F)(F)F)n1
Reactant: CON=C(C(=O)OC)c1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CON=C(C(=O)OC)c1cccc(Cl)c1COc1cc(C(F)(F)F)nc(OC(C)C)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
3.3 g of 2-isopropoxy-4-hydroxy-6-trifluoromethylpyrimidine and 2.4 g of potassium carbonate are stirred at room temperature (about 25° C.) for 30 min in 100 ml of dimethyl formamide and the mixture is then treated dropwise in the course of 1 hour with a solution of 4.8 g of methyl 2-methoxyimino-2-[2-bromomethyl-3-chlorophenyl]acetate in 30 ml of dimethylformamide. After a further 8 hours at room temperature, the reaction mixture is added to ice water and the product is extracted using tert-butyl methyl ether. The combined ether phases are dried and concentrated. The crude product thus obtained is purified by chromatography (silica gel/toluene). 4.2 g of the title compound are obtained.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@H:4]([CH3:8])[N:3]1[C:9]1[O:10][C:11]2[C:12](=[C:14]([C:18]([O-:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)[N:13]=1.[Li+:21].C([O-])(O)=O.[Na+].[CH:27]([O:30][C:31](Cl)=[O:32])([CH3:29])[CH3:28].Cl>C(Cl)(Cl)Cl.O>[CH:27]([O:30][C:31]([N:6]1[CH2:5][C@H:4]([CH3:8])[N:3]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([O-:20])=[O:19])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)[C@@H:2]([CH3:1])[CH2:7]1)=[O:32])([CH3:29])[CH3:28].[Li+:21]
Reactant: CC(C)OC(=O)Cl
Reactant: C[C@H]1CNC[C@H](C)N1c1nc2c(C(=O)[O-])cccc2o1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)OC(=O)N1C[C@H](C)N(c2nc3c(C(=O)[O-])cccc3o2)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vigorously stirred suspension of lithium 2-((2S,6S)-2,6-dimethylpiperazin-1-yl)benzoxazole-4-carboxylate (208 mg, 0.743 mmol) and NaHCO3 (187 mg, 2.23 mmol) in chloroform (12 mL) and H2O (2 mL) was added dropwise isopropylchloroformate (1M solution in toluene, 892 mL, 0.891 mmol). The reaction mixture was stirred at room temperature for 2 h, then neutralized with 1N aqueous HCl. The mixture was concentrated under reduced pressure to provide lithium 2-((2S,6S)-4-(isopropoxycarbonyl)-2,6-dimethylpiperazin-1-yl)benzoxazole-4-carboxylate. MS consistent.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[S:21][CH:22]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][NH2:39])[CH:33]=1>>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([NH:39][CH2:38][C:34]4[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=4)=[O:28])=[CH:30][CH:31]=3)[S:21][CH:22]=2)(=[O:16])=[O:15])=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cc2csc(-c3ccc(C(=O)O)cc3)n2)cc1
Reactant: NCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2csc(-c3ccc(C(=O)NCc4cccnc4)cc3)n2)cc1
Yield: 68.3 %

Procedure:
Reaction of oxalyl chloride (70 λL, 0.8 mmol) and benzoic acid 53 (200 mg, 0.54 mmol) with subsequent reaction with 3-pyridinylmethylamine (60 λL, 0.6 mmol) gave benzamide 54 (171 mg, 68%) as a white powder: mp (EtOAc) 178-181° C.; 1H NMR δ 9.19 (t, J=5.9 Hz, 1H, CONH), 8.57 (d, J=1.6 Hz, 1H, H-2″), 8.47 (dd, J=4.8, 1.5 Hz, 1H, H-6″), 7.97 (dd, J=6.7, 1.8 Hz, 2H, H-2, H-6), 7.81 (dd, J=6.7, 1.8 Hz, 2H, H-3, H-5), 7.74 (ddd J=8.1, 2.1, 1.6 Hz, 1H, H-4″), 7.68 (s, 1H, H-5′), 7.65 (dd, J=8.3, 1.7 Hz, 2H, H-2′″, H-6″), 7.41 (br d, J=8.3 Hz, 2H, H-3′″, H-5″), 7.36 (ddd, J=8.1, 4.8, 0.7 Hz, 1H, H-5″), 4.87 (s, 2H, CH2SO2), 4.51 (d, J=5.9 Hz, 2H, CH2N), 2.40 (s, 3H, CH3); 13C NMR δ 165.7, 165.5, 148.9, 148.1, 145.2, 144.3, 135.9, 135.3, 135.2, 135.0, 134.9, 129.5 (2), 128.2 (2), 128.1 (2), 125.9 (2), 123.4, 122.2, 57.0, 40.5, 21.0; MS m/z 464.8 (MH+, 100%). Anal. calcd for C24H21N3O3S2: C, 62.18; H, 4.57; N, 9.06. Found: C, 62.30; H, 4.55; N, 9.10%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[OH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([O-])=[O:31])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:28]=[CH:27][C:26]([N:23]5[CH2:24][CH2:25][CH:20]([OH:19])[CH2:21][CH2:22]5)=[CH:34][CH:33]=4)=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[CH:12][CH:13]=1)#[N:18]
Reactant: O=C([O-])c1ccc(N2CCC(O)CC2)cc1
Reactant: N#Cc1ccc(-n2ncc3cc(N)ccc32)cc1
Product: N#Cc1ccc(-n2ncc3cc(NC(=O)c4ccc(N5CCC(O)CC5)cc4)ccc32)cc1

Procedure:
Compound 404 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-cyanophenyl)indazole and 4-(4-hydroxypiperidino)benzoate. [M+H]+ calcd for C26H23N5O2: 438.19; found: 437.99.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[CH2:10]2)[S:7][CH:8]=1)([OH:3])=O.[Si:46]([O:63][CH:64]1[CH2:67][NH:66][CH2:65]1)([C:59]([CH3:62])([CH3:61])[CH3:60])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O>[Si:46]([O:63][CH:64]1[CH2:65][N:66]([C:1]([C:4]2[N:5]=[C:6]([N:9]3[CH2:10][CH:11]([S:13][C:14]4[C@H:15]([CH3:45])[C@@H:16]5[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:38])[CH3:39])[CH3:35])[C:32](=[O:44])[N:17]5[C:18]=4[C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])[CH2:12]3)[S:7][CH:8]=2)=[O:3])[CH2:67]1)([C:59]([CH3:62])([CH3:60])[CH3:61])([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)O)cs4)C3)[C@H](C)[C@H]12
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Agent: CCP(=O)(C#N)CC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N5CC(O[Si](c6ccccc6)(c6ccccc6)C(C)(C)C)C5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 32.2 %

Procedure:
Subsequently, to a solution of p-nitrobenzyl (1R,5S,6S)-2-[1-(4-carboxy-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.71 g, 2.53 mmol) and 3-t-butyldiphenylsilyloxyazetidine (947 mg, 3.04 mmol) (obtained as described above) in dimethylformamide (86 ml) were added diethylphosphoryl cyanide (461 μl, 3.04 mmol) and triethylamine (426 μl, 3.04 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred at room temperature for 5.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed successively with 0.5M aqueous hydrochloric acid solution, 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 toluene:acetonitrile (4:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(3-t-butyldiphenylsilyloxyazetidine-1-carbonyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (789 mg, yield 32%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.ClC(OC(Cl)C)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)[CH2:10][CH2:9]1
Reactant: FC(F)(F)c1csc(NC2CCN(Cc3ccccc3)CC2)n1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: FC(F)(F)c1csc(NC2CCNCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
To a stirred solution of (1-benzyl-piperidin-4-yl)-(4-trifluoromethyl-thiazol-2-yl)-amine (D8) (0.57 g, 1.68 mmol) and diisopropylethylamine (1.04 ml, 5.88 mmol) in dichloromethane (15 ml) at 0° C., was added 1-chloroethyl chloroformate (0.45 ml, 4.2 mmol). The reaction mixture was stirred at room temperature for 3 h. and after this period, diluted with dichloromethane and extracted with a saturated solution of sodium hydrogen carbonate (5 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was dissolved in methanol (5 ml) and the reaction mixture was stirred at reflux for 3 h. After evaporation of the solvent, the crude product was purified by column chromatography (silica gel; 5-8% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. The crude product was crystallized from acetonitrile to yield D9 (0.34 g, 81%) as a white solid. C9H12F3N3S requires 251. Found 252 (MH+).
Reaction SMILES: [Na].[CH3:2][C:3]1([CH3:10])[CH2:8][NH:7][C:6]([NH2:9])=[N:5][CH2:4]1.[C:11](OCC)(=[O:16])[CH2:12][C:13]([O-])=[O:14]>CO>[OH:16][C:11]1[N:9]=[C:6]2[NH:7][CH2:8][C:3]([CH3:10])([CH3:2])[CH2:4][N:5]2[C:13](=[O:14])[CH:12]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC1(C)CN=C(N)NC1
Agent: [Na]
Solvent: CO
Product: CC1(C)CNc2nc(O)cc(=O)n2C1
Temperature: 100 °C
Yield: 72 %

Procedure:
1.4 g of sodium are added in a fractionated way to 15 mL of MeOH. After total dissolution, 2.7 g of 5,5-dimethyl-1,4,5,6-tetrahydropyrimidin-2-amine solubilized beforehand in 5 mL of MeOH, and then 16.5 mL of ethyl malonate are added. The mixture is heated to 100° C., after 4 h of heating, the medium is dry concentrated. The obtained oil is taken up in ether. The precipitate is filtered and then the residue is taken up in 7 mL of H2O and acidified with conc. HCl up to pH 3-4. The precipitate formed is filtered, washed with ether and dried in the oven in vacuo. 2 g (yield=72%) of 2-hydroxy-7,7-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained as a beige solid used as such.