Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][NH:85][CH2:84][C@@H:83]1[CH3:88])=[O:81])[CH3:78]>CN(C=O)C>[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][N:85]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH:32]3[CH2:33][CH2:34][CH2:35]3)=[O:24])[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[CH2:84][C@@H:83]1[CH3:88])=[O:81])[CH3:78]
Reactant: CCOC(=O)N1CCNC[C@@H]1C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)C[C@@H]1C
Reaction time: 36 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 28 μl DIPEA, 64 mg HATU and 29 mg (S)-2-Methyl-piperazine-1-carboxylic acid ethyl ester. After stirring for 36 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 186 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][O:6][C:5](=[O:8])[O:4]1)=[CH2:2].[CH2:9]([O:13][C:14](=[O:18])[CH2:15][CH2:16][SH:17])[CH2:10][CH2:11][CH3:12].N(C(C)(C)C#N)=NC(C)(C)C#N>>[O:8]=[C:5]1[O:4][CH:3]([CH2:1][CH2:2][S:17][CH2:16][CH2:15][C:14]([O:13][CH2:9][CH2:10][CH2:11][CH3:12])=[O:18])[CH2:7][O:6]1
Reactant: C=CC1COC(=O)O1
Reactant: CCCCOC(=O)CCS
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCOC(=O)CCSCCC1COC(=O)O1
Temperature: 110 °C
Reaction time: 22 h

Procedure:
3.87 grams (33.9 mmol, MW: 114.10) 4-vinyl-1,3-dioxaolane-2-one, 5.0 grams (30.8 mol, MW: 162.25) butyl-3-mercaptopropionate and 0.505 grams (3.1 mmol, MW: 164.21) 2,2′-azobis(2-methylpropionitrile) (AIBN) were charged in a 25 milliliter thick sealed glass reactor. After addition, the reaction mixture was stirred for 22 hours at 110° C. The reaction was then stopped and cooled down to room temperature. The excess of unreacted 4-vinyl-1,3-dioxaolane-2-one was removed by air bath oven at 180° C. under vacuum for 1 hour. The final product was determined by IR, 13CNMR. Yield: 4.26 grams (50%). IR: (cm−1) 2960, 2933, 2873, 1803, 1731, 1456, 1390, 1351, 1246, 1169, 1065, 772. 13C NMR (CDCl3): 171.7, 154.7, 124.6, 113.4, 75.4, 69.2, 64.5, 35.0, 33.9, 30.5, 27.2, 19.1, 13.7.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][NH:7][C:8](=[O:30])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[N+:27]([O-])=O)[CH:10]=1>CO.[Pd]>[F:34][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][NH:7][C:8](=[O:30])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:18]=[CH:17][C:16]=2[NH2:27])[CH:10]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCOCC3)ccc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCOCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(5-morpholino-2-nitrophenyl)isonicotinamide (100 mg, 0.21 mmol, 1.00 equiv) in methanol (5 mL). The solution was treated with Pd/C (100 mg), and stirred under an atmosphere of hydrogen overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 50 mg (53%) of product as a yellow oil.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=1)(C)C>CCOC(C)=O>[C:6]([C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(OCCO)cc1
Solvent: CCOC(C)=O
Product: C#Cc1ccc(OCCO)cc1

Procedure:
The product was obtained analogously to Example 1.1c starting from 12.20 g (52.05 mmol) of 2-(4-trimethylsilanylethynylphenoxy)ethanol. Yield: 7.70 g (91% of theoretical); C1oH10O2 (M=162.185); calc.: molpeak (M+H)+: 163; found: molpeak (M+H)+: 163; Rf value: 0.32 (silica gel, PE/EtOAc 6:4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=2)[N:5]=[C:4]2[CH2:14][CH2:15][CH2:16][C:3]=12>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][CH2:11][CH:10]([OH:13])[CH:9]=2)[N:5]=[C:4]2[CH2:14][CH2:15][CH2:16][C:3]=12
Reactant: O=C1C=C(c2cc(Cl)c3c(n2)CCC3)CC1
Solvent: C1CCOC1
Product: OC1C=C(c2cc(Cl)c3c(n2)CCC3)CC1
Temperature: 55 °C
Reaction time: 4 h
Yield: 28.2 %

Procedure:
A 25-mL round bottom flask was charged with 3-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyclopent-2-enone (0.434 g, 1.85 mmol) and THF (8 mL) at rt. Borane-dimethylsulfide complex (0.22 mL, 2.32 mmol) was added and the resulting solution was stirred at 55° C. for 4 h. After this time, the reaction was quenched with methanol, treated with 2N aqueous HCl (5 drops), and concentrated under reduced pressure. The residue was diluted with methanol and then concentrated under reduced pressure. The residue was then purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as the eluent to afford the title compound (0.123 g, 28%) as an off-white solid. MW=235.71. 1H NMR (CDCl3, 500 MHz) δ 7.15 (s, 1H), 6.58 (q, J=2.0 Hz, 1H), 5.06-4.99 (m, 1H), 3.08 (t, J=7.5 Hz, 2H), 2.99 (t, J=7.5 Hz, 2H), 2.97-2.90 (m, 1H), 2.72-2.64 (m, 1H), 2.52-2.44 (m, 1H), 2.15 (quin, J=7.5 Hz, 2H), 1.93-1.85 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].[CH2:26]([N:33]1[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][C:34]1=[O:42])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:24][N:23]([CH3:25])[C:21]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:39]([C:36]1[CH:37]=[CH:38][N:33]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:34](=[O:42])[CH:35]=1)=[O:40])=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: O=C(O)c1ccn(Cc2ccccc2)c(=O)c1
Product: CN(C)C(=O)c1c(CNC(=O)c2ccn(Cc3ccccc3)c(=O)c2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
3-{[(1-Benzyl-2-oxo-1,2-dihydro-pyridine-4-carbonyl)-amino]-methyl}-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide was prepared starting from intermediate C and 1-benzyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid. MS calcd. for C32H28ClN4O4 [(M+H)+] 567.2, obsd. 567.1.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[CH3:37])[CH2:29][C:30]1([NH2:33])[CH2:32][CH2:31]1.FC(F)(F)C([O-])=O>>[CH3:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[CH3:37])[CH2:29][C:30]1([NH:33][CH2:21][CH:20]([C:12]2[C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[OH:24])[CH2:31][CH2:32]1
Reactant: Cc1ccc(CC2(N)CC2)cc1C
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: Cc1ccc(CC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)cc1C

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 175 mg (1 mmol) 1-(3,4-dimethyl-benzyl)-cyclopropylamine. Yield: 233 mg (47%, trifluoroacetate); mass spectroscopy: [M+H]+=383.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][C:3]=1[F:23].Cl[C:25]([O:27][CH2:28][CH2:29][CH3:30])=[O:26]>CCOC(C)=O.C([O-])(O)=O.[Na+].O>[CH2:28]([O:27][C:25](=[O:26])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][C:3]=1[F:23])[CH2:29][CH3:30]
Reactant: CCCOC(=O)Cl
Reactant: CCn1c(-c2ccc(N)c(F)c2)c(C#N)c2ccc(OC)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCOC(=O)Nc1ccc(-c2c(C#N)c3ccc(OC)cc3n2CC)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.2 %

Procedure:
A biphasic mixture of 2-(4-amino-3-fluorophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (74 mg, 0.24 mmol), prepared as described in example 1Gb, and propyl chloroformate (0.033 mL, 0.29 mmol) in EtOAc (3 mL) and saturated NaHCO3 (3 mL) is prepared at 0° C. and then allowed to warm to room temperature and stirred for 24 h. The reaction is then diluted with H2O and extracted with EtOAc (2×). The organic phases are washed with H2O and saturated NaCl and then dried and concentrated. Flash chromatography (EtOAc/hexanes 10-40%) gives 60 mg (63%) of [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-fluorophenyl]-carbamic acid propyl ester as an off-white solid.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[N:7][CH:6]=1)C.[BH4-].[Na+]>CO>[OH:3][CH2:4][C:5]1[CH:6]=[N:7][C:8]([C:11]#[N:12])=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1ccc(C#N)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
To a solution of ethyl-6-cyanonicotinate (prepared as per T. Sakamoto, S. Kaneda, S. Nishimura and H. Yamanaka Chem. Pharm. Bull. 1985, 33, 565) (1.58 g, 8.97 mmol) in MeOH (40 mL) was added NaBH4 (1.00 g, 26.4 mmol) and the reaction stirred at room temperature for 8 h. After removal of the solvent, the residue was taken up in 15% NaOH (5 mL) and stirred for 20 min. The mixture was then extracted repeatedly with CH2Cl2, and the combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (EtOAc/hexanes, 1:1) afforded 3-hydroxymethyl-6-cyanopyridine (414 mg, 34%). 1H NMR (CDCl3) δ 5.16 (s, 2H), 7.69 (d, 1H, J=6.8 Hz), 7.84 (d, 1H, J=6.8 Hz), 8.71 (s, 1H).
Reaction SMILES: CN(C)C(N1[CH2:10][CH:9]=[C:8]([C:11]2[NH:28][C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([NH2:26])[C:20]=4[CH3:27])[C:13]=3[CH:12]=2)[CH2:7][CH2:6]1)=O.ClC1C2C=C(C3CC[S:43]CC=3)NC=2N=CN=1>>[S:43]1[CH2:10][CH:9]=[C:8]([C:11]2[NH:28][C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:20]([CH3:27])=[C:21]([NH2:26])[CH:22]=[C:23]([F:25])[CH:24]=4)[C:13]=3[CH:12]=2)[CH2:7][CH2:6]1
Reactant: Clc1ncnc2[nH]c(C3=CCSCC3)cc12
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)N(C)C)CC3)cc12
Product: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCSCC3)cc12

Procedure:
Intermediate 16 was prepared analogue to Intermediate 6 by replacing Intermediate 3 with Intermediate 15.
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([C:7]([NH:9][C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[CH:19]=[CH:20][C:21]([CH2:23][O:24][Si](C(C)C)(C(C)C)C(C)C)=[CH:22][C:12]=3[N:11]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].Cl>O1CCOCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[CH:19]=[CH:20][C:21]([CH2:23][OH:24])=[CH:22][C:12]=3[N:11]=2)=[O:8])=[CH:35][CH:36]=1)#[N:2]
Reactant: COCCn1c(NC(=O)c2ccc(C#N)cc2)nc2cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: COCCn1c(NC(=O)c2ccc(C#N)cc2)nc2cc(CO)ccc21
Temperature: 95 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a suspension of the above benzamide (169 mg, 0.325 mmol) in dioxane (15 mL) was added 0.01 N HCl (15 mL) and the suspension warmed to 95° C. After 3 hours, the reaction appeared complete by TLC and the solution cooled to room temperature. The solid that crashed out of solution as the reaction cooled was collected by filtration, washed with water, and dried to afford 4-cyano-N-[5-hydroxymethyl-1-(2-methoxy-ethyl)-1H-benzimidazol-2-yl]-benzamide as a yellow solid (109 mg, 92%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C=O.[BH3-][C:12]#N.[Na+]>CC#N>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH3:12])[CH2:2][CH2:3]1
Reactant: [BH3-]C#N
Reactant: OCC1CCNCC1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN1CCC(CO)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-piperidylmethanol (1.0 g, 8.7 mmol) and HCHO (2 mL, 25 mmol, 37% in H2O) in CH3CN was added NaCNBH3 (0.5 g, 12.5 mmol). The resulting mixture was stirred for 1 h and filtered. The filtrate was concentrated and the residue was distilled (105° C., 40 torr) to give the title intermediate.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:14](=[O:27])[NH:15][CH2:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH2:19][C:20](=[O:26])[NH:21]3)=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[O:26]=[C:20]1[CH2:19][C:18]2[C:22](=[CH:23][CH:24]=[CH:25][C:17]=2[CH2:16][NH:15][C:14]([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([C:10]([F:13])([F:11])[F:12])[CH:8]=2)=[O:27])[NH:21]1
Reactant: COC(=O)c1sc(C(=O)NCc2cccc3c2CC(=O)N3)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1Cc2c(CNC(=O)c3cc(C(F)(F)F)c(C(=O)O)s3)cccc2N1
Reaction time: 15 h

Procedure:
A mixture of 5-[(2-oxo-2,3-dihydro-1H-indol-4-ylmethyl)-carbamoyl]-3-trifluoromethyl-thiophene-2-carboxylic acid methyl ester (270 mg, 0.68 mmol), lithium hydroxide monohydrate (280 mg, 6.77 mmol), THF (5 mL) and water (5 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 260 mg (99%). MS m/e 354.9 (M+H+).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:10]=[C:11]3[NH:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][CH2:16][N:12]3[C:13](=[O:15])[CH:14]=1)[CH2:2]2.[H-].[Na+].Cl[CH2:27][C@H:28]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[O:37][CH3:38])[OH:29]>CN(C=O)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C@H:28]([OH:29])[CH2:27][N:19]2[C:11]3=[N:10][C:9]([N:3]4[CH2:4][CH:5]5[O:8][CH:1]([CH2:7][CH2:6]5)[CH2:2]4)=[CH:14][C:13](=[O:15])[N:12]3[CH2:16][CH2:17][C@H:18]2[C:20]([F:22])([F:21])[F:23])=[C:31]([O:37][CH3:38])[CH:32]=1
Reactant: O=c1cc(N2CC3CCC(C2)O3)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: COc1cc(F)ccc1[C@H](O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1[C@H](O)CN1c2nc(N3CC4CCC(C3)O4)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
200 mg (0.61 mmol) of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 5 mL of DMF are added to a suspension of 60 mg (1.51 mmol) of sodium hydride in 10 mL of DMF. The reaction mixture is heated at 50° C. for 10 minutes. After addition of 162 mg (0.79 mmol) of (S)-2-chloro-1-(4-fluoro-2-methoxyphenyl)ethanol, the reaction is continued at room temperature overnight. The reaction medium is evaporated to dryness. The residue is purified by chromatography on a column of silica (eluent: 90/10 DCM/MeOH). 40 mg of (8S)-9-[(S)-2-(4-fluoro-2-methoxyphenyl)-2-hydroxyethyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Br:9])[N:3]=1.[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[C:10]([NH:18][C:19]([NH:8][C:6]1[CH:5]=[C:4]([Br:9])[N:3]=[C:2]([Br:1])[CH:7]=1)=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cc(Br)nc(Br)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1cc(Br)nc(Br)c1)c1ccccc1
Temperature: 65 °C
Yield: 91.2 %

Procedure:
To a solution of 2,6-dibromo-pyridin-4-ylamine (0.80 g, 3.17 mmol) in THF (50 mL) was added benzoylisothiocyanate (0.47 mL, 3.49 mmol). The reaction mixture was heated to 65° C. overnight. After completion of reaction (TLC monitoring), THF was distilled off and the crude solid was filtered and washed with hexane (2×50 mL) to get the desired product as a pale-yellow solid (1.20 g, 91%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].[C:12]([NH:15][NH2:16])(=O)[CH3:13]>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[C:12]([CH3:13])=[N:15][N:16]=[C:10]1[SH:11]
Reactant: CC(=O)NN
Reactant: Cc1cccc(C)c1N=C=S
Product: Cc1cccc(C)c1-n1c(C)nnc1S

Procedure:
Using the method of Example 1, Part A of U.S. Pat. No. 4,338,453, 2,6-dimethylphenyl isothiocyanate and acethydrazide are reacted to produce 4-(2,6-dimethylphenyl)-5-methyl-4H-1,2,4-triazole-3-thiol which is converted to 4-(2,6-dimethylphenyl)-3-methyl-4H-1,2,4-triazole. This triazole (1.87 g 0.01 mole) in 100 ml of tetrahydrofuran at -60° C. bath temperature is reacted with 6.9 ml of 1.6N n-butyllithium in hexane. The resulting mixture is stirred for fifteen minutes. Then using the procedure of Example 1, Part A above, this anion is reacted with 1-(β-phenethyl)-4-piperidinone to produce the product, which is recrystallized from ethyl acetate-hexane to give the subtitled product, mp 189°-192° C., with a C:H:N ratio of 73.30:7.77:14.27.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][S:17][CH2:18][C:19]1[C@H:24]([C:25]([OH:27])=[O:26])[N:23]2[C:28](=[O:40])[C@@H:29]([NH:30][C:31](=[O:39])[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:22]2[S:21][CH:20]=1>O1CCOCC1.C(O)(=O)C>[C:1]1([CH:7]([O:27][C:25]([C@@H:24]2[N:23]3[C:28](=[O:40])[C@@H:29]([NH:30][C:31](=[O:39])[CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C@H:22]3[S:21][CH:20]=[C:19]2[CH2:18][S:17][CH3:16])=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CSCC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CSCC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
A solution of 0.39 g of diphenyldiazomethane in 5 ml of petroleum ether is added dropwise over the course of half an hour to a solution of 0.5 g of 3-methylthiomethyl-7β -phenylacetylamino-2-cephem-4α-carboxylic acid in 20 ml of dioxane, while stirring. The solution is stirred for a further 15 hours at room temperature, treated with a few drops of glacial acetic acid and concentrated under reduced pressure. The residue is recrystallised from methyl acetate and gives pure 3-methylthiomethyl-7β-phenylacetylamino-2-cephem-4α-carboxylic acid diphenylmethyl ester which is dried for 16 hours at room temperature in a high vacuum. Melting point 175-177° C; thin layer chromatogram (silica gel): Rf = 0.77 (system: chloroform/methanol, 1:1); Rf = 0.17 (system: toluene/acetone, 2:1); [α]D20 + 342° ± 1° (c = 1.011 in dioxane); ultraviolet absorption spectrum (in 95% strength aqueous ethanol): λmax = 255 mμ (ε = 7,800) and λmin = 244 mμ (ε = 7,200), infra-red absorption spectrum (in methylene chloride): characteristic bands at 2.92μ, 5.61μ, 5.73μ, 5.92μ, 6.25μ and 6.67μ.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([B:22]2[O:26][C:25]([CH3:28])(C)C(C)[O:23]2)=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:30](C)([O-:32])=[O:31].[OH-].[Na+].Cl>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[B:22]([OH:23])[O:26][CH:25]([CH2:28][N+:30]([O-:32])=[O:31])[C:15]=2[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1OB(c2c(C=O)cc(Cl)cc2OCCCOCc2ccccc2)OC1(C)C
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])CC1OB(O)c2c(OCCCOCc3ccccc3)cc(Cl)cc21
Reaction time: 12 h

Procedure:
To a solution of 3-(3-benzyloxy-propoxy)-5-chloro-2-(4,4,5-trimethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (3.4 g, 7.8 mmol) and nitromethane (1.7 mL, 31.3 mmol) in THF (20 mL) was added a solution of NaOH (0.025 M, 40 mL). After 12 h, 2 N HCl was added until pH was 1. The solution was diluted with EtOAc (150 mL), washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by silica gel column chromatography (4:1 hexanes-EtOAc mobile phase) to give the title compound product (1.7 g, 56%) as a colorless gel. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.39-7.28 (m, 5H), 6.92 (s, 1H), 6.83 (s, 1H), 5.85 (br s, 1H), 5.81 (dd, J=8.5, 3.9 Hz, 1H), 4.70 (dd, J=13.2, 3.9 Hz, 1H), 4.59 (s, 2H), 4.47 (dd, J=13.0, 8.7 Hz, 1H), 4.21-4.07 (m, 2 H), 3.71-3.60 (m, 2H), 2.10 (quin, J=5.7 Hz, 2H).
Reaction SMILES: [C:1]1(=[O:10])[C@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.F[B-](F)(F)F.[CH3:16][O+](C)C>>[CH3:16][O:10][C:1]1[C@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][N:2]=1
Reactant: O=C1NC[C@@H]2CCCC[C@@H]12
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: COC1=NC[C@@H]2CCCC[C@@H]12

Procedure:
A sample of the title compound of EXAMPLE 171 (1.39 g, 10 mmol) was reacted with trimethyloxonium tetrafluoroborate (1.78 g, 12 mmol) by the method of EXAMPLE 26 to yield, after chromatography, 1.05 g (69%) of the title material.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:16]3[N:17]=[C:18]([CH2:21][S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[S:19][CH:20]=3)[C:11](=[O:15])[NH:12]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>C1COCC1>[C:25]1([S:22]([CH2:21][C:18]2[S:19][CH:20]=[C:16]([C:10]3[C:11](=[O:15])[NH:12][C:13]4[C:8]([CH:9]=3)=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=4)[N:17]=2)(=[O:24])=[O:23])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc2cc(-c3csc(CS(=O)(=O)c4ccccc4)n3)c(=O)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc(-c3csc(CS(=O)(=O)c4ccccc4)n3)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(2-benzenesulfonylmethyl-thiazol-4-yl)-1H-quinolin-2-one-7-carboxylic acid methyl ester (step (g), 0.9 g, 2.1 mmol) and THF (200 mL) was added 1N NaOH (4 mL). The solution was stirred at RT. After 2 h, an additional 4 mL of 1N NaOH was added. After an additional 3 h, 4 mL of 1N NaOH was added. After 24 h, TLC shows complete conversion. The solution was concentrated in vacuo and diluted with 100 mL of H2O. The aqueous solution was acidified with 2N HCl (aq) and a precipitate formed. The precipitate was filtered and dried in vacuo at 60° C. to give an off-white solid. MS m/z: 427.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4](=[S:7])[NH:5][NH2:6].[CH3:13][O:14][N:15]([CH2:23][CH2:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>C(O)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]1[S:7][C:25]([CH2:24][CH2:23][N:15]([O:14][CH3:13])[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:6][N:5]=1
Reactant: NNC(=S)c1cc(F)ccc1F
Reactant: CON(CCC(=O)c1ccccc1)C(=O)OC(C)(C)C
Solvent: CCO
Product: CON(CCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1)C(=O)OC(C)(C)C
Yield: 54.5 %

Procedure:
A mixture of 2,5-difluorobenzothiohydrazide (0.500 g 2.66 mmol) and tert-butyl methoxy(3-oxo-3-phenylpropyl)carbamate (1.11 g, 3.99 mmol) was stirred together in ethanol (5 mL) for 30 hours. The reaction mixture was concentrated under reduced pressure, and the residue was chromatographed (20% ethyl acetate in hexanes) to provide die product (0.650 g, 1.45 mmol) that was used in the next step without further purification.