Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH:11]=[C:10]([CH:12]=O)[N:9]=[CH:8]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[N:7]1[CH:11]=[C:10]([CH:12]=[CH:22][CH:23]=[O:24])[N:9]=[CH:8]1
Reactant: O=Cc1cn(-c2ncccn2)cn1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1cn(-c2ncccn2)cn1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 1-(2-pyrimidinyl)-1H-imidazole-4-carboxaldehyde (prepared as described in Reference Example 10) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 201 (M+H)+.
Reaction SMILES: B([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([F:14])[C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])(O)O.Br[C:16]1[C:21](=[O:22])[N:20]([CH3:23])[C:19]2[N:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])[N:25]=[CH:26][C:18]=2[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].CCOCC>O1CCOCC1.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>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([F:34])[C:27]=1[N:24]1[C:19]2[N:20]([CH3:23])[C:21](=[O:22])[C:16]([C:4]3[CH:5]=[C:6]([CH:10]=[C:11]([F:14])[C:12]=3[CH3:13])[C:7]([OH:9])=[O:8])=[CH:17][C:18]=2[CH:26]=[N:25]1
Reactant: Cn1c(=O)c(Br)cc2cnn(-c3c(F)cccc3F)c21
Reactant: Cc1c(F)cc(C(=O)O)cc1B(O)O
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: CCOCC
Solvent: C1COCCO1
Product: Cc1c(F)cc(C(=O)O)cc1-c1cc2cnn(-c3c(F)cccc3F)c2n(C)c1=O
Temperature: 130 °C
Yield: 78.1 %

Procedure:
In a 25 mL sealed glass tube, a mixture of tetrakis(triphenylphosphine)palladium(0) (42 mg, 37 μmol), 3-borono-5-fluoro-4-methylbenzoic acid (218 mg, 1101 μmol), and 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (312 mg, 917 μmol) in 4.6 mL of dioxane and 1.0 M solution of sodium carbonate (2.3 mL, 2.3 mmol) was heated in a microwave at 130° C. for 30 min. The reaction mixture was treated with 15 mL of ether and washed with 5 mL of 2 N NaOH, The ether layer was discarded. The aqueous extracts were acidified to pH 4 with 5 N HCl and extracted with 3×25 mL EtOAc. The combined EtOAc layers were dried over MgSO4, filtered and concentrated in vacuo (rotovap) affording the title compound (296 mg) as a viscous oil which solidified to an off-white amorphous solid under vacuum overnight. MS (ESI, pos.ion) m/z: 414.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:29])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:28].[OH-].[Na+].Cl>C1COCC1.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][C:10](=[O:29])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:28]
Reactant: CCOC(=O)c1cc(-c2ccc(NC(=O)Nc3c(F)cccc3F)c(C)c2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2cc(C(=O)O)on2)ccc1NC(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
Into a 100 ml round bottom flask was added ethyl 3-(4-(3-(2,6-difluorophenyl)ureido)-3-methylphenyl)isoxazole-5-carboxylate (1.0 equiv.), NaOH (5.0 equiv.) and 150 ml of 2:1 THF/Water. The mixture was stirred at room temperature for 15 minutes. The reaction mixture was slightly acidified to pH <7 by adding 2N HCl and then the solvent was evaporated. The solid was suspended in water and filtered, given water washings and air-dried. The resulting solid was triturated with minimum quantity of acetone and collected by filtration. This yielded the title compound as a white solid (91%) after it was dried in vacuo; mp 254-258° C. (dec.); 1H NMR (300 MHz; DMSO-d6) δ: 2.31 (s, 3H), 7.10-7.18 (m, 2H), 7.24-7.34 (m, 1H), 7.68-7.72 (m, 2H), 7.78 (s, 1H), 8.03-8.06 (d, J=8.4 Hz, 1H), 8.31 (s, 1H), 8.65 (s, 1H); IR (KBr) 3323, 3189, 3074, 3006, 1743, 1649, 1641, 1569, 1492, 1469, 1243, 1218, 1181, 1003, 833, 733 cm−1.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH2:22]([O:24][C:25](=[O:32])[C:26]([OH:31])([CH3:30])[C:27](O)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:32])[C:26]([OH:31])([CH3:30])[C:27]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2)=[O:28])[CH3:23]
Reactant: COCCN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Reactant: CCOC(=O)C(C)(O)C(=O)O
Product: CCOC(=O)C(C)(O)C(=O)N[C@@H]1C(=O)N(CCOC)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-methoxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2-hydroxy-2-methyl-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Colorless oil. (66%). MS: m/e=426(M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:32][CH3:33])=[C:19]([CH2:23][N:24]4[CH2:27][CH:26]([C:28]([O:30]C)=[O:29])[CH2:25]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>O1CCCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:32][CH3:33])=[C:19]([CH2:23][N:24]4[CH2:25][CH:26]([C:28]([OH:30])=[O:29])[CH2:27]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(CN2CC(C(=O)OC)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.4 %

Procedure:
A solution of methyl 1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylate (D13) (30.3 g, 62.3 mmol) in Tetrahydrofuran (THF) (200 mL), Ethanol (150 mL) and Water (60 mL) was added sodium hydroxide (4.99 g, 125 mmol). The reaction mixture was stirred at room temperature overnight. Then pH of the reaction mixture was adjusted with 6 N HCl until pH ˜2.0. White solid was precipitated. The organic solvent was removed in by rotary evaporator. The solid was collected through filtration. The solid was washed water (150 mL×3) and dried in vacuo to afford 1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-3 azetidinecarboxylic acid (31 g), which was used for the following procedure without further purification.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[C:11](Cl)[C:10]([S:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:18]=[C:17]([C:31]#[C:32][CH2:33][O:34][CH3:35])[CH:16]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+].[ClH:39]>C(O)C>[Cl:39][C:8]1[CH:9]=[C:10]([S:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:18]=[C:17]([C:31]#[C:32][CH2:33][O:34][CH3:35])[CH:16]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:3])=[O:36]
Reactant: Cl
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCOC)cc(OCCCN3CCOCC3)c2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCC#Cc1cc(OCCCN2CCOCC2)cc(Sc2ccc(OCC(=O)O)c(Cl)c2)c1
Reaction time: 1 h

Procedure:
{5-Chloro-4-[3-(3-methoxy-prop-1-ynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, and evaporated to dryness and purified by preparative HPLC (method B). Yield: 50 mg. HPLC-MS: m/z: 506.0 (M+); Rt: 1.56 min. δH(400 MHz; CDCl3) 2.06-2.15 (m, 2H), 2.82-2.92 (m, 2H), 3.15-3.23 (m, 2H), 3.45 (s, 3H), 3.56 (d, 2H), 3.78 (t, 2H), 3.95-4.03 (m, 4H), 4.30 (s, 2H), 4.89 (s, 2H), 5.91-5.94 (m, 1H), 6.63-6.66 (m, 1H), 6.93 (d, 1H), 7.01-7.03 (m, 1H), 7.40 (dd, 1H), 7.58 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][N:26]=1)[C:21](O)=O>>[Cl:17][C:18]1[CH:19]=[C:20]([C:21]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)[CH:24]=[CH:25][N:26]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1ccnc(Cl)c1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccnc(Cl)c2)o1
Yield: 47 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (1.92 mg, 8.83 mmol) was converted using 2-chloroisonicotinic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 1.41 mg, 47%) which was obtained as a white solid. MS: m/e=339.1 [M+H]+.
Reaction SMILES: S([Cl:11])(C1C=CC(C)=CC=1)(=O)=O.[N+:12]([C:15]1[CH:16]=[C:17]([CH2:25]O)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)([O-:14])=[O:13].C(N(CC)CC)C>ClCCl>[Cl:11][CH2:25][C:17]1[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cc(CO)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CCl)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.8 %

Procedure:
Add slowly tosyl chloride (1.1 g, 6.02 mmol) to the mixture of (3-nitro-5-(trifluoromethyl)phenyl)methanol (1.1 g, 5.18 mmol) and triethylamine (1.62 mL) in dichloromethane (20 mL) at 0° C., stir the resulting mixture for 15 hrs at room temperature. Concentrate the mixture to obtain the crude product, purify by flash chromatography (silica gel, EtOAc:PE=1:15) to afford the title compound (655 mg, 55%).
Reaction SMILES: CS(O[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH:19][C:20]([C:22]3[N:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]4=[N:24][CH:23]=3)=[O:21])[CH:13]=2)[N:8]=1)(=O)=O.CCN(C(C)C)C(C)C.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C=O)C>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]=[C:7]([CH2:6][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[O:11][N:10]=2)=[CH:13][C:14]=1[NH:19][C:20]([C:22]1[N:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]2=[N:24][CH:23]=1)=[O:21]
Reactant: Cc1ccc(-c2noc(COS(C)(=O)=O)n2)cc1NC(=O)c1cnc2ccccn12
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2noc(CN3CCOCC3)n2)cc1NC(=O)c1cnc2ccccn12

Procedure:
A solution of (3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)methyl methanesulfonate (44) (21.4 mg, 0.05 mmol), DIEA (13.0 mg, 0.1 mmol) and morpholine (13.0 mg, 0.15 mmol) in DMF (1 mL) was heated at 80° C. for 4 hours. The crude product was purified by preparative HPLC to yield N-(2-methyl-5-(5-(morpholinomethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (F22). 1H NMR (400 MHz, CD2Cl2) δ 9.60 (d, J=6.8 Hz, 1H), 8.60 (d, J=1.6 Hz, 1H), 8.45 (s, 1H), 8.06 (s, 1H), 7.89 (dd, J=2.0, 8.0 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.54 (m, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.15 (m, 1H), 3.93 (s, 2H), 3.75 (m, 4H), 2.67 (m, 4H), 2.48 (s, 3H). MS m/z 419.2 (M+1)+. Note: if HCl salt of morpholine (0.15 mmol) was used, AgNO3 (0.15 mmol) was needed to avoid replacement of OMs group by Cl.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[F:20][C:21]([F:31])([F:32])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: FC(F)(F)Oc1ccc(CNc2nccc(-n3cnc4ccccc43)n2)cc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 4-trifluoromethoxybenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 386.2 (M+1). 1H NMR (500 MHz, CDCl3): d partial 8.59 (s, 1H); 8.44 (br s, 1H); 8.02 (br s, 1H); 7.86 (d, J=8.3 Hz, 1H); 7.45 (d, J=8.4 Hz, 2H); 7.24 (d, J=8.3 Hz, 1H); 6.87 (d, J=5.2 Hz, 1H); 5.84 (br s, 1H); 4.76 (d, J=6.1 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:35]([O:39][C:40]([N:42]1[CH2:46][CH2:45][CH:44](OS(C)(=O)=O)[CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C>[C:35]([O:39][C:40]([N:42]1[CH2:46][CH2:45][CH:44]([N:18]2[CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:30])[F:31])[CH:23]=3)[N:21]=[C:17]2[CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:16][CH2:15]2)[CH2:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCN(C(=O)OCc3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.9 %

Procedure:
To a solution of 4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (1000.00 mg; 2.24 mmol; 1.00 eq.) in DMF 8 ml added NaH (107.27 mg; 2.68 mmol; 1.20 eq.), stirred at RT for 20 mins, added 3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1186.02 mg; 4.47 mmol; 2.00 eq.), the reaction mixture was stirred 85° C. for 5 hr, lc-ms showed around 40% desired, continued stirring for over night, no big changed, purified the product by HPLC (basic) with 30-100% acetonitrile/water, collected title compound 220 mg, yield 16%.
Reaction SMILES: [NH2:1][CH:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[NH2:12])[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[CH3:26][O:27]/[N:28]=[C:29](/[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)\[C:30](O)=[O:31]>O.O1CCCC1>[CH3:26][O:27]/[N:28]=[C:29](/[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)\[C:30]([NH:1][CH:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[NH2:12])[CH2:7][S:8][C@H:3]12)=[O:31]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CO/N=C(\C(=O)O)c1cscn1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1cscn1
Temperature: 15 °C
Reaction time: 0.75 h

Procedure:
On the other hand, 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (1.365 g) was suspended in a mixture of water (10 ml) and tetrahydrofuran (15 ml). While cooling with ice, triethylamine (1.01 g) was added to form a solution. To this ice-cooled solution was added dropwise the above active solution of (Z)-2-methoxyimino-2-(thiazol-4-yl)acetic acid over one hour. During the time triethylamine (total 0.78 g) was added in parts at suitable times to keep the reaction mixture at pH 6-7. After completion of the dropping, the mixture was stirred for 45 min under cooling with ice. Then the temperature was raised gradually to 15° C. After the mixture was stirred for 20 minutes at that temperature, the tetrahydrofuran was evaporated under reduced pressure. Then the aqueous layer was adjusted to pH 2-3 with 2N-HCl. The precipitates were filtered, washed with water, and dried in vacuo over phosphorus pentoxide to give the title compound (0.90 g). Further, ethyl acetate (20 ml) was added to the filtrate and the mixture was shaked. The insoluble matter formed on the interface between the aqueous layer and the ethyl acetate layer was filtered, and dried in vacuo over phosphorus pentoxide to give the title compound (0.61 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:11]2[CH:12]=[N:13][C:14]3[NH:15][CH2:16][CH2:17][CH2:18][C:19]=3[CH:20]=2)[C:7]=1[CH:8]([OH:10])[CH3:9].[NH2:21][C:22](N)=[O:23].CO.C(=O)=O>CC(O)C.CCO>[Cl:1][C:2]1[C:7]([CH:8]([OH:10])[CH3:9])=[C:6]([C:11]2[CH:20]=[C:19]3[C:14](=[N:13][CH:12]=2)[N:15]([C:22]([NH2:21])=[O:23])[CH2:16][CH2:17][CH2:18]3)[CH:5]=[N:4][CH:3]=1
Reactant: NC(N)=O
Reactant: CC(O)c1c(Cl)cncc1-c1cnc2c(c1)CCCN2
Agent: O=C=O
Solvent: CO
Solvent: CCO
Solvent: CC(C)O
Product: CC(O)c1c(Cl)cncc1-c1cnc2c(c1)CCCN2C(N)=O

Procedure:
Two enantiomers of 1-[3-chloro-5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-4-yl]-ethanol are each converted to Compounds 175 and 176 in Table 1 according to the procedure of Urea Formation Method II (Analytical conditions: LUX 5μ Cellulose 4 Analytical column; 30% 1:1:1 MeOH:EtOH:IPA (1% DEA):CO2 @ 3 mL/min; 40° C.; 200 bars; Retention time, Compound 176: 5.2 min, Compound 175: 6.0 min).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.Cl.Cl.[N:14]1[CH:19]=[CH:18][C:17]([S:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1.[OH-].[Na+]>O>[N:14]1[CH:19]=[CH:18][C:17]([S:20]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:9])=[CH:16][CH:15]=1
Reactant: c1cc(SC2CCNCC2)ccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(c1ccncc1)C1CCNCC1
Reaction time: 3 h
Yield: 90.8 %

Procedure:
m-Chloroperbenzoic acid (1.20 g) was added to a stirred solution of 4-[(4-pyridyl)thio]piperidine dihydrochloride (1.33 g) in water (30 ml) under ice-cooling, and the mixture was stirred at the same temperature for 3 hours and then at room temperature for 5.5 hours. The resultant mixture was diluted with water and the pH of the mixture was adjusted to about 11 with 5% sodium hydroxide solution. The solution was extracted several times with chloroform. The extracts were combined, dried over magnesium sulfate, and concentrated in vacuo. The oily residue was crystallized from n-hexane and the crystals were recrystallized from a mixture of n-hexane and isopropanol to give 4-[(4-pyridyl)sulfinyl]piperidine (0.95 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][CH:11]([C:14]1([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36].[Na+]>CO>[CH2:1]([O:8][C:9](=[O:29])[NH:10][CH:11]([C:14]1([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:19][CH2:18][CH:17]([NH2:36])[CH2:16][CH2:15]1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(NC(=O)OCc1ccccc1)C1(c2ccc(OC)cc2)CCC(=O)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(NC(=O)OCc1ccccc1)C1(c2ccc(OC)cc2)CCC(N)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
200 mg (0.51 mmol) of the ketone (97) were dissolved in 1.5 mL of absolute methanol, then 390 mg (5.06 mmol) of ammonium acetate and 31.8 mg (0.51 mmol) of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated, the residue dissolved in 50 mL of 1N aqueous sodium hydroxide and extracted twice with 100 mL of dichloromethane. The combined organic layer was dried over magnesium sulphate, filtered, and evaporated to give 150 mg of the title compound 98 in a purity sufficient to be used directly in the next step. Rt=1.18 min (Method 19). Detected mass: 397.3 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]=[C:13]([CH:16]=O)[CH:12]=[CH:11]3)[CH2:3][CH2:2]1.[CH3:18][N:19]([C@H:27]1[CH2:31][CH2:30][N:29]([CH:32]([C:37]2[CH:38]=[N:39][C:40]([NH:43][NH2:44])=[CH:41][CH:42]=2)[C:33]([F:36])([F:35])[F:34])[CH2:28]1)C(=O)OC(C)(C)C.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C.CC#N>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]=[C:13]([C:16]2[N:39]4[CH:38]=[C:37]([CH:32]([N:29]5[CH2:30][CH2:31][C@H:27]([NH:19][CH3:18])[CH2:28]5)[C:33]([F:34])([F:36])[F:35])[CH:42]=[CH:41][C:40]4=[N:43][N:44]=2)[CH:12]=[CH:11]3)[CH2:3][CH2:2]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(C(c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: O=Cc1ccc2cccc(OCC3CC3)c2n1
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCO
Product: CN[C@H]1CCN(C(c2ccc3nnc(-c4ccc5cccc(OCC6CC6)c5n4)n3c2)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.9 %

Procedure:
A solution of 8-(cyclopropylmethoxy)quinoline-2-carbaldehyde (0.14 g, 0.62 mmol) and tert-butyl methyl((3S)-1-(2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-yl)carbamate (0.20 g, 0.51 mmol) in ethanol (10 mL) was stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (10 mL) and treated with iodobenzene diacetate (0.20 g, 0.62 mmol) and stirred at ambient temperature for 4 hours. The mixture was partitioned between ethyl acetate (20 mL) and saturated sodium bicarbonate solution (10 mL). The organic layer was separated, washed with brine, dried (MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M; 10-90% CH3CN/water gradient). The residue was dissolved in dichloromethane (1 mL), treated with TFA (4 mL) and stirred at ambient temperature for 1 hour. The solution was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M; 10-70% CH3CN/water gradient). The TFA salt was dissolved in methanol (0.50 mL) and treated with 2N HCl in diethyl ether (4 mL) and stirred for 10 minutes. The solvent was removed under reduced pressure and the solid obtained suspended in MeCN (5 mL) and stirred for 10 minutes. The solid was collected by filtration to afford (3S)-1-(1-(3-(8-(cyclopropylmethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)-N-methylpyrrolidin-3-amine (0.129 g, 44%). LCMS APCI (+) m/z 497 (M+H).
Reaction SMILES: [Cl:1][C:2]1[O:25][C:5]2=[C:6]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[Li+].[CH3:27]C([N-]C(C)C)C.CI>C1COCC1>[Cl:1][C:2]1[O:25][C:5]2=[C:6]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:27]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(Cl)oc12
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(Cl)oc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.6 %

Procedure:
Di-tert-butyl (2-chlorofuro[2,3-c]pyridin-7-yl)imidodicarbonate (3.0 g, 8.15 mmol) in dry THF (100 mL) was cooled to −65° C. to −75° C. and LDA (1.8 M in THF/heptanes/ethylbenzene, 6.0 mL, 10.8 mmol), pre-cooled to the same temperature, was added slowly via syringe over a period of 10 min. The mixture was stirred for 1.5 h at −65° C. to −75° C. and then treated with methyl iodide (0.76 mL, 12.2 mmol) in dry THF added slowly via syringe. The mixture was allowed to warm to RT overnight and was quenched by the addition of water (50 mL) and diluted with EtOAc (100 mL). The phases were separated and the organic phase was dried over Na2SO4, and concentrated in vacuo leaving 3.2 g of a brown solid which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J=5.5 Hz, 1H), 7.39 (d, J=5.5 Hz, 1H), 2.22 (s, 3H), 1.40 (s, 18H).