Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3(O)[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc3c(N)ncnn23)C1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C=C(c2ccc3c(N)ncnn23)CCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 79.7 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-hydroxypiperidine-1-carboxylate (2.77 g, 8.31 mmol) in pyridine (55 mL) was added trifluoroacetic anhydride (2.35 mL, 14.1 mmol), dropwise. The ice bath was removed and the mixture was stirred at rt for 17 h. The mixture was concentrated to dryness. The crude solid was triturated with 3:1 EtOAc/hexanes then with MeOH to afford 2.09 g (76%) of the desired product. ES-MS m/z 316.04 [M+H]+, HPLC RT (min) 2.50.
Reaction SMILES: Cl.[NH2:2][C@@:3]([CH3:9])([CH2:6][CH2:7][CH3:8])[CH2:4][OH:5].[F:10][C:11]([F:33])([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:12][C@H:13]([NH:17][C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19])[C:14](O)=[O:15].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:33][C:11]([F:10])([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:12][C@H:13]([NH:17][C:18]([N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)=[O:19])[C:14](=[O:15])[NH:2][C@@:3]([CH2:4][OH:5])([CH3:9])[CH2:6][CH2:7][CH3:8]
Reactant: CCC[C@](C)(N)CO
Reactant: O=C(O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@@](C)(CO)NC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A mixture of (S)-2-amino-2-methyl-pentan-1-ol hydrochloride (104.4 mg, 0.67 mmol), (S)-4,4-difluoro-2-[(morpholine-4-carbonyl)-amino]-5-phenyl-pentanoic acid (231 mg, 0.67 mmol), EDCI (154 mg, 0.8 mmol), HOBT (108 mg, 0.8 mmol) and Diisopropyl ethylamine (0.23 mL) in DMF (2 mL) is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate, washed with cold 1N HCl, saturated NaHCO3 and then saturated NaCl solution. The organic phase is dried over MgSO4 and solvent evaporated under reduced pressure to give the crude product. Purification by Silica gel column chromatography, eluting with ethyl acetate and heptane mixture gives morpholine-4-carboxylic acid [(S)-3,3-difluoro-1-((S)-1-hydroxymethyl-1-methyl-butylcarbamoyl)-4-phenyl-butyl]-amide (223 mg, 75%).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>CC(C)=O>[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:2][C:3](=[O:5])[CH3:4])=[CH:16][CH:15]=1
Reactant: CSc1ccc(O)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1ccc(OCC(C)=O)cc1

Procedure:
A mixture of chloroacetone (10 ml), potassium carbonate (21 g), and 4-(methylthio)phenol (10 g) in acetone (200 ml) was heated under reflux for 6 h. The solvent was removed under reduced pressure and the residue partitioned between diethylether/water. The organics were separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5-10% ethylacetate/iso-hexane. Yield 12.43 g
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:8]1[C:9]([I:24])=[C:10]([C:18]([I:23])=[C:19]([NH2:22])[C:20]=1[I:21])[C:11]([NH:13][C:14](=[O:17])[CH2:15][NH2:16])=[O:12])([OH:7])=[O:6]>CC(N(C)C)=O>[C:5]([C:8]1[C:9]([I:24])=[C:10]([C:18]([I:23])=[C:19]([NH:22][C:1](=[O:3])[CH3:2])[C:20]=1[I:21])[C:11]([NH:13][C:14](=[O:17])[CH2:15][NH2:16])=[O:12])([OH:7])=[O:6]
Reactant: NCC(=O)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: CC(=O)Cl
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NC(=O)CN)c1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under agitation and cooling with wter, 13.5 ml. of acetyl chloride is added dropwise to 40.0 g. (65 millimoles) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine amide (IVc), m.p. 248°-249° C. (decomposition), in 80 ml. of dimethylacetamide. Then, the reaction mixture is stirred at room temperature for 11/2 hours, another 2 ml. of acetyl chloride is added thereto, and the mixture stirred for another hour. After the addition of 10 ml. of water, the reaction mixture is concentrated under vacuum, 70 ml. of water is added to the residue, and the mixture is stirred for 16 hours. The precipitate is vacuum-filtered and washed free of salt with water.
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]([N+:19]([O-])=O)[CH:10]=[C:11]([C:13](=[O:18])[NH:14][O:15][CH2:16][CH3:17])[CH:12]=1)=[O:6])[CH3:2].[C:22]([C:25]1[C:26](=[O:36])[O:27][C:28]([OH:35])=[C:29]([C:32](=O)[CH3:33])[C:30]=1[OH:31])(=[O:24])[CH3:23]>[Pd].C(O)C>[C:22]([C:25]1[C:26](=[O:36])[O:27][C:28](=[O:35])[C:29](=[C:32]([NH:19][C:9]2[CH:10]=[C:11]([C:13](=[O:18])[NH:14][O:15][CH2:16][CH3:17])[CH:12]=[C:7]([C:5](=[O:6])[NH:4][O:3][CH2:1][CH3:2])[CH:8]=2)[CH3:33])[C:30]=1[OH:31])(=[O:24])[CH3:23]
Reactant: CCONC(=O)c1cc(C(=O)NOCC)cc([N+](=O)[O-])c1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Agent: [Pd]
Solvent: CCO
Product: CCONC(=O)c1cc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)cc(C(=O)NOCC)c1
Reaction time: 1 h

Procedure:
A solution of 2.0 g. (0.0067 mol) of 3,5-bis-ethoxycarbamoylnitrobenzene in 150 ml. of 2B ethanol was hydrogenated over 200 mg. of 10% palladium-on-carbon at 50 psi. Reduction was complete in 1 hour, the catalyst was filtered, and to the colorless filtrate was added 1.42 g. (0.0064 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyranone. The mixture was heated under reflux for 45 minutes, cooled and the product filtered to yield 5-acetyl-4-hydroxy-3-[1-(3,5-bis-ethoxycarbamoylphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 234°-235° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][C:13](=[O:24])[N:14]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:10][CH:9]=1.I[CH2:26][CH2:27][O:28][CH2:29][CH2:30]I.C(O)(=O)C>CN(C=O)C.O.C(OCC)(=O)C>[Br:7][C:8]1[CH:16]=[C:15]2[N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:13](=[O:24])[C:12]3([CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:11]2=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)Cc2ccc(Br)cc21
Reactant: ICCOCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C(=O)C2(CCOCC2)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
Cesium carbonate (20.7 g, 63.5 mmol) was added portionwise over a 20 minute period to a stirred solution of tert-butyl 6-bromo-2-oxoindoline-1-carboxylate (preparation 8a, 6.0 g, 16.0 mmol) and 1-iodo-2-(2-iodoethoxy)ethane (6.58 g, 17.6 mmol) in N,N′-dimethylformamide (250 mL) at −20° C. under an argon atmosphere. After the addition the mixture was warmed to room temperature and stirred for 3 hours. Acetic acid (1.1 mL) followed by ethyl acetate and water were added to the reaction mixture and the organic layer was separated, washed with water, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (10:1 to 5:1 hexanes/ethyl acetate) gave the title compound (4.50 g, 61%) as a pale yellow solid.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[CH:3]=[C:2]1[C:17](OCC)=[O:18].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[OH:18][CH2:17][C:2]1[S:1][C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CCc2sc(CO)cc2C1
Yield: 93.3 %

Procedure:
tert-butyl 2-(hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate was prepared according to the procedure outlined in Example 1, (Step 2). Starting from 5-tert-butyl 2-ethyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (1.0 g, 3.21 mmol) and LiAlH4 (500 mg, excess), 807 mg (92% yield) of the alcohol derivative was isolated as white liquid. (M+H) 270.
Reaction SMILES: N[C:2]1[S:11][C:10]2[C:9](=[O:12])[C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1.N(OCCC(C)C)=O>CN(C=O)C>[N:3]1[C:4]2[CH2:5][CH2:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9](=[O:12])[C:10]=2[S:11][CH:2]=1
Reactant: Nc1nc2c(s1)C(=O)c1ccccc1CC2
Agent: CC(C)CCON=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2CCc2ncsc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a room temperature solution of 2-amino-9,10-dihydro-3-thia-1-aza-benzo[f]azulen-4-one (5.31 g, 23.1 mmol) in DMF (50 mL) is added isoamyl nitrite (5.95 g, 50.8 mmol) and the reaction stirred for 30 min. The reaction mixture is heated to 80° C. for 2 h, and then cooled to room temperature. The solvent is removed under reduced pressure and ice-cold H2O (100 mL) is added. The aqueous layer is extracted with EtOAc (2×150 mL) and the combined organic layers are dried (MgSO4), filtered and the solvent removed under reduced pressure. The dark red oil is subjected to flash chromatography (silica gel, 75:25 Hex/EtOAc) to afford the slightly impure product as an orange-red solid. The product is further purified by trituration using Hex/EtOAc (90:10) to afford the title compound (2.59 g, 52%) as an orange solid: Rf 0.33 (1:1 EtOAc/Hex); mp 83-86° C.; 1H NMR (300 MHz, CDCl3) 8.89 (s, 1H), 7.96 (dd, J=1.2, 7.7 Hz, 1H), 7.50 (dt, J=1.4, 7.4 Hz, 1H), 7.37 (m, 1H), 7.30 (d, J=7.5 Hz, 1H), 3.36 (m, 2H), 3.24 (m, 2H); ESI MS m/z 216 [C12H9NOS+H]+. Anal. Calcd for C12H9NOS: C, 66.95; H, 4.21; N, 6.51.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:24]1(O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(Cl)Cl>[C:1]1([NH:7][C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)N1CCN(Cc2ccc(O)cc2)CC1
Reactant: OC1CCCCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCN(Cc2ccc(OC3CCCCC3)cc2)CC1
Reaction time: 8 h
Yield: 28 %

Procedure:
To a mixture of 4-(4-hydroxy-benzyl)-piperazine-1-carboxylic acid phenylamide (311 mg) and cyclohexanol (150 mg) in DCM (4 mL) was added polymer-supported Ph3P (500 mg) followed by di-tert-butyl azodicarboxylate (345 mg). The reaction mixture was shaken overnight, and filtered. Chromatography of the filtrate gave the title compound as a white solid (110 mg). 1H NMR (400 MHz, CDCl3): 7.36-7.19 (m, 6H), 7.05-7.00 (m, 1H), 6.88-6.84 (m, 2H), 6.30 (s, 1H), 4.25-4.20 (m, 1H), 3.50-3.47 (m, 6H), 2.48-2.46 (m, 4H), 2.01-1.97 (m, 2H), 1.82-1.80 (m, 2H), 1.60-1.29 (m, 6H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C([O-])(O)=O.[Na+]>C(C#N)(C)=O>[N:21]1([CH2:3][C:4]2[N:8]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Reactant: c1c[nH]cn1
Agent: CC(=O)C#N
Agent: Cl
Agent: O=C([O-])O
Product: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Temperature: 65 °C

Procedure:
A mixture of 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride (0.10 mmol), 1H-imidazole (0.20 mmol, 2.0 eq) in AcCN (1 ml) was heated at 65° C. overnight. The mixture was basified with sat. NaHCO3 (5 ml), extracted with ethyl acetate or CH2Cl2 (2×5 ml). The combined organic solution was dried with Na2SO4, evaporated under vacuum. The product was purified by silica gel column chromatography (12 g silica gel RediSep column, eluted first with 10% ethyl acetate in hexane, then 20-50% acetone in hexane), to afford the product as a white solid. The product shows up as violet spot on TLC plate under UV light. m/e+ 303.4 for C19H19N4 (M+H)+; 1H-NMR (400 MHz, CDCl3, δ) 7.60-7.50 (m, 5H), 7.26 (d, J=8.065 Hz, 2H), 7.11 (m, 2H), 6.883 (s, 1H), 5.51 (s, 2H), 2.39 (s, 3H), 2.285 (s, 3H) ppm; 13C-NMR (100 MHz, CDCl3, δ), 146.681, 144.944, 138.582, 136.512, 130.787, 130.484, 129.832, 128.937, 128.330, 123.341, 120.710, 118.845, 117.396, 112.315, 40.969, 21.512, 18.608 ppm.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:32]([OH:34])=O)[CH2:19][C:20]3[CH:30]=[C:29]([CH3:31])[C:23]4[NH:24][C:25]([O:27][CH3:28])=[N:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.[CH3:39][O:40][CH:41]1[CH2:46][CH2:45][N:44]([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:43][CH2:42]1.C(N(CC)CC)C>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:30]=[C:29]([CH3:31])[C:23]4[NH:24][C:25]([O:27][CH3:28])=[N:26][C:22]=4[CH:21]=3)[C:32]([N:50]3[CH2:49][CH2:48][CH:47]([N:44]4[CH2:45][CH2:46][CH:41]([O:40][CH3:39])[CH2:42][CH2:43]4)[CH2:52][CH2:51]3)=[O:34])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)O)cc(C)c2[nH]1
Reactant: COC1CCN(C2CCNCC2)CC1
Solvent: CCN(CC)CC
Product: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)N3CCC(N4CCC(OC)CC4)CC3)cc(C)c2[nH]1

Procedure:
Prepared analogously to Example 7i from 90 mg (0.16 mmol) (R)-1-carboxy-2-(2-methoxy-7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 55 mg (0.20 mmol) 4-methoxy-[1,4′]bipiperidinyl (used as the bis-hydrochloride salt), using 100 μL (0.72 mmol) triethylamine.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH2:8][CH2:9][CH3:10])([OH:7])[CH2:5][CH2:4][NH:3]1.F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21].C(=O)([O-])[O-].[Li+].[Li+]>>[OH:7][C@@:6]1([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:4][N:3]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[C:20]([F:21])([F:23])[F:22])[C@H:2]1[CH3:1]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CCC[C@]1(O)CCN[C@H]1C
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CCC[C@]1(O)CCN(c2ccc(C#N)cc2C(F)(F)F)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-methyl-3-propylpyrrolidin-3-ol 0.5 oxalate (250 mg), 4-fluoro-3-(trifluoromethyl)benzonitrile (499 mg) and lithium carbonate (195 mg), the title compound was obtained as colorless oil (yield: 383 mg, yield: 93%).
Reaction SMILES: [F:1][C:2]1[C:3]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:18]([CH3:21])([O-:20])=[O:19].C([O-])(=O)C.[NH4+].[BH4-].[Na+].C(=O)([O-])O.[Na+]>CS(C)=O.O.C(O)(=O)C>[F:1][C:2]1[C:3]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14][CH2:21][N+:18]([O-:20])=[O:19])=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(COc2ncccc2F)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])CCc1ccc(COc2ncccc2F)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
To an acetic acid (20 mL) solution of 4-(3-fluoro-pyridin-2-yloxymethyl)-benzaldehyde (887 mg, 3.84 mmol) described in Manufacturing Example 149-1-2 were added nitromethane (1.04 mL, 19.2 mmol) and ammonium acetate (592 mg, 7.68 mmol), which was stirred under nitrogen atmosphere for 4 hours and 30 minutes at 100° C. Water was added to the reaction mixture at 0° C., which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrated was concentrated under a reduced pressure. To a solution of this residue in dimethyl sulfoxide (20 mL) and acetic acid (1 mL) was added sodium borohydride (291 mg, 7.68 mmol), which was stirred for 30 minutes at room temperature. Sodium hydrogencarbonate and water were added to the reaction solution at room temperature while cooling appropriately, which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (674 mg, 64%).
Reaction SMILES: [NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH2:10][CH2:11][S:12](=[O:15])(=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12.CN(C)C=O.[F:32][C:33]([F:42])([F:41])[CH2:34][S:35]([CH2:37][C:38](O)=[O:39])=[O:36]>C(N(CC)CC)C>[F:32][C:33]([F:42])([F:41])[CH2:34][S:35]([CH2:37][C:38]([NH:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:18][N:19]=[N:20][N:21]=3)[CH2:10][CH2:11][S:12](=[O:14])(=[O:15])[NH2:13])[CH2:7][S:8][C@H:3]12)=[O:39])=[O:36]
Reactant: O=C(O)CS(=O)CC(F)(F)F
Reactant: NC1C(=O)N2C(C(=O)O)=C(C(CCS(N)(=O)=O)Sc3nnn[nH]3)CS[C@H]12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)CC(F)(F)F)[C@H]2SC1

Procedure:
A suspension of 4.17 g. (0.01 mol.) of 7-amino-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 50 ml. of dry dimethylformamide is treated with 2 ml. of triethylamine and the mixture is stirred for 15 minutes at 25°. A slight excess of 0.01 mol. of the activated ester of 2,2,2-trifluoroethylsulfinylacetic acid is added to the mixture and it is stirred an additional hour. The reaction mixture is evaporated to dryness and water and ethyl acetate are added to the residue. The layers are separated, ethyl acetate is added to the aqueous phase and it is acidified to pH 2.5 by addition of 6N hydrochloric acid. The mixture is filtered, the layers are separated and the aqueous phase is extracted with ethyl acetate. The extract is washed with water, dried (MgSO4) and evaporated to dryness to give the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17]Br>CS(C)=O.CS(C)=O.CCOCC>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: BrCCCCBr
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CC1(c2ccc(Cl)cc2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a suspension of sodium hydride (60% suspension in mineral oil) (14.5 g, 362.96 mmol) in dimethyl sulfoxide (250 mL) was added dropwise a mixture of (4-chlorophenyl)acetonitrile (316) (25 g, 164.98 mmol) and 1,4-dibromobutane (35.6 g, 164.98 mmol) dissolved in dimethyl sulfoxide:ether (1:1; 300 mL) at 0° C. The reaction mixture was stirred for 30 min at same temperature and at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with HCl (1N; 25 mL) and water (200 mL) and extracted with ethyl acetate (3×100 mL). The separated organic part was washed with water (3×100 mL) and brine (100 mL) and dried and concentrated to get a crude product which was purified by silica CombiFlash column (3-5% ethyl acetate in hexane used as eluent) to afford 1-(4-chlorophenyl)-cyclopentanecarbonitrile (317) (33.9 g, 100%) as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10](O)[CH2:11][CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[O:13][CH2:12][CH2:11][CH2:10][O:5]1
Reactant: OCCCO
Reactant: O=Cc1ccccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Brc1ccccc1C1OCCCO1

Procedure:
ortho-Bromobenzaldehyde (4a) (8 g, 43.24 mmol) was stirred with 1,3 propanediol (4.7 ml, 64.86 mmol) and p-toluenesulfonic acid monohydrate (164 mg, 0.86 mmol) in benzene (150 ml) in a flask equipped with a Dean-Stark trap and a condenser. The mixture was heated at reflux for 12 hrs, cooled, and extracted with 2 M NaOH (100 ml), and brine (100 ml×3). The solution was dried over MgSO4, and the solvent evaporated to the title compound in quantitative yield.
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[C:8]2[CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:11]([S:13]C)=[CH:12][C:7]=2[N:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:5][C:4]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:28][CH3:29])[CH2:3]1.[CH2:35]1COC[CH2:36]1.[Li+].[OH-]>C(Cl)Cl.O.CC(O)=O>[O:1]=[S:2]1(=[O:34])[C:8]2[CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[C:11]([S:13][CH2:35][CH3:36])=[CH:12][C:7]=2[N:6]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:5][C:4]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:28][CH3:29])[CH2:3]1
Reactant: C1CCOC1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(SC)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(SCC)c(OCC(=O)O)cc2S(=O)(=O)C1
Reaction time: 1 h
Yield: 99 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5 tetrahydro-1,5-benzothiazepine (Method 43; 478 mg, 0.95 mmol) was added THF (15 ml), water (3 ml) and LiOH (34 mg, 1.4 mmol). The reaction was then stirred for 1 hour. Then AcOH (0.2 ml) was added along with water (10 ml) and DCM (10 ml) The aqueous layer was then extracted three times with DCM. The combined organic phases were then dried and concentrated to give the title compound 450 mg (99%). NMR (400 MHz) 0.7-0.9 (m, 6H), 1.0-1.7 (m, 8H), 2.2 (s, 3H), 3.2 (q, 2H), 3.7 (m, 2H), 4.8 (s, 2H), 6.65 (s, 1H), 0-7.9 (m, 6H), 7.05 (d, 2H), 7.25 (t, 2H), 7.35 (s, 1H), 8.4 (brs, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]>Cl>[F:13][C:12]([F:15])([F:14])[C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:16][C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19]([OH:21])=[O:20])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Agent: Cl
Product: O=C(O)c1ccccc1Nc1ccnc2cc(C(F)(F)F)ccc12

Procedure:
4-Chloro-7-trifluoromethylquinoline and 2-amino benzoic acid are refluxed in dilute hydrochloric acid for 1 hour to give 2-(7-trifluoromethyl-4-quinolylamino)benzoic acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[CH:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]([CH3:34])[CH2:31][C:32]#[CH:33]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:29][N:30]([CH3:34])[CH2:31][C:32]#[C:33][C:24]1[CH:23]=[C:22]([CH2:21][NH:20][C:15]2[C:14]([C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)=[O:13])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:27]=[CH:26][N:25]=1
Reactant: C#CCN(C)C
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2NCc2ccnc(Cl)c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CN(C)CC#Cc1cc(CNc2ncccc2C(=O)Nc2ccc(C(C)(C)C)cc2)ccn1
Temperature: 100 °C

Procedure:
A mixture of N-[4-(tert-butyl)phenyl](2-{[(2-chloro(4-pyridyl))methyl]amino}(3-pyridyl))carboxamide (0.15 g, 0.38 mmol, Example 139), 1-dimethylamino-2-propyne (62 mg, 0.76 mmol), PdCl2(PPh3)2 (13 mg, 0.0019 mmol) and CuI (7 mg, 0.019 mmol) in 1 mL of TEA was heated at 100° C. in a sealed tube for 3 h. The resulting mixture was filtered over Celite®. The filtrate was concentrated, and the residue was purified by prep-HPLC (reverse phase) to give the title compound. MS (ES+): 442 (M+H)+; (ES−): 440(M−H)−. Calc'd C27H31N5O−441.58.