Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C:6]1[C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:19][C:2]([F:1])([F:18])[CH2:3][NH:5][C:6]1[C:7]([N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Nc1cccnc1N1CCNCC1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: FC(F)(F)CNc1cccnc1N1CCNCC1
Reaction time: 0.17 h

Procedure:
1-[3-(2,2,2-Trifluoroacetamido)-2-pyridinyl]piperazine (PREPARATION 102), is dissolved in 5 ml of tetrahydrofuran and cooled to 0°. Then 4.84 ml of lithium aluminum hydride solution is added dropwise. After 10 min of stirring at 0°, the reaction is warmed to 20°-25° and stirred 45 min. The reaction is quenched at 0° with the dropwise addition of 0.4 ml of water, 0.6 ml of 10% aqueous sodium hydroxide, and 1 ml of water. The slurry is filtered through celite, washed with 20% methanol/chloroform and concentrated in vacuo to afford the title amine which is used without further purification, NMR (300 MHZ, CDCl3) 7.82, 6.97-6.92, 4.86, 3.75, and 3.06-3.01 δ.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21](I)[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31]>O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:14][C:15]3[C:16]([C:17]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:19])=[CH:20][C:21]([C:17]([O:18][CH3:13])=[O:19])=[CH:22][C:23]=3[CH3:24])=[O:18])=[CH:11][C:10]([C:26]([F:28])([F:27])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)c(C(=O)NC(C)C)c1
Temperature: 60 °C
Yield: 160.7 %

Procedure:
The title compound of step B (3.07 g, 5.7 mmol) was dissolved in tetrahydrofuran (30 mL) and treated with isopropylamine (1.69 g, 28.7 mmol). The mixture was heated at 60° C. for 2 hours and concentrated to dryness under reduced pressure. The residue was subjected to chromatography on silica gel using ethyl acetate/hexanes (40:60) as eluent. Pooling appropriate fractions and evaporation of solvent provided the title compound of Step C (2.4 g): m.p.: 199–200° C. 1H NMR (CDCl3): δ 10.3 (NH), 8.42 (1H), 7.84 (1H), 7.61 (1H), 7.44 (2H), 7.42 (1H), 6.01 (1H), 4.21 (m, 1H), 2.13 (s, 3H), 1.2 (6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH:17]([OH:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26](I)[CH3:27]>CN(C=O)C.C(OCC)(=O)C>[CH2:26]([N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[C@@H:12]([CH:17]([OH:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])[CH3:27]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(C)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN([C@H](C(=O)OC)C(C)O)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Compound 9C (3 g, 8.94 mmol) dissolved in DMF (15 ml) was added with K2CO3 (1.1 equiv., 1.36 g) and ethyl iodide (1.1 equiv., 1 ml) and the reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and washed several times with water and finally with Brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from ethyl ether and petroleum ether afforded 2.8 g of a semisolid. Yield=97%. 1HNMR (DMSO, 200 MHz) δ 1.00 (3H, d, J=6.2 Hz), 1.26 (3H, t, J=7 Hz), 3.32 (3H, s), 3.34 (2H, m), 4.02 (1H, bs), 4.23 (1H, m), 5.14 (1H, d, J=4.4 Hz), 7.62 (2H, m), 7.76 (2H, m)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20]3[CH2:21][CH2:22][O:23][CH2:24][CH:25]=3)=[C:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[C:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(C3=CCOCC3)c(C3CC3)cc2C1
Agent: O=C[O-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N1Cc2cc(C3CCOCC3)c(C3CC3)cc2C1

Procedure:
Prepared in analogy to Example A49(b) from 5-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and ammonium formate. Colourless oil. MS (m/e): 288.0 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:15][C:16]([CH:20]=O)([CH2:18][OH:19])[CH3:17].C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]([O:14][CH2:15][C:16]([CH3:20])([CH3:17])[CH:18]=[O:19])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CC(C)(C=O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)OCC(C)(C)C=O

Procedure:
To a hot (80° C.) solution of lauric acid (70 g., 0.35 mole), and hydroxypivaldehyde (30.6 g., 0.3 mole) in 120 g. of toluene was added 1.75 g. of p-toluenesulfonic acid monohydrate (0.009 mole). The mixture was then heated at total reflux for 1.5 hrs. and water generated in the reaction mixture was removed by azeotropic distillation. The reaction mixture was cooled, washed with saturated aqueous sodium bicarbonate and brine, then dried over magnesium sulfate, filtered, and evaporated in vacuo. GLC analysis of the product showed that it contained 90% of the desired laurate ester. Fractional distillation of the crude sample gave a product cut, b.p. 180° C./4.0 mm, of 95% purity (GLC, area %). NMR (CDCL3): 9.73 (s, 1H,--CHO), 4.2 (s, 2H, --CO2CH2 --), 2.3 (t, 2H, --CH2CO2 --), 0.9-1.9 (m, 23H, CH2 (CH2)10CH2CO 2 --), and 1.17 (s, 6H, --C(CH2)2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[N:19]1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:27][C:26]2[CH:25]=[CH:24][C:23]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:30][CH:29]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1

Procedure:
The title compound of Step A was prepared from (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester, of Preparation 20, and 4-pyrazol-1-yl-benzaldehyde, of Preparation 42, using the method described in Example 3, Step A, except no triethylamine was used. 1H NMR (400 MHz, CDCl3) δ 7.90 (m, 1H), 7.70 (m, 1H), 7.63 (d, 2H), 7.41 (d, 2H), 7.23 (m, 1H), 6.94 (m, 2H), 6.78 (dd, 1H), 6.44 (dd, 1H), 4.51 (s, 2H), 3.81 (s, 2H), 3.77 (s, 2H), 1.47 (s, 9H); MS 394 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>>[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([C:23](=[O:30])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:21][CH2:22]2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:31][CH:32]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccccc3)CC2)c2cccnc2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccccc3)CC2)c2cccnc2)cc1)c1ccccc1
Yield: 85.9 %

Procedure:
Using 4-amino-N-[2-(4-benzoylpiperidino)ethyl]-N-(3-pyridyl)benzamide (210.7 mg, 0.49 mmol), benzoyl chloride (0.07 ml, 0.60 mmol) and pyridine (0.05 ml, 0.62 mmol), the procedure of Inventive Example 165 was repeated to obtain 224.3 mg (85.9%) of the title compound in a colorless powder form.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:19][CH2:20][CH2:21]O)=[O:18])[CH:15]=2)[C:10]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=2)=[O:24])=[C:9]1[CH:35]([CH3:37])[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.CS(Cl)(=O)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[O:18][CH2:21][CH2:20][N:19]=3)[CH:15]=2)[C:10]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=2)=[O:24])=[C:9]1[CH:35]([CH3:37])[CH3:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)NCCO)cc2n1Cc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C3=NCCO3)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
General Procedure H. To a solution of 1-benzyl-N3-(3,4-difluorobenzyl)-N6-(2-hydroxyethyl)-2-isopropyl-1H-indole-3,6-dicarboxamide (Compound 63, 17 mg, 0.033 mmol) in CH2Cl2 (2 ml) at 0° C under argon was added Et3N (0.03 ml, 0.2 mmol), and then added MsCl (7 mg, 0.066 mmol). The reaction was stirred at 25° C. for 3 h, quenched with H2O diluted with EtOAc, washed with brine, dried over Na2SO4, concentrated in vacuo. The residue was purified by chromatography on silica gel (100% EtOAc) to yield the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]([Li])[CH:12]([CH3:14])[CH3:13].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: [Li]CC(C)C
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)CC(O)c1ccc(Cl)cc1Cl
Temperature: 0 °C

Procedure:
To a cooled (0° C.) stirred solution of 2,4-dichlorobenzaldehyde (2 g, 11.43 mmol) in THF (50 ml) under N2 is added isobutyllithium (7.86 ml, 12.57 mmol) slowly and the reaction is stirred at RT over the weekend. The reaction mixture is added to sat. ammonium chloride (100 ml) and extracted with EtOAc (140 ml). The organic portion is washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified by chromatography on silica (70 g/150 ml silica-column) eluting with 10% EtOAc/iso-hexane to give (2,4-dichloro-phenyl)-3-methyl-butan-1-ol as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.53 (1H, d, J 8.3), 7.36 (1H, d, J 2.0), 7.29 (1H, dd, J 8.3, 2.0), 5.18 (1H, dd, J 9.2, 3.7), 1.88 (1H, m), 1.61 (1H, ddd, 14.0, 9.2, 4.7), 1.52 (1H, ddd, 14.0, 9.1, 3.7), 1.03 (3H, d, J 6.6), 0.99 (3H, d, J 6.6).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[O:7][C:8]1[C:15]([CH3:16])=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=1[CH3:17])([CH3:3])[CH3:2].[NH2:23][NH:24][C:25]([NH2:27])=[O:26].C([O-])(=O)C.[Na+]>C(O)C>[CH3:16][C:15]1[CH:14]=[C:11]([CH:10]=[C:9]([CH3:17])[C:8]=1[O:7][C:6]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)[CH:12]=[N:23][NH:24][C:25]([NH2:27])=[O:26]
Reactant: COc1ccc(Oc2c(C)cc(C=O)cc2C)cc1C(C)C
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Oc2c(C)cc(C=NNC(N)=O)cc2C)cc1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of 4-(3-isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-benzaldehyde (19 mg, 0.063 mmol) in ethanol (1 ml) at room temperature was added semicarbazide (7.7 mg, 0.69 mmol) and sodium acetate (5.1 mg, 0.063 mmol). After stirring at room temperature for about one hour, the solvent was removed under vacuum, and the residue was dissolved in ethyl acetate (5 ml). The ethyl acetate solution was washed with water (3×5 ml), brine (5 ml), dried, filtered, and concentrated to afford the title compound (20 mg) as a yellow solid which was used directly in the next step without further purification. MS (APCl−) Calc: 355.2, found: 354.3 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:6]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:9]([CH3:20])[CH2:8]1.[C:26]([O:30][C:31]([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=[O:32])([CH3:29])([CH3:28])[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:26]([O:30][C:31]([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH2:21][C:22]([F:24])([F:25])[F:23])[C:6]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH:9]([CH3:20])[CH2:8]1)=[O:48])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC1CN(c2c(N)cnn2CC(F)(F)F)CCN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnn2CC(F)(F)F)CCN1C(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 20 h
Yield: 32.6 %

Procedure:
To a solution of tert-butyl (±)-4-(4-amino-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate (300 mg, 0.83 mmol), 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (294 mg, 0.83 mmol), HATU (410 mg, 1.08 mmol) in DMF (15 mL) was added TEA (2 mL). The mixture was stirred at 30° C. for 20 hours, poured into water (100 mL), and extracted with EtOAc (40 mL×3). The combined organic layers was washed with water (50 mL×2) and brine (30 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by preparative HPLC to give tert-butyl (±)-4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate as white solid (190 mg, 33%). MS (ESI) m/z: 702 [M+H+].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]#[N:14])[CH2:9]1.[Cl:15][C:16]1[C:22](Cl)=[CH:21][C:19]([NH2:20])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1>CN(C=O)C.CCOC(C)=O>[NH2:20][C:19]1[C:18]([N+:24]([O-:26])=[O:25])=[CH:17][C:16]([Cl:15])=[C:22]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]#[N:14])[CH2:9]2)[CH:21]=1
Reactant: N#CC1CCNC1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)C1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (2.93 g, 21.3 mmol) was added to a mixture of pyrrolidine-3-carbonitrile hydrochloride (1.41 g, 10.6 mmol) and 4,5-dichloro-2-nitroaniline (2.00 g, 9.7 mmol) in DMF (8 mL). The reaction mixture was stirred at 120° C. overnight, diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, concentrated and the crude was purified by chromatography to give the sub-title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([CH2:8][C:9]([OH:11])=O)=[O:7].[NH2:12][CH:13]1[C:30](=[O:31])[N:15]2[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]3[NH:26][N:25]=[N:24][CH:23]=3)[CH2:18][S:19][C@H:14]12>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([CH2:8][C:9]([NH:12][CH:13]1[C:30](=[O:31])[N:15]2[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]3[NH:26][N:25]=[N:24][CH:23]=3)[CH2:18][S:19][C@H:14]12)=[O:11])=[O:7]
Reactant: O=C(O)CS(=O)c1ccco1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12
Product: O=C(CS(=O)c1ccco1)NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12

Procedure:
348 mg. of 2-furylsulfinylacetic acid of the R form and 7-amino-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 109 mg. of 7-(2-furylsulfinylacetamido)-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid of the R form were obtained.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:23]=[C:22]2[C:18](=[N:19][CH:20]=[N:21]2)[C:17](=[O:24])[N:16]=1)[CH2:6][CH3:7].[OH-].[NH4+]>S(=O)(=O)(O)O>[CH2:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:1]([O-:4])=[O:2])=[CH:11][C:10]=1[C:15]1[N:23]=[C:22]2[C:18](=[N:19][CH:20]=[N:21]2)[C:17](=[O:24])[N:16]=1)[CH2:6][CH3:7]
Reactant: O=[N+]([O-])O
Reactant: CCCOc1ccccc1C1=NC(=O)C2=NC=NC2=N1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCCOc1ccc([N+](=O)[O-])cc1C1=NC(=O)C2=NC=NC2=N1
Temperature: 0 °C

Procedure:
A mixture of fuming nitric acid (0.23 ml) and sulphuric acid (4 ml) was added dropwise to a stirred solution of 2-(2-propoxyphenyl)purin-6-one (1.0 g) in sulphuric acid (4 ml) at 0° to -5° C. The temperature was maintained between -5° C. and +4° C. for 20 hours and then the mixture was poured into ice-water. The filtered solution was treated with concentrated ammonium hydroxide to pH 9 to give a crude product, 0.55 g. Recrystallisation twice from aqueous ethanol then once from acetonitrile gave the title compound, 0.2 g, m.p. 254°-256° C.
Reaction SMILES: [NH2:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[C:3]([C:6]#[N:7])[C:4]#[N:5].P([O-])(OCC)(SCC)=[S:18]>C(O)C.O>[NH2:1]/[C:2](/[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[C:3](/[C:4]#[N:5])\[C:6](=[S:18])[NH2:7]
Reactant: CCOP([O-])(=S)SCC
Reactant: N#CC(C#N)=C(N)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: O
Product: N#C/C(C(N)=S)=C(/N)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
A suspension of Example 96C (2.1 g, 9.8 mmol) and 90% diethyl dithiophosphate (1.8 mL, 10.8 mmol) in ethanol (15 mL) and water (15 mL) was heated to reflux for 24 hours, cooled to room temperature, poured into ice water (300 mL), and filtered. The filter cake was dried to provide 2.3 g (95% yield) of the desired product. MS(ESI(−)) m/e 247 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]([O:13][CH3:14])=[O:12])=[O:5].[Sn](Cl)(Cl)(Cl)Cl>CO>[NH2:19][C:18]1[C:2]([Cl:1])=[C:3]([CH:15]=[CH:16][CH:17]=1)[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]([O:13][CH3:14])=[O:12])=[O:5]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Product: COC(=O)[C@@H]1CCCN1C(=O)c1cccc(N)c1Cl
Yield: 92.2 %

Procedure:
A solution of 2.64 g of methyl (S)-1-(2-chloro-3-nitrobenzoyl)pyrrolidine-2-carboxylate and 10.0 g of tin chloride in 60 ml of methanol was refluxed for 1 hour. The reaction medium was filtered and the filtrate was concentrated by half its volume and extracted with ethyl acetate (3×50 ml). The organic phases were combined, dried over magnesium sulfate and evaporated. 2.20 g of methyl (S)-1-(3-amino-2-chlorobenzoyl)pyrrolidine-2-carboxylate were obtained. Yield=92%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[F:10])[CH:4]=1
Reactant: Fc1ccccc1CCl
Reactant: COc1ccc(O)cc1
Product: COc1ccc(O)c(Cc2ccccc2F)c1

Procedure:
Alkylation of 4-methoxyphenol with 2-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(2′-fluorobenzyl)phenol. This material was converted to compound 73 and compound 74 by the procedure similar to that in Example 18 method B.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([CH:15]=O)[CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([NH2:25])[CH:19]=1.S(=O)(O)[O-].[Na+]>CN(C=O)C.O>[Br:17][C:18]1[CH:23]=[CH:22][C:21]2[N:24]=[C:15]([C:4]3[CH:3]=[C:2]([CH3:1])[N:6]([CH2:7][C:8]4[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=4)[N:5]=3)[NH:25][C:20]=2[CH:19]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: Cc1ccc(Cn2nc(C=O)cc2C)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2nc(-c3nc4ccc(Br)cc4[nH]3)cc2C)cc1
Temperature: 110 °C

Procedure:
To a solution of 5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carbaldehyde (Step 2, 700 mg, 3.27 mmol) in DMF (25 mL) was added 4-bromo-o-phenylenediamine (1.2 g, 6.53 mmol) followed by sodium bisulfite (679 mg, 6.53 mmol), and the resulting mixture was heated at 110° C. for 5 h. After being cooled to rt, the reaction mixture was diluted with water. The aqueous phase was extracted with ethyl acetate (3×50 mL), and the combined organics were washed with water (1×50 mL) and brine (1×50 mL), dried (Na2SO4), filtered, and concentrated to dryness. The crude material was then purified with an ISCO CombiFlash Companion using gradient elution from 0% to 50% EtOAc in hexanes to afford the title compound as a mixture of regioisomers as a light yellow solid (600 mg, 48%): 1H NMR (300 MHz, DMSO-d6) δ 11.76 (m, 1H), 11.60 (s, 1H), 7.35-7.77 (m, 2H), 7.27-7.30 (m, 1H), 7.13 (d, 2H), 7.04 (d, 2H), 6.69 (s, 1H), 5.36 (s, 2H), 2.27 (s, 3H), 2.24 (s, 3H); ES-MS m/z 381.20, HPLC RT (Method B) 3.20 min.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=1[CH3:19])=[O:10])[NH:2]2.[N:20]1([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27](O)=[O:28])[CH:24]=[CH:23][CH:22]=[N:21]1>>[N:20]1([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:28])[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: O=C(O)c1ccccc1-n1cccn1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1ccccc1-n1cccn1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-pyrazol-1-yl-benzoic acid. LC-MS (basic): tR=1.19 min; [M+H]+=447.1.
Reaction SMILES: [NH2:1][CH:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:20]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[OH:4].[C:32]1([C:43](O)=[O:44])[CH:33]=[CH:34][CH:35]=[C:36]2[CH2:42][CH2:41][CH2:40][CH:39]=[CH:38][C:37]=12.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:10]=1)[CH:2]([NH:1][C:43]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[CH2:42][CH2:41][CH2:40][CH:39]=[CH:38][C:37]=12)=[O:44])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:30])([F:31])[CH:27]([F:28])[F:29])[CH:20]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-(phenyloxy)phenyl)-3-(3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)-1-propanol (300 mg, 0.69 mmol) in acetonitrile (16 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (130 mg, 0.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg, 1.03 mmol) and 1-hydroxy-1H-benzotriazole (106 mg, 0.69 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (285 mg, 68%).