Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].C[O:12][C:13](=O)[CH:14]([CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15](=O)[CH3:16].C(O)(=O)C>CO>[CH2:21]([O:20][CH2:19][CH2:18][C:14]1[C:13]([OH:12])=[N:9][CH:8]=[N:10][C:15]=1[CH3:16])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N=CN
Reactant: COC(=O)C(CCOCc1ccccc1)C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ncnc(O)c1CCOCc1ccccc1
Reaction time: 0.25 h

Procedure:
NaOMe (2.75 g, 50 mmol) is added to a stirred solution of formamidine acetate (25 mmol) in MeOH (75 ml) at room temperature. The mixture is stirred for 15 minutes. 2-(2-Benzyloxy-ethyl)-3-oxo-butyric acid methyl ester (20 mmol) is added and the mixture is stirred at room temperature overnight. Acetic acid (1.5 g, 20 mmol) is added and the solvent is removed in vacuo. Water (30 ml) is added to the residue and the mixture is extracted with 2-butanone (3×30 ml). The combined extracts are washed with brine (40 ml), dried (Na2SO4) and evaporated, to provide a yellow solid (160).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.O1CCOCC1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:16]([N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)n1cc(F)c(=O)[nH]c1=O
Yield: 42.7 %

Procedure:
2.6 g (0.02 mole) of 5-fluorouracil was suspended in a mixed solution of 35 ml. of dioxane and 10 ml. of pyridine and reacted with 6.7 g (0.048 mole) of benzoylchloride. The reaction mixture was treated in the same manner as in Example 1 and 2.00 g (42.5% yield) of 1-benzoyl-5-fluorouracil was obtained. The product was recrystallized from ethanol to give white needles melting at 170°-172°C. The results of an elementary analysis thereof were well in agreement with the calculated value as follows:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:31])[C@H:8]1[CH2:12][C@@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][N:9]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].O>CN(C)C=O>[CH3:5][O:6][C:7](=[O:31])[C@H:8]1[CH2:12][C@H:11]([N:1]=[N+:2]=[N-:3])[CH2:10][N:9]1[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25]
Reactant: COC(=O)[C@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
Sodium azide (515 mg) was added to a stirred solution of N-tert-butoxycarbonyl-cis-4-(p-toluenesulfonyloxy)-D-proline methyl ester (B, 1.65 g) in N,N-dimethylformamide (10 mL)-water (2 mL). After stirring at 80-90° C. for 1 hr, the solvents were removed in vacuo. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound (1.04 g) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[S:17][CH:18]=[C:19](C)[C:20]=2[Br:21])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:24]1SC(C)=CC=1.C([N-]C(C)C)(C)C.[Li+].CON(C)C(C1CCN(C(OC(C)(C)C)=O)CC1)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[S:17][C:18]([CH3:24])=[CH:19][C:20]=2[Br:21])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1csc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1Br
Reactant: Cc1ccc(Br)s1
Agent: CC(C)[N-]C(C)C
Agent: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Product: Cc1cc(Br)c(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)s1

Procedure:
Prepared essentially as in 29a except that 2-bromo-5-methyl thiophene is used as the starting material. In addition, 1.20 equivalents of lithium diisopropylamide and 1.24 equivalents of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid. tert-butyl ester are used for the reaction. Accordingly, stirring time of the reaction mixture may vary. Purification of the residue via flash column chromatography uses a gradient with a mixture of ethyl acetate: n-heptane (1:9) to ethyl acetate: n-heptane (2:8) to yield a yellow oil. LC/MS (ESI), m/e 332 (M-56) and 388 (MH+), retention time 2.15 minutes. Condition II.
Reaction SMILES: BrC1C=CC(O)=C(C2(O)C3C(=CC=CC=3)N(CCCCC)C2=O)C=1.O[C:26]1([C:41]2[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:43][C:42]=2[OH:51])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:27]1=[O:40]>>[OH:51][C:42]1[CH:43]=[CH:44][C:45]([C:47]([F:48])([F:49])[F:50])=[CH:46][C:41]=1[CH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:27]1=[O:40]
Reactant: CCCCCN1C(=O)C(O)(c2cc(C(F)(F)F)ccc2O)c2ccccc21
Agent: CCCCCN1C(=O)C(O)(c2cc(Br)ccc2O)c2ccccc21
Product: CCCCCN1C(=O)C(c2cc(C(F)(F)F)ccc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 15B, and making non-critical variations to replace 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-hydroxy-3-[2-hydroxy-5-(trifluoromethyl)phenyl]-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (78%): 1H NMR (300 MHz, CDCl3) δ 8.20-8.00 (br, 1H), 7.43-7.14 (m, 5H), 7.02 (d, 1H), 6.95 (d, 1H), 5.11 (s, 1H), 3.82-3.72 (m, 2H), 1.79-1.66 (m, 2H), 1.40-1.27 (m, 4H), 0.88 (t, 3H); MS (ES+) m/z 364 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.CON(C)[C:13](=[O:24])[C@@H:14]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:15].[Cl-].[NH4+].O>O1CCCC1>[Cl:8][C:7]1[C:2]([C:13](=[O:24])[C@@H:14]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH3:15])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Clc1cnc(Br)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ncc(Cl)cc1Cl
Temperature: -20 °C
Yield: 65.5 %

Procedure:
To 11.0 g of 2-bromo-3,5-dichloropyridine in 5 ml of tetrahydrofuran, 36.4 ml of a 1.3 M tetrahydrofuran solution of isopropylmagnesium chloride-lithium chloride complex was added dropwise with stirring at −20° C., and after the addition, the mixture was stirred at the same temperature for 15 minutes. Then, to the reaction mixture, 5.0 g of (S)—N-methoxy-N-methyl-2-(tert-butoxycarbonylamino)propionamide in 36 ml of tetrahydrofuran was added dropwise, and after the addition, the mixture was stirred at the same temperature for another 2 hours. After completion of the reaction, the reaction mixture was mixed with 30 ml of saturated aqueous ammonium chloride and 10 ml of water and extracted with ethyl acetate (40 ml×2), the resulting organic layers were combined, washed with water (40 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 10:0 to 3:7) to obtain 4.5 g of the desired product as a pale yellow oil.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH3:10][C:11]1[C:12]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:13]([O:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2.Cl[C:38](=[O:44])[CH2:39][C:40]([O:42][CH3:43])=[O:41]>C(Cl)Cl>[CH3:10][C:11]1[C:12]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:13]([O:23][C:24]2[CH:30]=[CH:29][C:27]([NH:28][C:38](=[O:44])[CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:26][CH:25]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2
Reactant: COc1ccc2c(Oc3ccc(N)cc3)c(-c3ccccc3)c(C)cc2c1
Reactant: COC(=O)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC(=O)Nc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.2 %

Procedure:
N-ethyldiisopropylamine (147 μL, 0.84 mmol, 3 equiv) was added to a solution of 38 (100 mg, 0.28 mmol, 1 equiv) in CH2Cl2 (5 mL) at 0° C. After 10 min, methyl 3-chloro-3-oxopropionate (60 μL, 0.56 mmol, 2 equiv) was added and the reaction was stirred at 0° C. for 3 h. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with saturated aqueous NaHCO3 (100 mL). The organic layer was dried over MgSO4, filtered, concentrated and the residue purified by silica gel flash column chromatography (30% EtOAc:hexanes) to provide 41 (87 mg, 68%) as a yellow oil. 1HNMR (400 MHz, DMSO-d6): δ 10.00 (s, 1H), 7.68 (s, 1H), 7.56 (m, 1H), 7.33-7.17 (m, 8H), 7.06-7.03 (m, 1H), 6.53 (m, 2H), 3.86 (s, 3H), 3.61 (s, 3H), 3.37 (s, 2H), 2.17 (s, 3H). MS m/z 455.87 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@@H:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[C:18]([CH2:28][PH:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([S:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1)[O:19][CH2:20][CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C=C(C(C)(C)C)C=1O)[CH:43]=[O:44])(C)(C)C.[Pb](=O)=O>C1C=CC=CC=1.ClCCCl>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@:15]([NH2:16])([O:44][CH3:43])[C@H:12]2[S:11][CH2:10][C:9]=1[C:18]([CH2:28][PH:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])([S:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1)[O:19][CH2:20][CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CCOC(C[PH](=O)OC(C)(C)C)(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=[Pb]=O
Solvent: c1ccccc1
Solvent: ClCCCl
Product: CCOC(C[PH](=O)OC(C)(C)C)(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)[C@](N)(OC)[C@H]2SC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.32 g (2.4 mol) of 7β-amino-3-(1-ethoxy-t-butoxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid t-butyl ester and 0.56 g (2.4 mmol) of 3,5-di-t-butyl-4-hydroxybenzaldehyde in 100 ml of dry benzene is refluxed for 4 hours under a Dean-Stark trap. The solution is evaporated under reduced pressure to leave a residue which is dissolved in 100 ml of 1,2-dichloroethane and cooled to ca. 5° in an ice bath. Three grams of freshly prepared lead dioxide is added in portions over 20 minutes until the starting material is completely consumed. The mixture is filtered through Celite and the filter cake is washed with two 20 ml portions of cold 1,2-dichloroethane. The filtrate is treated with 25 ml of methanol (distilled from magnesium) and the reaction mixture is allowed to stand at room temperature until complete consumption of the oxidized intermediate and formation of a new slower-moving product is shown by thin layer chromatography. The mixture is evaporated and the residue is dissolved in 30 ml of methanol and treated with 2.5 g of Girard reagent T (trimethylaminoacetohydrazide chloride). The reaction mixture is stirred at room temperature for 3 hours, then evaporated to give a residue which is partitioned between ethyl acetate and 20% sodium chloride solution. The organic phase is washed with 10% sodium chloride solution and saturated sodium chloride solution. The organic phase is dried (MgSO4), filtered and evaporated to dryness to give 7β-amino-7α-methoxy-3-(1-ethoxy-t-butoxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:8][C:5]2=[N:6][CH:7]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:8]([CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1cc2cc(Cl)cnc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC(=O)c1cc2cc(Cl)cnc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a stirred solution of methyl 5-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (0.986 g, 4.68 mmol) N,N-dimethylformamide (20 ml) at room temperature under a nitrogen atmosphere was added potassium carbonate (0.647 g, 4.68 mmol). After 30 minutes iodomethane (0.321 ml, 5.15 mmol) was added and the resulting mixture was stirred at room temperature overnight. Brine was added and the mixture was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was coated onto hydromatrix and purified by column chromatography (silica gel; heptane/ethyl acetate 4/1) to give methyl 5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (0.89 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH2:15][CH2:16][CH3:17].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[O:13][CH2:15][CH2:16][CH3:17]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Product: CCCOc1cc(OC)ccc1C(=O)OC

Procedure:
A stirred mixture of methyl 4-methoxysalicylate (25 g), bromopropane (15.6 ml), potassium iodide (2.82 g) and anhydrous potassium carbonate (27.53 g) was heated under reflux for 48 hours. The cooled reaction mixture was filtered and the filtrate was evaporated under reduced pressure to yield an oil which was dissolved in diethyl ether (200 ml). The ethereal solution was extracted with aqueous sodium hydroxide to remove unreacted starting material and the organic phase was then washed with water and brine, dried (magnesium sulphate) and evaporated under reduced pressure to yield methyl4-methoxy-2-propoxy-benzoate, 22.45 g.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO.C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][Si:11]([C:24]([CH3:25])([CH3:26])[CH3:27])([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: CC(C)(C)[Si](Oc1ccc(Br)c(C=O)c1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1ccc(Br)c(CO)c1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
The product from Step A (8.87 g, 20.2 mmol) was dissolved in methanol (50 mL) and methylene chloride (20 mL). Sodium borohydride (764 mg, 20.2 mmol) was added in portions at 0° C., and the solution was stirred for 2 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride until hydrogen evolution ceased. The resulting suspension was concentrated in vacuo and then partitioned between methylene chloride (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title product as a yellow oil which was sufficiently pure for use in the next step.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([OH:18])[N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Na+].Cl[C:27]([F:32])([F:31])C([O-])=O>CN(C=O)C.O>[F:31][CH:27]([F:32])[O:18][C:13]1[N:12]=[C:11]([S:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:16]=[C:15]([OH:17])[CH:14]=1
Reactant: Oc1cc(O)nc(SCc2cccc(F)c2F)n1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cc(OC(F)F)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
To a solution of 2-[[(2,3-difluorophenyl)methyl]thio]-4,6-pyrimidinediol (3 g) in DMF (30 mL), cesium carbonate (4.3 g) and chlorodifluoro-acetic acid sodium salt (1.9 g) was added. The resulting mixture was heated at 100° C. for 2 h. The reaction mixture was cooled then diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and dried (MgSO4), filtered and evaporated. Purification was by column chromatography on silica gel using EtOAc/isohexane (2:8) as eluent to give the subtitle compound as a white solid. Yield: 0.4 g
Reaction SMILES: [N:1]([CH2:4][C@:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1Br)([OH:7])[CH3:6])=[N+:2]=[N-:3].[B:15](OC(C)C)(OC(C)C)[O:16]C(C)C.[Li]CCCC>C1(C)C=CC=CC=1>[N:1]([CH2:4][C@@:5]1([CH3:6])[O:7][B:15]([OH:16])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]1=2)=[N+:2]=[N-:3]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C[C@@](O)(CN=[N+]=[N-])c1ccccc1Br
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: C[C@]1(CN=[N+]=[N-])OB(O)c2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
(S)-1-azido-2-(2-bromophenyl)propan-2-ol (8.7 g, 34.0 mmol) and triisopropyl borate (9.4 mL, 40.8 mmol) were dissolved in 170 mL of toluene. The reaction mixture was refluxed with a Dean/Stark apparatus to remove the toluene and the residue was dissolved in 150 mL of dry THF. This solution was cooled to −78° C. and BuLi (25M in Hexanes, 15.6 mL, 39.1 mmol) was added dropwise and stirred for 30 min. The reaction mixture was warmed to room temperature and allowed to stir for 3 hrs before being quenched with 50 mL of 6M HCl and concentrated under vacuum. This was extracted 3× with 100 mL of DCM. The combined organic layers were dried over MgSO4 and evaporated under vacuum. Purified by silica gel chromatography (20-30% Et2O/petroleum ether) to give 2.1 g (30%) of (S)-3-(azidomethyl)-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol as a dark yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[Cl:24][C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:30]([C:28]3[S:29][C:25]([Cl:24])=[CH:26][CH:27]=3)=[O:31])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)s3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F (R3=Me) and 5-chloro-thiophene-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([C:10](=[O:12])[CH3:11])[C:7](=[O:9])[CH3:8])[CH3:2].IC.[C:16](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([C:7](=[O:9])[CH3:8])([CH3:16])[C:10](=[O:12])[CH3:11])[CH3:2]
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)CC(C)(C(C)=O)C(C)=O
Yield: 67.8 %

Procedure:
48.3 g of 3-acetyl-4-oxo-pentanoic acid ethyl ester, 41 g of iodo-methane, 34 g of potassium carbonate, and 90 ml of acetone were mixed and refluxed for 9 hours. After cooling, 100 ml of petroleum ether was added, and the solid was filtered off and washed with acetone and petroleum ether. Fractional distillation yielded 33.4 g of 3-acetyl-3-methyl-4-oxo-pentanoic acid ethyl ester (boiling point: 69° C./0.02 mbar; purity: 97%; colorless).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](Cl)(Cl)[Cl:4].[C:9]([O:13]C=C)(C)(C)[CH3:10]>[Hg]>[Cl:4][C:3]([C:2]([F:8])([F:7])[F:1])=[CH:10][CH:9]=[O:13]
Reactant: C=COC(C)(C)C
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Agent: [Hg]
Product: O=CC=C(Cl)C(F)(F)F
Temperature: 40 °C
Yield: 60 %

Procedure:
A mixture of 1,1,1-trifluoro-2,2,2-trichloroethane and tert-butylvinyl ether in a 3:1 molar ratio is introduced to a jacketed photochemical reaction vessel. The mixture is irradiated using a medium-pressure mercury UV lamp so as to maintain the temperature of the mixture at about 35-45° C. for about 2 hours. The resultant reaction mixture is concentrated to remove volatiles and distilled to produce 3-chloro-4,4,4-trifluorobut-2-enal in a 60% yield.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:23]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:24]=2[C:25](O)=[O:26])[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.[N:48]1(OC(N(C)C)=[N+](C)C)[C:52]2N=CC=[CH:56][C:51]=2N=N1>CN(C)C=O>[C:1]([C:4]1[CH:5]([C:23]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:24]=2[C:25]([NH:48][CH2:52][C:51]#[CH:56])=[O:26])[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCNC(=O)c1cc(C#N)ccc1C1C(C(C)=O)=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Reaction time: 0.08 h

Procedure:
2-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-4-yl]-5-cyano-benzoic acid (intermediate 6) (70 mg, 0.15 mmol) and triethylamine (35 μL, 0.25 mmol) are suspended in N,N-dimethylformamide (1.5 mL) and the mixture is shaken for 5 min. A solution of O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (61.1 mg, 0.16 mmol) in N,N-dimethylformamide (0.5 mL) and triethylamine (35 μL, 0.25 mmol) is added and the reaction mixture is shaken for 1.5 h at room temperature. The product is purified by reversed phase HPLC. Yield 48 mg; ESI mass spectrum [M+H]+=495; Retention time HPLC: 0.99 min (HPLC method Z011_S03).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[Br:13][C:14]1[CH:18]=[C:17]([C:19]2[O:24][C:23](=[O:25])[C:22]3[CH:26]=[C:27]([Cl:31])[CH:28]=[C:29]([CH3:30])[C:21]=3[N:20]=2)[N:16]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[N:15]=1>O.O1CCCC1>[Br:13][C:14]1[CH:18]=[C:17]([C:19]([NH:20][C:21]2[C:29]([CH3:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:22]=2[C:23]([N:4]([CH3:3])[NH:5][CH3:6])=[O:25])=[O:24])[N:16]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[N:15]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Reactant: CNNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNN(C)C(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 134.3 %

Procedure:
To a mixture of 0.13 g of N,N′-dimethylhydrazine dihydrochloride, 1 ml of water, 0.14 g of potassium carbonate and 10 ml of tetrahydrofuran was added 0.23 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 30 ml of water, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate to obtain 0.35 g of 3-bromo-N-[4-chloro-2-(N,N′-dimethylhydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[C:16]=2[CH3:24])[C@H:10]1[CH2:25][CH3:26])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:23][C:17]1[C:16]([CH3:24])=[C:15]([N:11]2[C:12](=[O:14])[CH2:13][C@H:9]([OH:8])[C@@H:10]2[CH2:25][CH3:26])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: CC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(Cl)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
To a solution of 4-[(2S,3S)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-chloro-3-methylbenzonitrile (134.5 mg) in tetrahydrofuran (10 mL)-methanol (5 mL) was added 6 mol/L hydrochloric acid (5 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10/1→1/4) to give the title compound as a colorless solid (yield: 66.2 mg, 69%).