Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@:30]2([CH3:31])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:32])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:25])[CH:18]=[CH:19][C@H:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:33]C(=O)C)[CH2:6]1)(=O)C>CCOCC>[CH3:25][C@@H:17]([C@@H:16]1[C@@:26]2([CH3:32])[CH2:27][CH2:28][CH2:29]/[C:12](=[CH:11]\[CH:10]=[C:9]3\[CH2:8][C@@H:7]([OH:33])[CH2:6][C@H:5]([OH:4])[C:30]\3=[CH2:31])/[C@@H:13]2[CH2:14][CH2:15]1)/[CH:18]=[CH:19]/[C@@H:20]([CH:21]([CH3:22])[CH3:23])[CH3:24]
Reactant: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)C=C[C@H](C)C(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Solvent: CCOCC
Product: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)/C=C/[C@H](C)C(C)C)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Yield: 33.1 %

Procedure:
1α,3β-Diacetoxy-ergosta-5,7,22-trien (X) (200 mg) from Example 7 was dissolved in ether (400 ml) and the solution was irradiated with high pressure mercury lamp (UM-452, Ushio Electric Co., Ltd.) for 10 minutes. After distilling off ether under reduced pressure, ethanol (50 ml) was added and the mixture was heated under reflux for 1 hr. Subsequently, a solution of potassium hydroxide (1 g) in ethanol (10 ml) was added and further heated under reflux for 10 minutes. The whole reaction was carried out in a nitrogen stream. After cooling, the reaction product was extracted with ether (200 ml). The extract was washed with water, dried over Na2SO4 and ether was distilled off under reduced pressure. Chromatography on silica gel of the residue (eluted with 95/5 chloroform/ethyl acetate) gave 55 mg of a crude 1α-hydroxy vitamin D2 (XI). Crystallization of the crude vitamin from hexane/acetone gave 35 mg (17.5% yield) of a pure 1α-hydroxy vitamin D2 (XI) as crystals, m.p. 146°-147° C., λ max 265 nm (ε=18500, ethanol), [α]D20 +47° (c=0.25, ethanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[C:12]([O:16][C:17](=[O:22])[NH:18][CH2:19][CH2:20][NH2:21])([CH3:15])([CH3:14])[CH3:13].Cl.C(N=C=N)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:12]([O:16][C:17](=[O:22])[NH:18][CH2:19][CH2:20][NH:21][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)Cc1cccc(F)c1
Agent: CCN=C=N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNC(=O)Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of 3-fluorophenylacetic acid (1.93 g, 12.5 mmol) in CH2Cl2 (50 mL) was added tert-butyl-N-(2-aminoethyl)carbamate (2.0 g, 12.5 mmol), 4-dimethylaminopyridine (1.53 g, 12.5 mmol) and 1-[3-dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (2.4 g, 12.5 mmol). The mixture was stirred at room temperature for 16 h then washed with water (50 mL) and citric acid (10%, 2×50 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2 :MeOH (95:5→90:10), to afford the title amide (3.7 g, 100%) as a colourless solid. mp 125-128° C. 1H NMR (250 MHz, CDCl3) δ 1.43 (9H, s), 3.18-3.40 (4H, m), 3.53 (2H, s), 4.82 (1H, br s), 6.23 (1H, br s), 6.94-7.06 (3H, m), 7.26-7.40 (2H, m). MS (ES+) (297, M+1).
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([Cl:13])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)(=[O:4])=[O:3].[F-:14].[K+].C(OCC)(=O)C>O1CCOCC1.O>[F:14][S:2]([C:5]1[S:6][C:7]([Cl:13])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)(=[O:4])=[O:3]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(S(=O)(=O)F)sc1Cl
Temperature: 50 °C
Reaction time: 4 h

Procedure:
2--Chlorosulphonyl-4-nitro-5-chlorothiophene (20.1 parts) were stirred in p-dioxane (80 parts) at room temperature. Potassium fluoride (5.2 parts) in water (20 parts) was added and the mixture heated to 50° C. Stirred under these conditions for 4 hours, then cooled and poured onto ice/water. Ethyl acetate was then added to extract the product and separated. Dried over magnessium sulphate then screened and concentrated to yield the product 2-fluorosulphonyl-4-nitro-5-chloro thiophene (20.4 parts).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[C:24](=[N:30]O)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1>N1C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:15][C:14]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:13][CH:12]=3)=[N:30][C:24]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(Cl)cc1
Reactant: NCc1ccc(CN2CCOCC2)cc1
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2ccc(CN3CCOCC3)cc2)[nH]c1-c1ccc(Cl)cc1
Yield: 61.5 %

Procedure:
4-(Morpholinomethyl)phenylmethylamine (8 g) and ethyl 3-(4-chlorophenyl) -2-hydroxyimino-3-oxopropionate (8.26 g) were dissolved in pyridine (120 ml) and the mixture was refluxed under heating for 12 hr. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography to give the objective ethyl 5-(4-chlorophenyl)-2-[4-(morpholinomethyl)phenyl]imidazole-4-carboxylate (8.46 g), melting point 183-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])=[N:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH:34](Br)([CH3:36])[CH3:35]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:12][C:11]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH:34]([CH3:36])[CH3:35])[CH2:24][CH2:23]3)=[O:21])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nc(C(=O)N3CCNCC3)cc2-c2ccccc2)cn1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(=O)N3CCN(C(C)C)CC3)cc2-c2ccccc2)cn1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperazine (0.446 g) obtained in Example 16 in N,N-dimethylformamide (7.5 mL), potassium carbonate (0.505 g) and isopropyl bromide (0.30 mL) were added at room temperature, and the mixture was stirred at 60° C. for 16 hours, and then cooled in air. The reaction mixture was partitioned between water and ethyl acetate. Subsequently, the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as an oily product (0.283 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].F[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)COc1ncc(O)cc1Cl
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)COc1ncc(Oc2ccc(C#N)cc2)cc1Cl
Temperature: 110 °C
Yield: 74.4 %

Procedure:
5-Chloro-6-isobutoxypyridin-3-ol (Preparation 16, 145 mg, 0.719 mmol) and potassium carbonate (400 mg, 2.561 mmol) were dissolved in DMSO (3.00 mL). Then 4-fluorobenzonitrile (200 mg, 1.651 mmol) was added and mixture was heated at 110° C. for 18 hours. The reaction mixture was diluted with EtOAc (15 mL) and washed with water (15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0 to 20% EtOAc in heptane to yield the title compound as a clear oil (162 mg, 74%):
Reaction SMILES: [O:1]=[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:3]=[CH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].[CH3:20]O>S(=O)(=O)(O)O>[O:1]=[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:3]=[CH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH3:20])=[O:9]
Reactant: CO
Reactant: O=C(O)c1cccc(C=CC(=O)c2ccccc2)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C=CC(=O)c2ccccc2)c1

Procedure:
A slurry of 3-(3-oxo-3-phenyl-1-propenyl)-benzoic acid (2.84 g, 11.26 mmol) in methanol (150 mL) is treated with a few drops of sulfuric acid and heated under reflux for 8 hours. Upon cooling, a solid forms which is collected by filtration and washed thoroughly with methanol to provide 0.9 g of the title compound.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[N+:13]([O-])=O.[NH4+].[Cl-]>C1COCC1>[Cl:12][C:11]1[C:6]([Cl:5])=[C:7]2[C:8]([CH:1]=[CH:2][NH:13]2)=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1ccc2cc[nH]c2c1Cl
Temperature: -30 °C
Reaction time: 1 h

Procedure:
800 ml of a 1M solution of vinylmagnesium bromide in THF are cooled to −45° C. under a nitrogen atmosphere, a solution of 51.2 g of 2,3-dichloronitrobenzene in 1000 ml of THF is then added dropwise and the mixture is left stirring at −30° C. for 1 hour. The reaction mixture is poured onto 1000 ml of a saturated NH4Cl solution and extracted with ether, the combined organic phases are washed with water and with a saturated NaCl solution and dried over MgSO4, and the solvents are evaporated under vacuum. The residue is chromatographed on silica gel, elution being carried out with a cyclohexane/EtOAc mixture (95/5; v/v). 27.75 g of the expected compound are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([C:26]2[CH:36]=[CH:35][C:29]3[N:30]([CH3:34])[C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(#N)C.O>[CH3:34][N:30]1[C:29]2[CH:35]=[CH:36][C:26]([C:24]([C:20]3[N:21]=[CH:22][N:23]=[C:18]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[C:15]6[C:10](=[N:11][CH:12]=[CH:13][CH:14]=6)[NH:9][C:8]5=[O:16])[CH2:5][CH2:6]4)[CH:19]=3)=[O:25])=[CH:27][C:28]=2[O:32][C:31]1=[O:33]
Reactant: Cn1c(=O)oc2cc(C(=O)c3cc(Cl)ncn3)ccc21
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)oc2cc(C(=O)c3cc(N4CCC(n5c(=O)[nH]c6ncccc65)CC4)ncn3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
78 mg (0.40 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one, 0.10 g (0.40 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3-methyl-3H-benzoxazol-2-one and 0.070 mL (0.40 mmol) DIPEA were combined in 2 mL DMF and shaken overnight at RT. The mixture was diluted with acetonitrile/water and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31][C:32]1[C:41]([C@H:42](O)[CH3:43])=[CH:40][C:39]2[C:34](=[C:35]([F:45])[CH:36]=[CH:37][CH:38]=2)[N:33]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:31][C:32]1[C:41]([C@@H:42]([N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH3:43])=[CH:40][C:39]2[C:34](=[C:35]([F:45])[CH:36]=[CH:37][CH:38]=2)[N:33]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@@H](O)c1cc2cccc(F)c2nc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](c1cc2cccc(F)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 81.8 %

Procedure:
In a round bottomed flask was combined phthalimide (6.38 g, 43.3 mmol), triphenylphosphine (1.14 g, 43.3 mmol), and (R)-1-(2-chloro-8-fluoroquinolin-3-yl)ethanol (8.15 g, 36.2 mmol) in THF (240 mL). The solution was cooled to 0° C. and diisopropylazodicarboxylate (DIAD, 8.5 mL, 43.3 mmol) was added dropwise. The reaction was allowed to warm to rt overnight. The reaction was concentrated to a volume of ˜100 mL and diluted with 1 L of Et2O and 200 mL of water. The layers were separated and the aqueous layer was back extracted with 200 mL of Et2O. The combined organic layers were washed with 160 mL of brine, dried over MgSO4, filtered, and concentrated. Column chromatography using 100% DCM afforded (S)-2-(1-(2-chloro-8-fluoroquinolin-3-yl)ethyl)-isoindoline-1,3-dione (10.5 g, 82% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.60 (br s, 1H), 7.74 (m, 2H), 7.64 (m, 3H), 7.45 (td, J=7.8, 4.9 Hz, 1H), 7.35 (ddd, J=10.2, 7.8, 1.2 Hz, 1H), 5.89 (q, J=7.2 Hz, 1H), 1.90 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]([NH:19][C:20]1[CH:25]=[C:24](F)[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28])=[O:18]>CS(C)=O.O>[CH3:16][C:17]([NH:19][C:20]1[CH:25]=[C:24]([O:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28])=[O:18]
Reactant: CC(=O)Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,4-dichlorophenol (1.2 g, 7.6 mmol) and potassium carbonate (2.1 g, 15.2 mmol) is stirred together in dimethylsulfoxide (20 ml). N-methylcarbonyl 2-nitro-5-fluoroaniline (1.5 g, 7.6 mmol) is added in portions. After 1 hour, the reaction is heated to 100° for 1.5 hours. The reaction is then cooled to RT and diluted with water. A solid is collected, dissolved in chloroform, washed with water, dried and stripped to give N-methylcarbonyl 2-nitro-5-(2,4-dichlorophenoxy)aniline.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]3)=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(#N)C>[CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[N:15]3[CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1ccc(C)n1-c1ccc2c(c1)NC(=O)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)N1C(=O)CCc2ccc(-n3c(C)ccc3C)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A mixture of 7-(2,5-dimethyl-1H-pyrrol-1-yl)-3,4-dihydroquinolin-2(1H)-one (1.4 g, 5.8 mmol) and potassium carbonate (2.4 g, 17.5 mmol) in ACN (40 mL) was stirred for 30 min then ethyl 2-bromopropanoate (2.1 g, 11.6 mmol) was added and the mixture was heated to reflux overnight. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. EtOAc (50 mL) and water (30 mL) was added to the residue and the organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-30% EtOAc in petroleum ether) to give ethyl 2-(7-(2,5-dimethyl-1H-pyrrol-1-yl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)propanoate (1.6 g, 81%). 1H NMR (CDCl3, 400 MHz): δ 7.26 (d, J=7.2 Hz, 1H), 6.87 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 5.91 (s, 2H), 4.98 (q, J=6.8 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 2.96 (m, 2H), 2.72 (m, 2H), 2.05 (s, 6H), 1.61 (d, J=7.2 Hz, 3H), 1.19 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:55]=[CH:54][CH:53]=[C:52]3[C:48]=2[CH:49]=[N:50][NH:51]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>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>[NH:51]1[C:52]2[C:48](=[C:47]([C:2]3[C:10]4[C:9]([NH:11][C@H:12]([C:14]5[N:19]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)[C:18](=[O:26])[C:17]6=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]6[N:15]=5)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=3)[CH:55]=[CH:54][CH:53]=2)[CH:49]=[N:50]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cccc5[nH]ncc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 53.6 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (78 mg, 0.32 mmol), sodium carbonate (43 mg, 0.41 mmols) and bis(triphenylphosphine)palladium(II) dichloride (12 mg, 0.02 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to give 44 mg (51% yield) of the title compound. Purity 83%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[C:6]([CH3:17])[C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[C@@H:30]([C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)[CH2:31][CH2:32][CH3:33])(=O)=O.O>CC1CCCO1>[CH3:17][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([CH3:1])[C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]1)[O:18][C@H:30]([C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCC[C@@H](OS(C)(=O)=O)c1ccc(C(=O)OC)cc1
Reactant: Cc1cc(O)cc(C)c1-n1cc(C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC1CCCO1
Product: CCC[C@H](Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)OC)cc1
Temperature: 65 °C

Procedure:
To a solution of 3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenol (intermediate 26) (12.6 g, 49 mmol) in 2-methyltetrahydrofuran (70 mL) was added cesium carbonate (23.5 g, 72 mmol) and the solution of mesylate from step 2. The reaction was heated to 65° C. for 5 h. The reaction was then cooled to room temperature and water (80 mL) was added. The aq. layer was split and the organic solution was used in the next step without isolation.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14](C(OC(C)(C)C)=O)[C:13](=[O:22])[C:12]([CH3:24])([CH3:23])[O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[NH:14][C:13](=[O:22])[C:12]([CH3:24])([CH3:23])[O:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(C)(C)OC[C@H]1c1cc(F)cc(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)OC[C@@H](c2cc(F)cc(F)c2)NC1=O
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (5R)-5-(3,5-difluorophenyl)-2,2-dimethyl-3-oxomorpholine-4-carboxylate from Step F (225 mg, 0.66 mmol) in CH2Cl2 (3 mL) at ambient temperature was added TFA (0.49 mL, 6.6 mmol). After stirring for 1 h, the reaction mixture was concentrated in vacuo to give the title compound. MS: m/z=242 (M+1).
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[N:5]1[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[CH:25]=[N:24][S:23][N:22]=3)[C@H:4]1[S:3]2.[Br-].[Al+3].[Br-].[Br-]>ClCCl>[CH3:1][CH:2]1[CH:15]=[C:6]([C:7]([O:9][CH2:10][C:11]([Cl:13])([Cl:14])[Cl:12])=[O:8])[N:5]2[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[CH:25]=[N:24][S:23][N:22]=3)[C@H:4]2[S:3]1
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc3cnsn3)[C@H]1S2
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3cnsn3)[C@H]2S1
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-{2-(1,2,5-thiadiazol-3-yl)acetamido}penam-3-carboxylate (16.5 g.) in dried dichloromethane (100 ml.) was gradually dropwise added to a solution of aluminum bromide (17.5 g.) in dichloromethane (100 ml.) at below -10° C. Then, the mixture was stirred for 2 hours at below 0° C. and stirred for further 2 hours at room temperature. After the reaction, the reaction mixture was washed in turn with 2% hydrochloric acid (100 ml.) twice, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate. After drying, the solvent was distilled off to give powdery 2,2,2-trichloroethyl 2-methyl-7-{2-(1,2,5-thiadiazol-3-yl)acetamido}-3-cephem-4-carboxylate (13.2 g.), mp 180° to 185° C. (dec.).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[N:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:25]=O>C(O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:15][CH2:16][N:17]([CH3:25])[CH2:18][CH2:19]4)[N:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(N3CCNCC3)c(F)cc2c1=O
Reactant: C=O
Solvent: O=CO
Product: CN1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1

Procedure:
A suspension of 1.3 g (4.0 mmole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid, 13.3 ml of 37% formalin and 13.3 ml of 88% formic acid was refluxed for four hours. The resulting solution was evaporated in vacuo. The residue was suspended in aqueous ethanol, the resulting precipitate removed by filtration, washed with water and dried in vacuo to give 1.24 g of the title compound, mp 236°-237° C.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1I)(C)(C)C.Cl.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[SH:29])[CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:17])=[C:10]([S:29][C:27]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:28]=2[N:19]=[CH:20][CH:21]=[CH:22]3)[CH:11]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1I
Reactant: Sc1cccc2cccnc12
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: OCCO
Product: O=C(O)COc1ccc(Cl)cc1Sc1cccc2cccnc12
Temperature: 80 °C

Procedure:
A mixture of the product from step (i) (0.262 g), 8-quinolinethiol hydrochloride (0.141 g), copper (1) iodide (7 mg), potassium carbonate (0.295 g) and ethylene glycol (0.08 ml) in iso-propanol (3 ml) was heated at 80° C. for 48 h. The mixture was partitioned between DCM/2M hydrochloric acid, the organics dried, evaporated under reduced pressure and the residue purified by chromatography on silica eluting with DCM:methanol:acetic acid (90:9:1). The residue was triturated with diethylether/methanol, filtered and dried, yield 0.101 g.