Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:24])=[C:6]([CH:23]=1)[CH2:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][O:15][C@H:16]2[CH2:20][CH2:19][O:18][CH2:17]2)=[CH:10][CH:9]=1.[CH2:25]([Li])CCC.C[Si](C)(C)[O:32][C@@H:33]1[C@@H:38]([O:39][Si](C)(C)C)[C@H:37]([O:44][Si](C)(C)C)[C@@H:36]([CH2:49][O:50][Si](C)(C)C)[O:35][C:34]1=[O:55].CS(O)(=O)=O>C1(C)C=CC=CC=1.O1CCCC1.C1(C)C=CC=CC=1.CO>[Cl:24][C:5]1[CH:4]=[CH:3][C:2]([C:34]2([O:55][CH3:25])[C@H:33]([OH:32])[C@@H:38]([OH:39])[C@H:37]([OH:44])[C@@H:36]([CH2:49][OH:50])[O:35]2)=[CH:23][C:6]=1[CH2:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][O:15][C@H:16]2[CH2:20][CH2:19][O:18][CH2:17]2)=[CH:10][CH:9]=1
Reactant: [Li]CCCC
Reactant: Clc1ccc(Br)cc1Cc1ccc(OCCO[C@H]2CCOC2)cc1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: COC1(c2ccc(Cl)c(Cc3ccc(OCCO[C@H]4CCOC4)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
To a −65° C. solution of (S)-3-(2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethoxy)tetrahydrofuran (200 mg, 0.49 mmol) in anhydrous toluene/tetrahydrofuran (6 mL, v/v=2:1) was added dropwise n-butyllithum (2.5 M in hexane, 0.3 mL), and the pale yellow mixture was stirred for 30 min at −65° C. The mixture was transferred to a −65° C. solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (280 mg, 0.73 mmol) in toluene (4 mL). The mixture was stirred at −65° C. for 2 h until starting material was consumed. The reaction was quenched with methanesulfonic acid (0.04 mL, 1.7 mmol) in methanol (6 mL), and the mixture was allowed to warm to 20° C. and stirred overnight. The reaction was quenched with saturated sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium bicarbonate, then with water and then with brine prior to drying over anhydrous sodium sulfate. Removal of volatiles afforded 200 mg of crude solid product, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.[OH2:22].N1[CH:28]=[CH:27]C=CC=1>>[C:27]([O:20][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:21])[C:14](=[CH:13][CH2:12][C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:19]1)(=[O:22])[CH3:28]
Reactant: O
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Reaction time: 16 h

Procedure:
Dehydroepiandrosterone (2.88 g, 10 mmol) is dissolved in a mixture (100 ml) of anhydride acetic and pyridine (1:1 v/v) and left at room temperature for 16 h. The mixture is then poured carefully into iced water and after 16 h, crystals are filtered and dried in vacuo.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][CH2:8][O:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:4][O:3]1.CNN>ClCCl.C(OCC)C>[CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][CH2:8][O:9][NH2:10])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CCON2C(=O)c3ccccc3C2=O)O1
Agent: CNN
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)OCC(CCON)O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.7 %

Procedure:
To a vigorously stirring suspension of 1,2,4-butanetriol (5.8 g, 54.6 mmol) in dichloromethane (20 mL) was added 2,2-dimethoxypropane (6.8 mL, 54.6 mmol) and catalytic p-toluenesulfonic acid. After 5 minutes, the solution became homogenous and was allowed to stir for an additional 30 minutes. The reaction mixture was then concentrated in vacuo to afford (2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethanol (7.72 g, 96.7%). To a stirring solution of (2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethanol (6.95 g, 47.5 mmol), triphenylphosphine (12.5 g, 47.5 mmol) and N-hydroxyphthalimide in freshly distilled tetrahydrofuran (200 mL) at 0° C. was slowly added (over 20 minutes) diethylazodicarboxylate. The dark red solution was allowed to stir for 2 hours at 0° C. and then allowed to warm to room temperature while stirring for 17 hours. The yellow solution was concentrated in vacuo and dissolved in chloroform (100 mL). The solids were filtered and filtrate concentrated. This filtration was repeated twice. The remaining yellow oil was purified on silica gel eluting with hexanes-ethyl acetate (4:1) to afford 2-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-isoindole-1,3-dione (8.1 g, 58.7%). To a stirring solution of 2-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-isoindole-1,3-dione (0.86 g, 2.95 mmol) in dichloromethane (10 mL) at 0° C. was added methylhydrazine (0.16 mL, 2.95 mmol). The resultant solution was allowed to warm to room temperature and stirred for 3 days. The resulting suspension was diluted with diethyl ether (20 mL) and filtered. The filtrate concentrated in vacuo to afford O-(2,2-dimethyl-[1,3]dioxolan-4-ylethyl)-hydroxylamine (0.36 g, 75.3%): 1H NMR (400 MHz; CDCl3) δ 4.18 (quint, 1H, J=5.9), 4.07 (dd, 1H, J=5.9, 7.8), 3.86 (t, 2H, J=6.2), 3.56 (t, 1H, J=7.6), 1.89 (m, 2H), 1.36 (s, 3H), 1.20 (s, 3H); MS(APCI+)=162.
Reaction SMILES: CS(CCC[C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH2:17][C:18]([NH2:20])=[O:19])=[CH:14][CH:13]=[CH:12][CH:11]=2)(=O)=O.[CH3:21][NH:22][CH3:23].CCOC(C)=O.O.[CH2:31]1[CH2:35]OC[CH2:32]1>[Cl-].[Na+].O>[CH3:21][N:22]([CH2:32][CH2:31][CH2:35][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]([CH2:17][C:18]([NH2:20])=[O:19])=[CH:8]1)[CH3:23]
Reactant: CS(=O)(=O)CCCc1[nH]c2ccccc2c1CC(N)=O
Reactant: C1CCOC1
Reactant: CNC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)CCCn1cc(CC(N)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
A suspension of 1-(methanesulfonylpropyl-indole-3-acetamide (1.0 g, 3.20 mmol) in THF (15 mL) was treated with a 40% aqueous solution of dimethylamine (13.5 mL, 0.108 mole) and the resultant reaction solution was capped and stirred at room temperature for 18 hours. The reaction was worked up extractively using EtOAc (50 mL), water (2× 50 mL) and brine (25 ml). The combined aqueous layers were back-extracted three times with EtOAc (3× 25 mL) and the combined organic layer dried (MgSO4) and the solvent removed in vacuo to give 0.77 g (92%) of 1-(Dimethylaminopropyl)-indole-3-acetamide. NMR. MS (FD) m/z=259 (M+, 100%).
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C(OC([N:31]1[C@H:38]2[C@H:34]([CH2:35][N:36]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:37]2)OS1(=O)=O)=O)(C)(C)C.O.[C:49]1([CH3:59])[CH:54]=[CH:53][C:52]([S:55]([OH:58])(=[O:57])=[O:56])=[CH:51][CH:50]=1>CCOC(C)=O>[S:55]([C:52]1[CH:53]=[CH:54][C:49]([CH3:59])=[CH:50][CH:51]=1)([OH:58])(=[O:57])=[O:56].[S:55]([C:52]1[CH:53]=[CH:54][C:49]([CH3:59])=[CH:50][CH:51]=1)([OH:58])(=[O:57])=[O:56].[CH2:39]([N:36]1[CH2:35][C@@H:34]([F:1])[C@H:38]([NH2:31])[CH2:37]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CN(Cc3ccccc3)C[C@@H]2OS1(=O)=O
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H]1CN(Cc2ccccc2)C[C@H]1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A solution of 1M tetrabutylammonium fluoride in THF (1.27 L, 1.27 mol, 2.5 eq) and (3aR,6aS)-5-benzyl-2,2-dioxo-tetrahydro-1-oxa-2λ6-thia-3-5-diaza-pentalene-3-carboxylic acid t-butyl ester (180 g, 0.508 mol, 1.0 eq) were heated at 60° C. (jacket temperature) for 2 hr. Upon reaction completion, the mixture was partially distilled under vacuum to remove the THF. After concentration to a low stir volume, THF was displaced with EtOAc (2×500 mL). After again reducing to a low stir volume, EtOAc (3.6 L) and p-toluenesulfonic acid monohydrate (396 g, 2.10 mol, 4.1 eq) were charged and heated at 80° C. for 2 hr. The mixture was cooled to 10° C. over 1.5 hr and then granulated at 10° C. for 2 hr. The solid product was filtered and washed with EtOAc (2×900 mL) and dried at 50° C. in a vacuum oven for 12 hr. The title compound was isolated as an air stable crystalline solid in 83% yield (231 g, 419 mmol). 1H NMR (400 MHz, D2O) δ ppm 7.69-7.61 (m, 4 H) 7.56-7.42 (m, 5 H) 7.36-7.29 (m, 4 H) 5.65-5.49 (m, 1 H) 4.47 (br. s., 2H) 4.37-4.23 (m, H) 4.15 (ddd, J=12.8, 8.2, 1.4 Hz, 1 H) 3.88 (dd, J=19.1, 1.2 Hz, 1 H), 3.74 (ddd, J=33.2, 14.0, 5.5 Hz, 1 H) 3.44 (dd, J=12.8, 8.2 Hz, 1 H) 2.34 (s, 6 H). m/z (EI+) for C11H15FN2 194.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[CH:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:25]1[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[C:23][C:25]4[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)s1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.9) (89 mg, 0.25 mmol) and 5-bromo-thiophene-2-sulfonic acid amide (61 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (42 mg, 32%). MS (ISP) 517.0 [(M+H)+]; mp 231-232° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].[NH:15]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]2[N:27]=[CH:26][C:25]([NH:28][C:29]([C:31]3[CH:32]=[N:33][N:34]([C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=4)[C:35]=3[CH3:36])=[O:30])=[CH:24][C:23]=2[CH3:47])[CH2:17][CH2:16]1.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C=O>[CH3:8][N:9]([CH3:14])[S:10]([N:15]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]2[N:27]=[CH:26][C:25]([NH:28][C:29]([C:31]3[CH:32]=[N:33][N:34]([C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:45])([F:44])[F:46])=[CH:39][N:38]=4)[C:35]=3[CH3:36])=[O:30])=[CH:24][C:23]=2[CH3:47])[CH2:17][CH2:16]1)(=[O:12])=[O:11]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCCN(S(=O)(=O)N(C)C)CC1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
Triethylamine (0.16 ml) and dimethylsulfamoyl chloride (157 mg) were added at room temperature to a solution of N-[6-(azepan-4-yl)-5-methylpyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (250 mg) described in Example K66(1) in tetrahydrofuran (5.5 ml) and N,N-dimethylformamide (5.5 ml), and stirred at 60° C. for three hours. After completion of the reaction, the reaction solution was cooled to room temperature, saturated aqueous solution of sodium bicarbonate was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (chloroform/methanol) to give the titled compound (133 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[N:8](CC2C=CC(OC)=CC=2)[C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][C:12]([Cl:17])=[CH:11][N:10]=2)=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[NH:8][C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][C:12]([Cl:17])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cc(Cl)cnc2n(Cc2ccc(OC)cc2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(Cl)c2cc(Cl)cnc2[nH]c1=O
Yield: 99.3 %

Procedure:
A solution of 4,6-dichloro-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (77) (6.0 g, 14.73 mmol) in neat TFA was refluxed for 3 h. The solution was cooled and the excess TFA was distilled under vacuum. The residue was suspended in saturated NaHCO3 solution, sonicated briefly and filtered. The solids were washed by water, and dried at room temperature to yield 4.2 g (99%) of 4,6-dichloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (79) as white solids. MP: 228° C.; 1H-NM (DMSO-d6): δ 1.29 (t, J=7.2 Hz, 3H), 4.37 (q, J=7.2 Hz, 2H), 8.38 (d, J=2.4 Hz, 1H), 8.75 (d, J=2.4 Hz, 1H), 13.10 (s, 1H); EIMS: 287 (M).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1>>[CH3:1][C:2]1[C:14]2[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccc2c1[nH]c1cc(O)ccc12
Reactant: Fc1cccc(CBr)c1
Product: Cc1nccc2c3ccc(OCc4cccc(F)c4)cc3n(Cc3cccc(F)c3)c12
Yield: 85 %

Procedure:
The title compound was synthesized from 1-methyl-7-hydroxy-β-carboline (0.5 g, 1.587 mmol) in presence of 1-bromomethyl-3-fluorobenzene (0.6 g, 3.173 mmol) as described here above.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([F:8])[CH2:5][N:4]1[C:9]([NH:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]([NH2:23])=[O:22])[CH:13]=1)=[O:10].[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.O>C(Cl)Cl>[F:8][C@H:6]1[CH2:5][N:4]([C:9]([NH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([NH2:23])=[O:22])[CH:13]=2)=[O:10])[C@H:3]([CH2:2][NH:1][C:31](=[O:32])[CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7]1
Reactant: NC[C@@H]1C[C@@H](F)CN1C(=O)Nc1cn(C(N)=O)c2ccccc12
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: NC(=O)n1cc(NC(=O)N2C[C@H](F)C[C@H]2CNC(=O)Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-[((2S,4R)-2-aminomethyl-4-fluoro-pyrrolidine-1-carbonyl)-amino]-indole-1-carboxylic acid amide (50 mg, 0.16 mmol, prepared as described in Scheme B11) and phenylacetyl chloride (23 μL, 0.17 mmol) in CH2Cl2 (0.5 mL), was added triethylamine (24 μL, 0.17 mmol) and the resulting suspension was stirred at RT under N2 overnight. The mixture was poured into water and extracted with CH2Cl2 (×2). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19×50 mm, eluent: 20% to 100% CH3CN in H2O in 15 min, CH3CN and H2O containing 0.1% HCOOH, flow: 20 mL/min) to give after lyophilization of the purified fractions the desired material. Rf, TLC (EtOAc)=0.1; MS (LC-MS): 438.1 [M+H]+, 897.2 [2M+Na]+, 393.1 [M−CONH2]−; tR (HPLC conditions f): 1.70 min.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[C@@H:20]2[C@@H:16]([O:17][C:18](=[O:21])[CH2:19]2)[CH2:15][C@H:14]1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[O:21]=[C:18]1[O:17][C@H:16]2[CH2:15][C@@H:14]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:13]([CH:12]=[O:11])[C@H:20]2[CH2:19]1
Reactant: O=C1C[C@@H]2[C@@H](CO)[C@H](OCc3ccccc3)C[C@@H]2O1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OCc1ccccc1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of oxalyl chloride (3.3 mL, 38.1 mmoL) in dichloromethane (35 mL) at −78° C., was added DMSO (5.4 mL, 76.3 mmoL) and the mixture was stirred for 15 min. A solution of (3aR,4S,5R,6aS)-hexahydro-4-(hydroxymethyl)-5-(phenylmethoxy)-2H-cycloenta[b]furan-2-one (5, R1 is phenyl, and R2 and R3 are H, 5 g, 19 mmoL) in dichloromethane (35 mL) was then slowly added at −78° C. and the reaction mixture stirred for 0.5 h. Triethylamine (24 mL, 170 mmoL) was added at −78° C. and the reaction mixture stirred for 0.5 h. After completion of the reaction, the reaction mixture was washed with water (20 mL), and the organic layer was concentrated to dryness under vacuum to yield (3aR,4R,5R,6aS)-hexahydro-2-oxo-5-(phenylmethoxy)-2H-cyclopenta[b]furan-4-carboxaldehyde (6, R1 is phenyl, and R2 and R3 are H) in 80% yield.
Reaction SMILES: [F:1][C:2](F)([CH2:12][CH:13](I)[Si](C)(C)C)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])=O.[NH3:20]>O1CCCC1>[F:1][C:2]1[CH:12]=[CH:13][NH:20][C:3]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11]
Reactant: N
Reactant: Cc1ccccc1C(=O)C(F)(F)CC(I)[Si](C)(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1-c1[nH]ccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 78 %

Procedure:
To a solution (20 mL) of 2,2-difluoro-4-iodo-1-(2-methylphenyl)-4-trimethylsilylbutan-1-one (2.5 g) in tetrahydrofuran was added 28% aqueous ammonia solution (6 mL), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile (15 mL) and water (8 mL), and potassium fluoride (0.75 g) was added. The reaction mixture was stirred at 60° C. for 3 hr, and concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=20:1) to give the title compound as a pale-yellow oil (yield 0.87 g, 78%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([OH:14])[C:3]=1[C:15](=[O:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=O)=[CH:28][CH:27]=1)#[N:25].O>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]2[C:3]=1[C:15](=[O:17])[CH:16]=[C:30]([C:29]1[CH:33]=[CH:34][C:26]([C:24]#[N:25])=[CH:27][CH:28]=1)[O:14]2
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)c1c(O)cc(N2CCOCC2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1ccc(-c2cc(=O)c3c(O)cc(N4CCOCC4)cc3o2)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 1.5 %

Procedure:
To a suspension of 1-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)-ethanone (45 mg, 0.190 mmol) and K2CO3 (130 mg, 0.948 mmol) in acetone (3 mL) was added 4-cyanobenzoyl chloride 33 mg, 0.20 mmol). The reaction vessel was sealed and heated to 60° C. for 14 h. After cooling to room temperature, water (about 2 mL) was added, and the mixture was allowed to stir for about 10 min. The contents were transferred to a separatory funnel and extracted with EtOAc (3×15 mL). The organic layer was dried (MgSO4) and concentrated. The concentrate was suspended in 50% EtOAc/hexanes and filtered to yield 1 mg (1%) of 4-(5-hydroxy-7-morpholin-4-yl-4-oxo-4H-chromen-2-yl)-benzonitrile.
Reaction SMILES: P(Cl)(Cl)Cl.[C:5]1([CH2:11][C:12]([NH:14][CH:15]2[C:47](=[O:48])[N:17]3[C:18]([C:31]([O:33][CH:34]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])=[C:19]([CH:23]=[CH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:20][S:21](=O)[C@H:16]23)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>CN(C)C=O>[C:5]1([CH2:11][C:12]([NH:14][CH:15]2[C:47](=[O:48])[N:17]3[C:18]([C:31]([O:33][CH:34]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[C:19]([CH:23]=[CH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:20][S:21][C@H:16]23)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3ccccn3)CS(=O)[C@H]12
Solvent: O
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3ccccn3)CS[C@H]12
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
Phosphorus trichloride (15.2 g) was added to the solution of benzhydryl 7-phenylacetamido-3-[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylate-1-oxide (trans isomer) (22.2 g) in dimethylformamide (220 ml) at -30° C. and the solution was stirred at -30° to -25° C. for 10 minutes. The reaction mixture was poured into cold water (1 l) and resulting precipitates were collected by filtration. The filtrate was dissolved in ethyl acetate (300 ml) and the ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated to give benzhydryl 7-phenylacetamido-3-[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylate (trans isomer) (15.9 g).
Reaction SMILES: [O:1]([C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[O:1]([C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Yield: 92.1 %

Procedure:
A slurry of 5.00 g (15.6 mmol) of methyl 4-(4-phenoxyphenoxy)benzoate from Example 30, 0.28 g (50.0 mmol) of potassium hydroxide, 50 ml of methanol and 50 ml of deionized water is refluxed for 48 hours. Methanol is added until the mixture is homogenous. Aqueous hydrochloric acid is added until the solution is strongly acidified, and the slurry is cooled. The resulting precipitate is filtered, washed with 300 ml of deionized water and dried in air. It is recrystallized from a minimum volume of hot 2-1 by volume methanol and water solution to yield 4.40 g (92 percent yield) of 4-(4-phenoxyphenoxy)benzoic acid having a melting point of 185° C. as measured by DSC.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:30])[N:6]2[C@H:22]1[CH2:27][CH2:26][C@H:25]([O:28]C)[CH2:24][CH2:23]1.ClCl.[F:33][C:34]1([F:38])[CH2:37][NH:36][CH2:35]1>ClC1C2C(=NC(=O)N=1)N=CN=2>[F:33][C:34]1([F:38])[CH2:37][N:36]([C:2]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[N:8]=[C:7]3[C:3]=2[NH:4][C:5](=[O:30])[N:6]3[C@H:22]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]2)[CH2:35]1
Reactant: CO[C@H]1CC[C@H](n2c(=O)[nH]c3c(Cl)nc(-n4cnc5ccc(C#N)cc54)nc32)CC1
Reactant: FC1(F)CNC1
Agent: ClCl
Agent: O=C1N=C(Cl)C2=NC=NC2=N1
Product: N#Cc1ccc2ncn(-c3nc(N4CC(F)(F)C4)c4[nH]c(=O)n([C@H]5CC[C@H](O)CC5)c4n3)c2c1

Procedure:
Synthesized from 3-(6-chloro-9-(trans-4-methoxycyclohexyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)-3H-benzo[d]imidazole-5-carbonitrile by demethylation, followed by displacement of chlorine in the 6-chloropurinone with 3,3-difluoroazetidine. 1HNMR (300 MHz, CDCl3+CD3OD) δ, ppm: 9.12 (s, 1H), 8.92 (s, 1H), 7.90 (d, 1H), 7.64 (dd, 1H), 4.71 (t, 4H), 4.46-4.32 (m, 1H), 3.98-3.83 (m, 1H), 2.64-2.46 (m, 2H), 2.24-2.15 (m, 2H), 1.97-1.87 (m, 2H), 1.62-1.46 (m, 2H); MS (EI) m/z 467.0 (MH)+.