Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[CH:22][C:21]([CH2:24][CH2:25][CH3:26])=[CH:20][N:19]=1.BrC1C=CC2N=C(OC3CCN(C4N=CC(CCC)=CN=4)CC3)SC=2C=1>>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:18]4[N:23]=[CH:22][C:21]([CH2:24][CH2:25][CH3:26])=[CH:20][N:19]=4)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: CCCc1cnc(Cl)nc1
Reactant: Brc1ccc2nc(N3CCNCC3)sc2c1
Agent: CCCc1cnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)nc1
Product: CCCc1cnc(N2CCN(c3nc4ccc(Br)cc4s3)CC2)nc1

Procedure:
Compound 13C was prepared from Compound 13B and 2-chloro-5-propylpyrimidine in a similar manner to the procedure described for Compound 1C in Example 1. 1H NMR (500 MHz, chloroform-d) δ ppm 8.20 (2H, s), 7.73 (1H, dd, J=1.7, 0.6 Hz), 7.40-7.43 (2H, m), 3.96-4.00 (4H, m), 3.70-3.74 (4H, m), 2.44 (2H, t, J=7.4 Hz), 1.57-1.64 (2H, m), 0.95 (3H, t, J=7.3 Hz). LC/MS (m/z)=419 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][N+:11]([O-])=[C:10]([CH3:15])[CH:9]=1.C(OC(=O)C)(=[O:18])C>>[OH:18][CH2:15][C:10]1[CH:9]=[C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:13]=[CH:12][N:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: COCCCCOc1cc[n+]([O-])c(C)c1
Product: COCCCCOc1ccnc(CO)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5.06 g (0.024 mol) of 4-(4-methoxybutoxy)-2-methylpyridine 1-oxide was dissolved in 80 ml of acetic anhydride to obtain a solution. This solution was stirred at 100° C. for one hour, cooled and distilled to remove the solvent. 150 ml of 1N hydrochloric acid was added to the residue. The obtained mixture was stirred at 100° C. for one hour, cooled, neutralized with sodium hydrogencarbonate and extracted with 200 ml of chloroform twice. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent and the residue was dried in a vacuum to obtain 5.66 g of the title compound as a crude oil.
Reaction SMILES: CO[C@H]1CC[C@H](C[N:10]2C(=O)CNC3N=CC(C4C(C)=CC(C(N)=O)=NC=4)=[N:20][C:11]2=3)CC1.[CH3:31][O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([CH2:39][N:40]2[C:45](=[O:46])[CH2:44][NH:43][C:42]3[N:47]=[CH:48][C:49]([C:51]4[C:52]([CH3:59])=[CH:53][C:54]([C:57]#[N:58])=[N:55][CH:56]=4)=[N:50][C:41]2=3)[CH2:35][CH2:34]1.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:31][O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([CH2:39][N:40]2[C:41]3=[N:50][C:49]([C:51]4[CH:56]=[N:55][C:54]([C:57]5[N:20]=[CH:11][NH:10][N:58]=5)=[CH:53][C:52]=4[CH3:59])=[CH:48][N:47]=[C:42]3[NH:43][CH2:44][C:45]2=[O:46])[CH2:35][CH2:34]1
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C#N)cc4C)nc32)CC1
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C(N)=O)cc4C)nc32)CC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(-c5nc[nH]n5)cc4C)nc32)CC1
Temperature: 65 °C

Procedure:
5-(8-(((trans)-4-Methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide. 5-(8-(((trans)-4-Methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin -2-yl)-4-methylpicolinonitrile (0.607 g, 1.55 mmol), trifluoroacetic acid (2.0 mL, 26.0 mmol) and sulfuric acid (0.5 mL, 9.38 mmol) were combined and heated at 65° C. for 1 h. Reaction pH was adjusted to 10 with sodium carbonate and the resulting solution was extracted with ethyl acetate (3×15 mL). Organic layers were collected, dried over magnesium sulfate, concentrated and purified using reverse-phase preparatory HPLC (10-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Clean fractions were combined and condensed under reduced pressure and dried under high vacuum to afford the title compound as a yellow solid (0.425 g, 1.04 mmol, 67% yield). MS (ESI) m/z 411.5 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3Cl)[CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[NH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([NH2:36])=[CH:31][CH:30]=2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3[NH:36][C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([CH3:26])=[CH:35]4)[CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc3nccc(Cl)c3s2)CC1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 4-[7-chloro-thieno[3,2-b]pyridine-2-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester and 2-methyl-1H-indol-5-ylamine by a method analogous to Example 1C. MS: 492 (MH+); HPLC Rf: 5.42 min.; HPLC purity 95%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[N:18]=[CH:17]3)[CH2:10][C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(CC)C.Br[CH2:40][CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([Si:23]([CH:27]([CH3:29])[CH3:28])([CH:30]([CH3:32])[CH3:31])[CH:24]([CH3:25])[CH3:26])[N:18]=[CH:17]3)[CH:10]([CH2:40][CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(N3CCN(Cc4ccccc4)C(=O)C3)ccc21
Reactant: BrCC1CCOCC1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(N3CCN(Cc4ccccc4)C(=O)C3CC3CCOCC3)ccc21
Temperature: 25 °C
Yield: 57.7 %

Procedure:
To a solution of 1-benzyl-4-(1-triisopropylsilanyl-1H-indazol-5-yl)-piperazin-2-one (0.78 g, 1.7 mmol) in 8.5 mL THF at −78° C. was added sec-butyllitium (1.3 mL, 1.9 mmol) drop-wise over 5 minutes. After 30 minutes 4-bromomethyl-tetrahydropyran (0.36 g, 2.0 mmol) was added in one portion and mixture was warmed to room temperature. After 18 hours H2O was added and the mixture was extracted with ethyl acetate. The combined organic layerss were washed with H2O, brine, dried over NaSO4, filtered and concentrated in vacuo. Purification via flash chromatography afforded 1-benzyl-3-(tetrahydro-pyran-4-ylmethyl)-4-(1-triisopropylsilanyl-1H-indazol-5-yl)-piperazin-2-one (0.55g, 90%) as a white foam.
Reaction SMILES: [C:1]1([C:7]2([C:13]([OH:15])=[O:14])[CH2:9][CH:8]2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[N+:16]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2([C:13]([OH:15])=[O:14])[CH2:9][CH:8]2[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)C1CC1(C(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Product: O=C(O)C1CC1(C(=O)O)c1ccc([N+](=O)[O-])cc1

Procedure:
To a stirred slurry of 20.6 g of 1-phenylcyclopropane-1,2-dicarboxylic acid in 25 ml of concentrated sulfuric acid at 0° C. is added 15 ml of concentrated nitric acid over 30 minutes. The resultant solution is then stirred at ambient tmperature for 30 minutes and then poured onto ice. The crystalline product is recrystallized from hexane-ethyl acetate to give 1-(p-nitrophenyl)-cyclopropane-1,2-dicarboxylic acid as colorless crystals, m.p. 138°-144° C.
Reaction SMILES: [I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:22]([Li])[CH2:23][CH2:24][CH3:25].[CH:27]([C:29]1[CH:30]=[C:31](C=CC=1)[C:32]([O:34][CH3:35])=[O:33])=O>O1CCCC1.CCCCCC>[CH:24]([C:23]1[CH:22]=[C:31]([CH:30]=[CH:29][CH:27]=1)[C:32]([O:34][CH3:35])=[O:33])=[CH2:25]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1cccc(C(=O)OC)c1
Temperature: -50 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 590 mg of methyl triphenylphosphonium iodide in 50 ml of dry tetrahydrofuran cooled to -50° C. was added dropwise 5.3 ml of 2.5M n-butyl lithium in hexane. The resulting mixture was allowed to warm to 0° C. over a period of one hour. The mixture was then cooled to -70° C. and 2.0 g of methyl 3-formylbenzoate in 20 ml of dry tetrahydrofuran was added dropwise over a period of 20 minutes. The reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was concentrated in vacuo and the residue treated with water (200 ml) and extracted with diethyl ether (2×200 ml). The extracts were combined, washed with water and a brine solution and dried over magnesium sulfate. Removal of the solvent gave 2 g of an oil which was flash chromatographed on silica gel (30% ethyl acetate--hexane; v:v) , 2.0 g. Distillation in vacuo gave 1.36 g.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([N:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]([C:26](=[O:28])[CH3:27])[C@@H:21]([CH3:29])[CH2:20][N:19]4[C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32](C4CCCCO4)[N:31]=3)[CH:13]=[N:12]2)[CH2:10][CH2:9]1>ClCCl>[CH:8]1([N:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]([C:26](=[O:28])[CH3:27])[C@@H:21]([CH3:29])[CH2:20][N:19]4[C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[NH:32][N:31]=3)[CH:13]=[N:12]2)[CH2:9][CH2:10]1
Reactant: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2N(c2nn(C3CCCCO3)c3ccccc23)C[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2N(c2n[nH]c3ccccc23)C[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.5 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a solution of 1-((2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.048 g, 0.097 mmol) in dichloromethane (2.0 mL) and the mixture stirred at rt for 4 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to afford (S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(1H-indazol-3-yl)-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)ethanone (0.039 g, 98%) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.76-1.04 (m, 4 H), 1.09-1.33 (m, 3 H), 2.23 (s, 3 H), 3.54-3.77 (m, 2 H), 3.78-3.99 (m, 1 H), 4.36 (br s, 1 H), 6.67-6.85 (m, 1 H), 6.87-7.14 (m, 2 H), 7.26-7.46 (m, 4 H), 7.53 (d, J=8.50 Hz, 1 H), 7.87 (s, 1 H), 12.70-12.87 (m, 1 H). MS (ESI, pos. ion) m/z 413 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15]C)=[C:10]([Cl:17])[CH:9]=2)=[O:5])[CH3:2].B(Br)(Br)Br.C(OCC)(=O)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[C:10]([Cl:17])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OC)c(Cl)cc2[nH]1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(O)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (−78° C.) solution of 6-chloro-5-methoxy-1H-indole-2-carboxylic acid ethyl ester (example 39, step 1, 930 mg, 1.0 eq.) in dichloromethane (20 mL), was slowly added a solution of boron tribromide 1M in dichloromethane (7.33 mL, 2.0 eq.). The mixture was stirred at room temperature for 1 h, partitionned between ethyl acetate and ice water. The aqueous layer was extracted with ethyl acetate and the combined organic fractions were washed with 10% sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, evaporated to dryness and purified on silica gel, eluting with a 4:1 to 3:1 gradient of cyclohexane/ethyl acetate, to yield 655 mg (74%) from the desired product as light brown solid. MS (m/e): 239.2 (M+, 35%).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:11][C:12]3[C:17]([N:18]=2)=[CH:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][CH:13]=3)[CH2:4][CH2:3]1.[OH-].[Na+].Cl>CO.O>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:11][C:12]3[C:17]([N:18]=2)=[CH:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=3)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCN(C)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-methyl-1,4-diazepan-1-yl)-2-phenylquinoxaline-6-carboxylate (126.6 mg, 0.34 mmol, 1.00 equiv) in methanol (12 mL), a solution of sodium hydroxide (72.6 mg, 1.81 mmol, 5.00 equiv) in water (2.5 mL). The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The resulting mixture was sent for prop-HPLC. This resulted in 46 mg (38%) of 3-(4-methyl-1,4-diazepan-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][OH:7])(=[O:3])[CH3:2].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].N1C=CN=C1.O>CN(C=O)C>[C:11]([Si:8]([CH3:10])([CH3:9])[O:7][CH2:6][CH2:5][CH2:4][C:1](=[O:3])[CH3:2])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)CCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 66 h
Yield: 58.6 %

Procedure:
A solution of 3-acetyl-1-propanol (3.000 g, 29.37 mmol), tert-butyidimethylsilyl chloride (4.522 g, 30.00 mmol), and imidazole (5.004 g, 73.5 mmol) in DMF (40 mL) was heated at 40° C. for 5 h and was stirred at room temperature for 66 h. Water (60 mL) was added and the product was extracted into EtOAc (4×50 mL). The combined organic extracts were washed with water (2×50 mL), dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (hexanes:EtOAc 9:1) provided the title compound (3.722 g). 1H NMR (400 MHz, CDCl3) δ 3.59 (t, 2H), 2.49 (t, 2H), 2.13 (s, 3H), 1.76 (m, 2H), 0.86 (s, 9H), 0.02 (s, 6H); MS 217 (M+1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:27][CH:28]([CH3:32])[CH2:29][CH:30]=[O:31]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:30]([OH:31])[CH2:29][CH:28]([CH3:32])[CH3:27])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)CC=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC(O)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (5.0 g, 19.3 mmol) in dry tetrahydrofuran (125 mL) at −78° C. was added lithium diisopropylamide (14.5 mL, 29 mmol) dropwise. The mixture was stirred at −78° C. for 10 min and then treated with 3-methylbutanal (3.9 g, 45 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1.5 h. At this time, the reaction was quenched with a saturated aqueous sodium chloride solution. The resulting mixture was then extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (10-15% ethyl acetate/petroleum ether) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-butan-1-ol (3.4 g, 51.8%) as a white solid: 1H NMR (300 MHz, d6-DMSO): δ 8.29 (d, 1H, J=3.3 Hz), 8.10 (d, 2H, J=7.8 Hz), 7.96 (d, 1H, J=7.5 Hz), 7.72-7.59 (m, 3H), 7.28-7.24 (m, 1H), 6.81 (s, 1H), 5.55-5.46 (m, 2H), 2.05-1.90 (m, 1H), 1.81-1.73 (m, 1H), 1.04 (d, 3H, J=6.3 Hz), 0.97 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:18][CH2:19][O:20]CC1C=CC(OC)=CC=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C([O-])(O)=O.[Na+]>ClCCl.O>[Si:1]([O:8][C@@H:9]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:18][CH2:19][OH:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(COCC[C@H](CCc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H](CCO)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
(S)-3-(t-butyldimethylsilyloxy)-5-(4-methoxy-benzyloxy)-1-phenyl pentane (15 g, 36.2 mmol) was dissolved in a solvent mixture of dichloromethane-water (20:1) (252 ml) DDQ (8.2 g, 36.2 mmol) was added thereto and the mixture was stirred for 30 minutes at room temperature. After completion of the reaction, saturated aqueous NaHCO3 solution (100 ml) was added to the reaction solution to stop the reaction. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to give (S)-3-(t-butyldimethylsilyloxy)-5-phenyl-pentan-1-ol (10.6 g, Yield 99%) of a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[N:42][O:43][CH2:44][C:45]([O:47]C(C)(C)C)=[O:46])[C:17]([NH:19][CH:20]2[C:40](=[O:41])[N:22]3[C:23]([C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=4)=[O:28])=[CH:24][CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1)=[O:9]>C1(OC)C=CC=CC=1>[CH:8]([NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[N:42][O:43][CH2:44][C:45]([OH:47])=[O:46])[C:17]([NH:19][CH:20]2[C:40](=[O:41])[N:22]3[C:23]([C:27]([O:29][CH2:30][C:31]4[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=4)=[O:28])=[CH:24][CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=CNc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 89.8 %

Procedure:
Trifluoroacetic acid (40 ml.) was added to a suspension of 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-t-butoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 10 g.) in anisole (10 ml.) at 5° C., and stirred at room temperature for 70 minutes. After evaporating the solvent from the resultant mixture in vacuo, the residue was triturated with diethyl ether. The precipitates were collected by filtration and dried to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 8.2 g.).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:6])[CH3:5].[O-]CC.[Na+].[C:11]([O:18][CH2:19][CH3:20])(=[O:17])[C:12]([O:14]CC)=O>CCO>[CH3:1][O:2][CH2:3][C:4](=[O:6])[CH2:5][C:12](=[O:14])[C:11]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: COCC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)COC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
Methoxyacetone (5.22 mL, 56.8 mmol) was added dropwise to a cold (0° C.), stirred solution of sodium ethoxide (21% in EtOH, 20.2 g, 62.4 mmol) and EtOH (50 mL), under an argon atmosphere. The reaction mixture was stirred for 30 min at 0° C. Then, diethyl oxalate (7.71 mL, 56.8 mmol) was added. The reaction mixture was allowed to warm to rt, stirred for 16 h, quenched by addition of 1N HCl (75 mL), and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude material was purified by silica gel column chromatography (hexane/EtOAc 5-10%) to afford the title compound (3.21 g) as a yellow oil. tR: 0.70 min (LC-MS 2); ESI-MS: 189.1 [M+H]+ (LC-MS 2); Rf=0.25 (hexane/EtOAc 1:1, CPS staining).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([NH2:20])=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[C:21]1([CH3:36])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1C1C=CC=CC=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([NH2:20])=[C:8]([S:10]([C:13]2[CH:14]=[C:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:36])[CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: Cc1ccccc1-c1ccccc1B(O)O
Reactant: COC(=O)c1cc(S(=O)(=O)c2cccc(Br)c2)c(N)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cc(S(=O)(=O)c2cccc(-c3ccccc3C)c2)c(N)s1

Procedure:
5-Amino-4-(2′-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic acid methyl ester was prepared following the procedure as in Example 1: step c using 5-amino-4-(3-bromo-benzenesulfonyl)-thiophene-2-carboxylic acid methyl ester (598.9 mg, 1.6 mmol) (Example 20: steps a–c), o-tolyl-phenyl boronic acid (435.6 mg, 3.2 mmol), Pd(PPh3)4 (366.6 mg, 0.32 mmol), aqueous Na2CO3 (2M, 6.4 mL, 12.8 mmol), ethanol (6.4 mL) and toluene (12.8 mL). Purification by flash column chromatography (Biotage Flash™ System—40 M SiO2 column) (25% EtOAc in hexanes) of the residue yielded the adduct (137 mg, 23%) as a light brown solid. ESI-MS (m/z): Calcd. for C19H17NO4S2: 387.02; found: 388.3. 5-Amino-4-(2′-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic acid methyl ester (61 mg, 16 mmol) was then converted to the amidine and purified as described in Example 20: step f to isolate the title compound (6 mg, 10%) as a light brown solid. 1H-NMR (CD3OD): δ: 7.96–7.99 (m, 1H), 7.95 (s, 1H), 7.93–7.94 (m, 1H), 7.63–7.69(m, 3H), 7.18–7.32 (m, 3H), 2.22 (s, 3H). ESI-MS (m/z): Calcd. for C18H17N3O2S2: 372.0 (M+H); found: 372.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:13]=[C:14]([NH:18][C:19]3[C:24]([N+:25]([O-])=O)=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:15]=[CH:16][CH:17]=2)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O1CCOCC1.[Fe]>[NH2:25][C:24]1[C:19]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:10](=[O:11])[NH:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:13]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Nc1cc(Cl)cc(Cl)c1)c1cccc(Nc2ncccc2[N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Nc1cccnc1Nc1cccc(C(=O)Nc2cc(Cl)cc(Cl)c2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
A mixture of 2-[3-(3,5-dichlorophenylcarbamoyl)phenylamino]-3-nitropyridine (565 mg) and iron powder (0.4 g) in acetic acid (5 ml) and 1,4-dioxane (5 ml) was stirred at 80° C. for 3 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 3-amino-2-[3-(3,5-dichlorophenylcarbamoyl)phenylamino]pyridine (284 mg).