Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:15])[CH2:7][N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])(C)(C)C.[ClH:16]>O>[ClH:16].[CH:9]([N:8]([CH2:7][C:6]([OH:15])=[O:5])[CH:12]([CH3:13])[CH3:14])([CH3:10])[CH3:11]
Reactant: CC(C)N(CC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: O
Product: CC(C)N(CC(=O)O)C(C)C

Procedure:
5.4 g (25 mMol) diisopropylamino-acetic acid tert-butylester 2 was stirred with 6.25 ml (75 mMol) 12 M HCl in 25 ml water for 2.5 h at 60° C. After distillation in vacuo of water and excess of HCl, the residue was dried with toluene azeotropically.
Reaction SMILES: C(OC(=O)[N:7]([C:20]1[N:21]([C:30]2[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([OH:39])=[CH:32][C:31]=2[OH:40])[N:22]=[N:23][C:24]=1[C:25](=[O:29])[NH:26][CH2:27][CH3:28])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:27]([NH:26][C:25]([C:24]1[N:23]=[N:22][N:21]([C:30]2[CH:35]=[C:34]([CH:36]([CH3:37])[CH3:38])[C:33]([OH:39])=[CH:32][C:31]=2[OH:40])[C:20]=1[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][CH:9]=1)=[O:29])[CH3:28]
Reactant: CCNC(=O)c1nnn(-c2cc(C(C)C)c(O)cc2O)c1N(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)c1nnn(-c2cc(C(C)C)c(O)cc2O)c1Nc1ccc(N2CCOCC2)cc1
Yield: 45 %

Procedure:
A solution of the intermediate from Step D in DCM/TFA (1/1, 2 ml) was stirred for 12 hours at RT. The reaction mixture was concentrated under reduced pressure and the crude reaction mixture was purified by column chromatography (DCM/MeOH: 95/5). The title compound was obtained as a slightly brown solid.
Reaction SMILES: C([Mg]Cl)(C)C.[Li+].[Cl-].[CH2:8]([O:15][C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20](Br)[CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C[O:26][B:27](OC)[O:28]C>C1COCC1>[CH2:8]([O:15][C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([B:27]([OH:28])[OH:26])[CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cn1cc(Br)cc(OCc2ccccc2)c1=O
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cc(B(O)O)cc(OCc2ccccc2)c1=O
Temperature: -10 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a solution of isopropylmagnesium chloride (2 M in THF, 2.04 mL) was added LiCl (173 mg, 4.08 mmol) and the resulting solution was stirred for 1 h. THF (3 mL) was added to this solution, cooled to −10° C. Solid 3-(benzyloxy)-5-bromo-1-methylpyridin-2(1H)-one (400 mg, 1.36 mmol) was added and stirred for 1 h. Trimethylborate (0.456 mL, 4.08 mmol) was added to the reaction mixture, stirred at −10° C. for 1 h and then quenched with cone HCl (0.6 mL). The cooling bath was removed, stirred at room temperature overnight and concentrated. Purification by preparative HPLC (5-95% CH3CN/H2O over 20 min, 0.05% added TFA) afforded 276 mg [5-(benzyloxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]boronic acid (78%) as a white solid. LC/MS (M+H)+260.2.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][CH:12]=[CH2:13])[N:6]1C(OC(C)(C)C)=O)=[O:4].S(Cl)(Cl)=O>CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][CH:12]=[CH2:13])[NH:6]1)=[O:4]
Reactant: C=CCC1CCCC(C(=O)OC)N1C(=O)OC(C)(C)C
Solvent: O=S(Cl)Cl
Solvent: CO
Product: C=CCC1CCCC(C(=O)OC)N1
Reaction time: 8 h

Procedure:
The crude 6-allyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester obtained from the previous step is dissolved in MeOH (500 mL) and treated with thionyl chloride (20 mL). The solution is stirred overnight and the solvent removed in vacuo. The crude residue is dissolved in EtOAc, washed with saturated NaHCO3, dried (MgSO4), and concentrated to yield 2.1 g of the desired product. The product is used in the next step without purification. 1H NMR (CDCl3) δ 5.82 (m, 1H), 5.22–5.10 (m, 2H), 3.75 (s, 3H), 3.37 (dd, J=11.1, 2.8 Hz, 1H), 2.60 (m, 1H), 2.21 (m, 2H), 2.10–1.10 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:17])([F:16])[CH2:12][CH2:13][CH2:14]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[F:10][C:11]([F:17])([F:16])[CH2:12][CH2:13][CH2:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCCC(F)(F)F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=Cc1ccc(OCCCC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (20 g, 164 mmol) and 4,4,4-trifluorobutan-1-ol (25 g, 195 mmol) in anhydrous CH2Cl2 (500 mL) at 0° C. under Ar was added a solution of PPh3 (51.5 g, 196 mmol) in CH2Cl2 (200 mL) over 15 min, and then DIAD (36.4 g, 180 mmol) in anhydrous CH2Cl2 (150 mL) was added dropwise. The mixture was stirred at 0° C. for 0.5 h. The reaction was warmed to rt and stirred for another 3 h. The solvent was removed in vacuo and the residue was triturated with CH2Cl2 three times to remove insoluble solids. The combined CH2Cl2 washings were concentrated and the residue was purified by silica gel chromatography (330 g silica gel, eluted with EtOAc in hexanes) to provide Intermediate 2A (27 g, 71%) as a light brown oil. LCMS Anal. Calc'd for C11H11F3O2 232.20, found [M+H] 233.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:29]/[O:30][C:31]([CH3:40])([CH3:39])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][NH:24][CH2:25][C@H:26]([OH:28])[CH3:27])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:46](N2C=NC=C2)=[O:47])C=1>C(Cl)(Cl)Cl.CCOC(C)=O.O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:29]/[O:30][C:31]([CH3:39])([CH3:40])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[CH2:25][C@@H:26]([CH3:27])[O:28][C:46]2=[O:47])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](O)CNC[C@H]1NC(=O)[C@H]1NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42 %

Procedure:
To a solution of tert-butyl 2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((((R)-2-hydroxypropyl)amino)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (185 mg, 0.316 mmol) in chloroform (3.16 mL) was added CDI (257 mg, 1.58 mmol). After stirring at rt for 20 min the solution was diluted with EtOAc/water and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM, 0-100%) to afford the title compound (81 mg, 42%). LCMS: Rt=0.92 min, m/z=611.2 (M+1) Method 2m_acidic.
Reaction SMILES: [CH2:1]1[C:22]2[CH:5]([CH2:6][C:7]3[C:20]([CH:21]=2)=[CH:19][C:18]2[C:9](=[CH:10][C:11]4[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:8]=3)[CH2:4][CH2:3][CH2:2]1.[C:23]1(Cl)C(=O)C(Cl)=C(Cl)C(=O)[C:24]=1Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:18]3[C:9](=[CH:10]2)[CH:8]2[C:7]4[C:20]([CH:19]3[CH:23]=[CH:24]2)=[CH:21][C:22]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=4)=[CH:15][CH:14]=1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: C1=C2CCCCC2Cc2cc3cc4ccccc4cc3cc21
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C1=CC2c3cc4ccccc4cc3C1c1cc3ccccc3cc12
Temperature: 50 °C
Yield: 85.8 %

Procedure:
A stirred mixture of the hexahydropentacene (221.78 g, 0.720 mol), chloranil (362.6 g, 1.475 mol) and 4 L toluene is kept at reflux for 2½h. The mixture is cooled to about 50° C. and 350 mL 33% sodium hydroxide solution is gradually added. The organic layer is separarted, while the aquous layer is washed with toluene. The combined toluene layers are filtered over aluminium oxide and are rotary evaporated. The residue is stirred with a mixture of 500 mL toluene and heptane. Filtration and washing gives 188.0 g of the product (0.618 mol, 86%). 1H-NMR (CDCl3): δ 5.35 (dd, 2H), 7.05 (dd, 2H), 7.4 (m, 4H), 7.75 (m, 8H).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[CH3:15][CH:16]([NH2:22])[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]>>[Cl:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2]([NH:22][CH:16]([CH3:15])[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[N:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:11]=1
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Cl)cc21
Reactant: CC(C)CCC(C)N
Product: CC(C)CCC(C)NC1=NS(=O)(=O)c2cc(Cl)ccc2N1

Procedure:
Starting from 3,7-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (300 mg; 1.19 mmol) and 1,4-dimethylpentylamine (1.0 g; 8.68 mmol) with the use of same procedure as in example 21 210 mg (53.5%) of the title compound was prepared; m.p. >220° C.; 1H-NMR (DMSO-d6) ppm; 10.4 (s, 1H, NH), 7.7 (d, 1H, H-8), 7.6 (dd, 1H, H-5), 7.25 (d, 1H, H-7), 7.1 (br, 1H, NH), 3.88 (q, 1H, CH2), 1.55 (m, 3H), 1.21 (m, 2H), 1.1 (d, 3H, CH3), 0.9 (d, 6H, 2×CH3); MS:EI/70eV: 330 (M+), 258, 231, 190, 126, 69, 55, 44. Analysis: C10H12ClN3O2S requires C, 50.98; H, 6.11; N, 12.74; (found C, 51.14; H, 6.43; N, 12.64)
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:35][C@H:36]4[CH2:41][CH2:40][C@H:39]([CH3:42])[CH2:38][CH2:37]4)[C:24]([N:26]4[CH2:31][CH2:30][O:29][C@@H:28]5[CH2:32][CH2:33][CH2:34][C@@H:27]45)=[N:25][C:21]=3[CH:20]=[C:19]([C:43]#[N:44])[N:18]=2)[CH:14]=[N:15][CH:16]=1>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:35][C@H:36]4[CH2:41][CH2:40][C@H:39]([CH3:42])[CH2:38][CH2:37]4)[C:24]([N:26]4[CH2:31][CH2:30][O:29][C@@H:28]5[CH2:32][CH2:33][CH2:34][C@@H:27]45)=[N:25][C:21]=3[CH:20]=[C:19]([C:43](=[N:2][OH:3])[NH2:44])[N:18]=2)[CH:14]=[N:15][CH:16]=1
Reactant: NO
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (24.3 mg, 0.35 mmol), sodium bicarbonate (44 mg, 0.52 mmol), and water (0.52 mL) were combined in a vial and stirred for 15 minutes. This solution was added to a vial containing 4-(5-chloropyridin-3-yl)-2-((4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (85.8 mg, 0.175 mmol) dissolved in ethanol (1.2 mL). The mixture was sealed and heated at 100° C. for 1 hour. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-2-((4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide. MS ESI calc'd. for C27H34ClN7O2 [M+H]+ 524. found 524.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13]C)=[O:12])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][CH:9]2[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CC1c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CC1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 7 (390 mg, 2.0 mmol) in MeOH (5 mL) was added 2N NaOH (5 mL) slowly. The reaction solution was stirred at room temperature for 2 h then diluted with H2O (25 mL). After extraction with ether (20 mL), the aqueous layer was acidified with 2N HCl (2.1 mL). The resulting solution was extracted with ether (3×40 mL). The combined organic layers were dried over MgSO4 and concentrated to give 8 (325 mg, 1.8 mmol, 99%) as a light yellow oil: 1H NMR (500 MHz, CDCl3) δ 0.87-0.91 (dd, J=6.0, 13.5 Hz, 1H), 1.21-1.29 (m, 1H), 1.39-1.43 (ddd, J=5.0, 6.5, 8.0 Hz, 1H), 1.67-1.72 (m, 1H), 1.90-1.94 (m, 1H), 2.58-2.63 (m, 1H), 6.79-6.82 (dd, J=2.0, 5.5 Hz, 1H), 6.90-6.95 (m, 2H), 7.24-7.28 (m, 1H), 8.90-11.00 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 17.8, 24.4, 26.9, 31.8, 113.3, 113.5, 113.8, 114.0, 122.30, 122.32, 130.2, 130.3, 142.4, 142.5, 162.2, 164.2, 179.8; LCQ-MS (M−H+) calcd for C10H8FO2 179. found 179.
Reaction SMILES: C(Cl)(Cl)=O.[CH:5]([NH:7][C@@H:8]1[C:32](=[O:33])[N:10]2[C:11]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:12]([CH3:15])[CH2:13][S:14][C@H:9]12)=O.N1C=CC=CC=1>C(Cl)Cl>[N+:7]([C@@H:8]1[C:32](=[O:33])[N:10]2[C:11]([C:16]([O:18][CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:17])=[C:12]([CH3:15])[CH2:13][S:14][C@H:9]12)#[C-:5]
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Agent: O=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: [C-]#[N+][C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)CS[C@H]12
Yield: 81.5 %

Procedure:
A solution of phosgene (3.27 g, 33 mmole) in methylene chloride (ca. 25 ml.) at -20° was added to a stirred solution of diphenylmethyl (6R, 7R)-7-formamido-3-methyl-ceph-3-em-4-carboxylate (prepared as described in Belgian Patent Specification No. 761,897) (12.24 g., 30 mmole) in methylene chloride (500 ml.) containing pyridine (12 ml., 150 mmole), at -20°. The solution was washed with water (2 × 250 ml.) and the organic layers combined with the methylene chloride backwash (250 ml.) of the aqueous layers, dried, and evaporated to a brown foam, which was then dissolved in ethyl acetate (100 to 150 ml.). This solution was added to petroleum-ether (b.p. 40° to 60°) to precipitate the product, which was isolated by filtration and dried to give the title compound as a pale-pink solid (9.539 g., 24.4 mmole, 81.5%); m.p. 117° - 118°; [α]D ± 0°; λmax. 252.5 nm (ε 7,030); λinf. 257,263.5 nm (ε 6,690; 6,480); νmax. 2150 (C=N), 1795 (azetidin-2-one), 1722 (CO2R), 1498, 752 and 735 cm.-1 ([C6H5 ]2CH); τ 2.40 to 2.80 (m, [C6H5 ]2CH), 3.04 (s, [C6H5 ]2CH), 4.88 (d, J 4.5 Hz, C7 -H), 5.10 (d, J 4.5 Hz, C6 -H), 6.69 (s, C2 -H2), 7.81 (s, C3 -CH3). (Found; C, 67.2; H, 4.8; N, 6.9; S, 8.1; C22H18N2O3S (390.4) requires: C, 67.6; H, 4.6; N, 7.2; S, 8.2%).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7](=[O:21])[N:6]3[N:22]=[CH:23][N:24]=[C:5]3[C:4]=2[CH:3]=1.[CH:25]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:25]1([N:28]2[CH2:33][CH2:32][N:31]([C:2]3[CH:11]=[N:10][C:9]4[N:8]([CH2:12][C:13]5[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=5)[C:7](=[O:21])[N:6]5[N:22]=[CH:23][N:24]=[C:5]5[C:4]=4[CH:3]=3)[CH2:30][CH2:29]2)[CH2:27][CH2:26]1
Reactant: C1CN(C2CC2)CCN1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(Br)cnc32)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(N4CCN(C5CC5)CC4)cnc32)cc1
Temperature: 100 °C
Yield: 36.2 %

Procedure:
9-Bromo-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (63 mg, 0.16 mmol) and 1-cyclopropylpiperazine (103 mg, 0.82 mmol) were dissolved in toluene (2 ml) and nitrogen was bubbled through the mixture while 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (41 mg, 0.07 mmol), cesium carbonate (159 mg, 0.49 mmol) and palladium(II) acetate (7 mg, 0.03 mmol) were added. The mixture was heated at 100° C. for 16 hours. It was concentrated under a stream of nitrogen and the residue was taken up in DMF, filtered and purified by preparative HPLC to afford 25 mg (27%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:18]C(=O)C(C)(C)C)[C:12]=2[C:14]([O:16][CH3:17])=[O:15])[C@H:7]2[CH2:25][CH2:26][O:27][C@H:6]2[CH2:5]1)(=[O:3])[CH3:2]>S(=O)(=O)(O)O.CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:18])[C:12]=2[C:14]([O:16][CH3:17])=[O:15])[C@H:7]2[CH2:25][CH2:26][O:27][C@H:6]2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1N(C(C)=O)C[C@@H]1OCC[C@H]21
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1c(N)ccc2c1N(C(C)=O)C[C@@H]1OCC[C@H]21
Yield: 77.4 %

Procedure:
Concentrated sulfuric acid (5 drops) was added to a solution of methyl cis-(3aRS,9bRS)-5-acetyl-7-(2,2-dimethylpropionylamino)-1,2,3a,4,5,9b-hexahydro-furo[2,3-c]quinoline-6-carboxylate (Intermediate 30, 0.15 g) in methanol (5 mL) and the solution was stirred and heated at reflux for 48 hours. After cooling, the mixture was evaporated to low volume and the residue was dissolved in ethyl acetate and carefully washed with saturated aqueous sodium bicarbonate solution. The organic layer was filtered through a phase separator and the filtrate was evaporated to dryness to give methyl cis-(3aRS,9bRS)-5-acetyl-7-amino-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-6-carboxylate (0.09 g) as a brown gum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O>CS(C)=O>[F:26][C:25]([F:28])([F:27])[CH2:24][O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(F)cc1OCC(F)(F)F
Yield: 63.3 %

Procedure:
5-Fluoro-2-nitrophenol (3.07 g, 19.5 mmol) was dissolved in 50 mL of DMSO with cesium carbonate (7.62 g, 23.4 mmol) and stirred. 2,2,2-Trifluorethyl trifluoromethanesulfonate (5.00 g, 21.5 mmol) was added with 5 mL of DMSO. The reaction was stirred overnight and quenched with 50 mL of H2O. The mixture was poured into 1:1 diethyl ether/hexanes and H2O. The layers were separated, and the organic layer was washed with 10% K2CO3 (aqueous) (2×), H2O, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 2.95 g (63%) of the title compound of step A. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (dd, J=9.0, 6.0 Hz, 1H), 7.45 (dd, J=10.7, 2.5 Hz, 1H), 7.08 (ddd, J=9.0, 7.9, 2.6 Hz, 1H), 4.97 (q, J=8.6 Hz, 2H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[SH:11].Br[CH2:13][CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1>C1COCC1>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11][CH2:13][CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: BrCCCOC1CCCCO1
Reactant: Fc1ccc(S)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(SCCCOC2CCCCO2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
Sodium hydride (60%) (1.72 g, 44.8 mmol) was added to a solution of 2,4-difluorobenzenethiol (CAS no. 1996-44-7) (4.6 mL, 40 mmol) in THF (150 mL) at 0° C., under argon. The mixture was allowed to warm to room temperature and 2-(3-bromopropoxy)oxane (CAS no. 33821-94-2) (7.6 mL, 45 mmol) was added. The reaction was stirred at ambient temperature for 16 hours. The mixture was poured into ice/water (250 mL) and extracted with ethyl acetate (250 mL). The organic extract was washed with brine, dried (MgSO4) and the solvent removed under reduced pressure. The residue was purified by flash chromatography, eluting with 0-10% ethyl acetate in isohexane afford the product (10.8 g, 84%). 1H NMR δ(400 MHZ, CDCl3): 1.49-1.61 (m, 4H), 1.65-1.73 (m, 1H), 1.75-1.90 (m, 3H), 2.96 (t, 2H), 3.46-3.52 (m, 2H), 3.79-3.87 (m, 2H), 4.55-4.56 (m, 1H), 6.80-6.86 (m, 2H), 7.38-7.44 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:18][NH:19][C@H:20]1[CH2:39][N:24]2[C:25]3[C:30]([C:31]([CH2:32][C:33]([O:35]CCC)=[O:34])=[C:23]2[CH2:22][CH2:21]1)=[CH:29][CH:28]=[CH:27][CH:26]=3>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([N:19]([CH3:18])[C@H:20]2[CH2:39][N:24]3[C:25]4[C:30]([C:31]([CH2:32][C:33]([OH:35])=[O:34])=[C:23]3[CH2:22][CH2:21]2)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:11])=[CH:6][CH:7]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)C(c1ccc(F)cc1)N1CCCCC1
Product: CN(C(=O)C(c1ccc(F)cc1)N1CCCCC1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from (4-fluorophenyl)(piperidin-1-yl)acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 478.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[N:14]1[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([CH3:21])[C:15]1=[O:22].[H][H]>[Ni].O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[N:14]1[C:15](=[O:22])[C:16]([CH3:21])=[C:17]([CH3:20])[C:18]1=[O:19]
Reactant: CC1=C(C)C(=O)N(c2cc(C(=O)O)c([N+](=O)[O-])cc2F)C1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CC1=C(C)C(=O)N(c2cc(C(=O)O)c(N)cc2F)C1=O
Yield: 92.6 %

Procedure:
67.8 g of N-(2-fluoro-5-carboxy-4-nitrophenyl)-2,3-dimethylmaleic acid imide are hydrogenated using hydrogen in the presence of 14 g of Raney nickel catalyst in 1000 ml of tetrahydrofuran at a temperature of 20°-25° under normal pressure. When the stoichiometric amount of hydrogen has been consumed, the catalyst is separated off and the solution is concentrated by evaporation. 56.7 g of N-(2-fluoro-5-carboxy-4-aminophenyl)-2,3-dimethylmaleic acid imide having a melting point of 270° are thus obtained.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=1.Cl[Si:16]([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:9]([F:14])[CH:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: Fc1cc(F)cc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c(F)cc(Cl)cc1F
Temperature: -70 °C
Reaction time: 8 h

Procedure:
A solution of 2.5M n-BuLi in hexanes (60 ml, 0.15 mol) was added dropwise to a solution of 1-chloro-3,5-difluorobenzene (19.2 g, 0.13 mol) in THF (200 mL) cooled to −70° C. under Ar. After the addition was complete, the mixture was stirred for 1 h before a solution of chlorotrimethylsilane (21.7 g, 0.2 mol) in THF (25 mL) was added dropwise. The reaction was allowed to warm to rt with stirring overnight before cooling and quenching with H2O. The phases were separated and pentane (200 mL) was added; after washing with H2O the solution was dried over MgSO4 and carefully concentrated in vacuo to yield the title compound as a solution in THF (46 g) which was in the next step without further purification.