Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:5][C:4]=2[CH:3]=1.[F:25][C:26]([F:55])([F:54])[C:27]1[C:31](B(O)O)=[CH:30][N:29]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:28]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[O:11]=[C:8]1[NH:7][C:6]([C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:5][C:4]2[CH:3]=[C:2]([C:31]3[C:27]([C:26]([F:54])([F:55])[F:25])=[N:28][N:29]([C:35]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:30]=3)[S:10][C:9]1=2
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1c1nc2cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3C(F)(F)F)sc2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
tert-butyl (2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylate (1.41 g) produced in Example 83, step B, [3-(trifluoromethyl)-1-trityl-1H-pyrazol-4-yl]boronic acid (1.72 g), sodium carbonate (902 mg), ethanol (15 mL) and water (3 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. Tetrakis(triphenylphosphine)palladium(0) (197 mg) was added, the atmosphere in the flask was purged again with argon, and the mixture was stirred at 80° C. for 15 hr. Ethyl acetate (20 mL) and water (10 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane), and the object fraction was concentrated under reduced pressure to give tert-butyl (2S)-2-{4-oxo-6-[3-(trifluoromethyl)-1-trityl-1H-pyrazol-4-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}piperidine-1-carboxylate as a colorless oil. To a solution of tert-butyl (2S)-2-{4-oxo-6-[3-(trifluoromethyl)-1-trityl-1H-pyrazol-4-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}piperidine-1-carboxylate produced above in methanol (4 ml) was added 4M hydrochloric acid/ethyl acetate solution (1 mL), and the mixture was stirred at 60° C. for 15 hr. The precipitated solid was collected by filtration to give the title compound (530 mg) as a colorless solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[CH:20]2.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[CH:20]3)[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1CN(Cc2ccccc2)CCC1Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.6 %

Procedure:
1-Benzyl-3-methyl-4-piperidone (152.7 mg), 5-aminoindazole (100 mg), and acetic acid (0.02 ml) were dissolved in methanol (10 ml). Acetic acid (five drops) was added to the solution, and a borane-pyridine complex (0.06 ml) was then added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. After the completion of the reaction, a saturated aqueous sodium hydrogencarbonate solution (1 ml) was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine and was dried over sodium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography [silica gel, chloroform/methanol] to give the title compound (95.3 mg, yield 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:20]([CH2:21][CH3:22])[CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH:12]2[CH2:23][OH:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.N#N.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:34][N:35]([CH3:39])[C:36](=[O:37])[O:24][CH2:23][CH:12]1[N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:20]([CH2:21][CH3:22])[CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13]1
Reactant: CN(C)C(=O)Cl
Reactant: CCC1CC2(CC(CO)N1S(=O)(=O)c1ccc(Cl)cc1)OCCO2
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1CC2(CC(COC(=O)N(C)C)N1S(=O)(=O)c1ccc(Cl)cc1)OCCO2
Reaction time: 0.08 h
Yield: 136.6 %

Procedure:
(8-(4-Chlorophenylsulfonyl)-9-ethyl-1,4-dioxa-8-azaspiro[4.5]decan-7-yl)methanol (111; 1.19 g, 3.18 mmol) and triethylamine (2.21 ml, 15.9 mmol) were added to CH2Cl2 (15 mL) in a flame-dried flask and placed tinder N2. DMAP (77.8 mg, 0.637 mmol) was added and the mixture stirred for 5 minutes. Dimethylcarbamoyl chloride (0.88 mL, 1.54 mmol) was added dropwise and the reaction stirred for 18 hours. The reaction mixture was concentrated under reduced pressure, and equal portions of EtOAc and water were added. The aqueous layer was extracted with several more portions of EtOAc. The combined organic layers were washed with a dilute NaOH solution, 10% citric acid, brine, dried over Na2SO4 and concentrated to yield 940 mg of 112 as a yellow oil. The material was purified by column chromatography using EtOAc/hexanes gradients to yield 836 mg (59%) of a mixture of cis/trans isomers.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O[BH-](O[C:24](=[O:26])[CH3:25])OC(=O)C)(=O)C.[Na+]>>[CH3:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:7][C:6]3[O:26][C:24]4[C:25](=[N:4][CH:3]=[CH:2][CH:1]=4)[CH:5]=3)[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cccnc1N1CCNCC1
Agent: [Na+]
Product: Cc1cccnc1N1CCN(Cc2cc3ncccc3o2)CC1

Procedure:
The product from Example 35B, 1-(3-methyl-2-pyridinyl)piperazine, and sodium triacetoxyborohydride were processed as described in Example 35C to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.68 (m, 4H), 3.29 (s, 3H), 3.58 (m, 4H), 3.79 (s, 2H), 6.41 (d, J=8.48 Hz, 1H), 6.49 (d, J=7.12 Hz, 1H), 6.85 (s, 1H), 7.18 (dd, J=4.75, 8.14 Hz, 1H) 7.36 (dd, J=7.12, 8.14 Hz, 1H), 7.73 (dd, J=1.02, 8.14 Hz, 1H), 8.51 (dd, J=1.36, 4.75 Hz, 1H); MS (DCI/NH3) m/z 309.2 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([OH:16])([CH3:15])[CH3:14])C1C=CC=CC=1.CC(O)=O>CO.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([OH:16])([CH3:15])[CH3:14]
Reactant: CC(C)(O)[C@H]1CCCN1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(O)[C@H]1CCCN1
Reaction time: 24 h
Yield: 122.4 %

Procedure:
A mixture of (R)-2-(1-benzyl-pyrrolidin-2-yl)-propan-2-ol (582 mg, 2.65 mmol), HOAc (3 mL), and Pd(OH)2/C (200 mg) in MeOH was shaken in a Parr bottle with H2 under 50 psi for 24 h. The reaction mixture was then filtered through celite eluting with MeOH. HCl (g) was passed through the filtrate, and the filtrate was then concentrated to afford the title compound as a gray solid (419 mg, 95%). MS: 130.1 (MH+); HPLC Rf: n.d.; HPLC purity: n.d.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[Si:10](Cl)([CH3:13])([CH3:12])[CH3:11]>ClCCl>[Si:10]([C:7]1[NH:6][C:5](=[O:8])[N:4]([Si:10]([CH3:13])([CH3:12])[CH3:11])[C:3](=[O:9])[C:2]=1[F:1])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Product: C[Si](C)(C)c1[nH]c(=O)n([Si](C)(C)C)c(=O)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-fluorouracil (130 mg, 1.0 mmol) in dichloromethane (5 mL), N,O-Bis-TMS-Acetamide (0.86 mL, 3.5 mmol) and TMS-Cl (0.1 mL) were added. After 2 h stirring at room temperature (clear solution) the reaction mixture was concentrated under reduced pressure to afford bis-TMS-5-fluorouracil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][N:10]([CH3:19])[CH2:9]1)(C)(C)C.[ClH:21]>>[ClH:21].[CH3:19][N:10]1[CH2:11][C@@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@H:8]([NH2:7])[CH2:9]1
Reactant: CN1C[C@@H](NC(=O)OC(C)(C)C)[C@H](c2ccccc2)C1
Agent: Cl
Product: CN1C[C@@H](N)[C@H](c2ccccc2)C1
Temperature: 50 °C

Procedure:
tert-Butyl((3S,4R)-1-methyl-4-phenylpyrrolidin-3-yl)carbamate (521 mg, 1.885 mmol) was dissolved in methanolic HCl, (3 N, 10 mL) and heated to 50° C. for 2 h. The reaction mixture was concentrated in vacuo to afford (3S,4R)-1-methyl-4-phenylpyrrolidin-3-amine hydrochloride, which was carried onto the next step without further purification. MS ESI calc'd. For C11H16N2 [M+1]+ 177. found 177.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([F:20])[C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:8])[N:7]=1.[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([NH2:42])([CH3:41])[CH3:40])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([NH:42][C:2]1[C:3](=[O:21])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([F:20])[C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:8])[N:7]=1)([CH3:40])[CH3:41])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(N)c1ccccc1CCCOCc1ccccc1
Reactant: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(Br)c2=O)c1
Product: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC(C)(C)c3ccccc3CCCOCc3ccccc3)c2=O)c1

Procedure:
The subtitle compound was prepared using a similar method to Example 252h from methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-5-fluoro-4-methylbenzoate (Example 252g) and 2-(2-(3-(benzyloxy)propyl)phenyl)propan-2-amine (Example 323e).
Reaction SMILES: C(OC([N:8]([C:22]1[N:23]=[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]2[C:31]=1[CH3:32])[S:9]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])=O)(C)(C)C>Cl.O1CCOCC1>[ClH:30].[Cl:30][C:27]1[CH:28]=[CH:29][C:24]2[N:25]([C:31]([CH3:32])=[C:22]([NH:8][S:9]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=3)(=[O:11])=[O:10])[N:23]=2)[CH:26]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)N(C(=O)OC(C)(C)C)c2nc3ccc(Cl)cn3c2C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(S(=O)(=O)Nc2nc3ccc(Cl)cn3c2C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 15-C (0.820 g, 1.71 mmol) was dissolved in 4N HCl in dioxane (44 mL) and the reaction mixture was stirred for 24 h at room temperature. The solvent was evaporated in vacuo and the crude product was washed with ethyl ether. The resulting solid was filtered, washed with additional ethyl ether, and dried in vacuo to give compound 15-D as a white solid (0.610 g, 86%); MS m/z (M+H+) 380.
Reaction SMILES: C[C:2]1(C)[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:3]1.C[Mg]Cl.CC1(C)CCC[CH:19]([C:23](=[O:25])C)[CH2:18]1.C1(C(O)(C)C)CCCCC1.C(OC(=O)C)(=O)C.C(OC(=O)CC)(=O)CC>>[C:23]([O:11][C:8]([CH:4]1[CH2:3][CH2:2][CH2:7][CH2:6][CH2:5]1)([CH3:9])[CH3:10])(=[O:25])[CH2:19][CH3:18]
Reactant: CC1(C)CCCC(C(C)(C)O)C1
Reactant: CC(=O)C1CCCC(C)(C)C1
Agent: CC(C)(O)C1CCCCC1
Agent: CCC(=O)OC(=O)CC
Agent: C[Mg]Cl
Solvent: CC(=O)OC(C)=O
Product: CCC(=O)OC(C)(C)C1CCCCC1

Procedure:
The following compounds were prepared analogously to the method described in Example 16, except that the alcohol component used was 2-(3,3-dimethylcyclohexyl)-2-propanol, [which can be prepared from methylmagnesium chloride and 1-(3,3-dimethylcyclohexyl)-ethanone by a Grignard reaction] instead of 2-cyclohexyl-2-propanol. The esterification was carried out with acetic anhydride (Example 18) or propionic anhydride (Example 19). Thus, only the spectroscopic data are indicated at this point:
Reaction SMILES: P(O[CH2:9][CH3:10])(OCC)OCC.[Cl:11][C:12]1(Cl)[C:16]([Cl:17])=[C:15]([Cl:18])[C:14]([Cl:19])=[C:13]1[Cl:20]>O>[Cl:11][C:12]1[C:16]([Cl:17])([CH2:9][CH3:10])[C:15]([Cl:18])=[C:14]([Cl:19])[C:13]=1[Cl:20]
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Reactant: CCOP(OCC)OCC
Solvent: O
Product: CCC1(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl
Yield: 96.4 %

Procedure:
A solution of triethyl phosphite (182.8 g., 1.1 mole) in 200 ml. of petroleum ether (pentane range) was charged to the equipment of the preceding example, which was immersed into a rock-salt-ice mixture. When the temperature of the solution reached 0°C. hexachlorocyclopentadiene (272.8 g., 1.0 mole), dissolved in 100 ml. of light petroleum ether, was added slowly to the well stirred solution at such a rate that the temperature of the mixture did not exceed +5°C. The addition required 10 hours. The clear, brown solution was poured with good stirring into a 5 liter 3 neck flask containing 2 liters of water and, after 1 hour of stirring, the product was steam distilled. After the separation of the low boiling petroleum ether 1,2,3,4,5-pentachloro-5-ethyl-cyclopentadiene, completely free of any phosphorus compound, distilled over as a pale yellow heavy oil, nD25 1.5398, the infrared spectrum of which matched perfectly that of the previous example. The product weighed 257.0 g., which corresponds to a 96.4% yield.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH:30]=O)[CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:30][C:22]2[CH:21]=[N:20][C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cnc2ccccc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available quinoline-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions B): tR=0.68 min.; [M+H]+: 377.36 g/mol.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]3[CH:12]=[C:13]([C:16]#[C:17][Si](C)(C)C)[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]([NH:22]C(=O)C(C)(C)C)[NH:3]1.C(O)(=O)C>CO.O>[NH2:22][C:4]1[NH:3][C:2](=[O:1])[C:11]2[C:10]3[CH:12]=[C:13]([C:16]#[CH:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3ccc(C#C[Si](C)(C)C)cc3c2c(=O)[nH]1
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: C#Cc1ccc2ccc3nc(N)[nH]c(=O)c3c2c1
Yield: 58.5 %

Procedure:
A solution of N-(1,2-dihydro-1-oxo-9-(trimethylsilylethynyl)benzo[f]quinazolin-3-yl)pivalamide (0.24 g, 0.61 mmol) and K2C03 (0.50 9'3.6 mmol) in methanol (-50 ml) was stirred at reflux for 2.5 hours. The solution was then diluted with water (-20 ml) acidified with acetic acid, and the resulting solid filtered and dried at 900 C under reduced pressure. The solid was resuspended in ethanol (- 20 ml), filtered, and dried to give 3-amino-9-ethynyl benzo[f]quinazolin- 1(2H)-one (0.084 g) as a tan solid. 1H NMR (DMSO-d, 200 MHz) δ: 4.26 (s, 1H, ethynyl CH), 6.63 (br s, 2H, NH2), 7.32 (d, J=9 Hz, 1H, Ar'), 7.47 (dd, J=8,2 Hz, 1H, Ar), 7.87 (d, J=8 Hz, IH, Ar), 8.02 (d, J =9 Hz, 1H, Ar), 9.78 (s, 1H, Ar), 11.34 (br s, 1H, NH). Mass spectrum (CI-CH4): 236 (M+1, 100%). Anal. Calculated for C1-4H9N3 0: (, 71.48; H, 3.86; N, 17.86. Found: C, 71.30; H, 3.92; N, 17.68.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:18]=[C:17]([NH2:19])[CH:16]=[C:6]([C:7]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.N1C=CC=CC=1.[Cl:27][CH2:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:18]=[C:17]([NH:19][S:31]([CH2:30][CH2:29][CH2:28][Cl:27])(=[O:33])=[O:32])[CH:16]=[C:6]([C:7]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:13][CH2:14][CH3:15])=[O:8])[CH:5]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCCN(CCC)C(=O)c1cc(N)cc(C(=O)OC)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN(CCC)C(=O)c1cc(NS(=O)(=O)CCCCl)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
A solution of 5-amino-N,N-dipropyl-isophthalamic acid methyl ester (D88) (1.4 g, 5.0 mmol, 1 equiv), DMAP (100 mg) and pyridine (392 mg, 5.0 mmol, 1.1 equiv) in CH2Cl2 (20 ml) was treated dropwise with 3-chloropropane-1-sulfonyl chloride (946 mg, 5.3 mmol, 1.1 equiv). The resulting mixture was stirred for 16 h at room temperature and then diluted with AcOEt (100 ml). The resulting solution was washed with 2N aqueous HCl solution (50 ml) followed by saturated aqueous NaHCO3 solution (50 ml), dried over MgSO4 and concentrated in vacuo. The residue was triturated with Et2O to give 5-(3-chloro-propane-1-sulfonylamino)-N,N-dipropyl-isophthalamic acid methyl ester (D91) (1.8 g, 86%) as a pink solid.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH2:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C@@H:16]2[C@H:19]([NH:20][C:21](=[O:37])/[C:22](=[N:29]\[O:30][C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33])/[C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)[C:18](=[O:38])[N:17]2[S:39]([OH:42])(=[O:41])=[O:40])[N:11]=1.Cl[S:44]([NH:47]C(=O)OC(C)(C)C)(=[O:46])=[O:45].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:28][C:25]1[S:26][CH:27]=[C:23](/[C:22](=[N:29]/[O:30][C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33])/[C:21](=[O:37])[NH:20][C@H:19]2[C@@H:16]([CH2:15][N:12]3[N:11]=[C:10]([CH2:9][NH:8][S:44](=[O:46])(=[O:45])[NH2:47])[CH:14]=[N:13]3)[N:17]([S:39]([OH:42])(=[O:41])=[O:40])[C:18]2=[O:38])[N:24]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncc(CN)n1)c1csc(N)n1)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncc(CNS(N)(=O)=O)n1)c1csc(N)n1)C(=O)O

Procedure:
Prepared in an analogous manner to example 53, using 2-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid TFA salt, crude compound (200 mg, 0.318 mmol), tert-butyl chlorosulfonylcarbamate (68 mg, 0.318 mmol), DIPEA (113 mL, 0.636 mmol) and DMF (1 mL). LCMS: m/z=609.1 (M−1). 1H NMR (400 MHz, D2O): δ 7.65 (s, 1H), 6.98 (s, 1H), 5.40 (d, J=6.0 Hz, 1H), 4.85-4.83 (m, 1H), 4.76-4.74 (m, 2H), 4.13 (s, 2H), 1.26 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][CH2:14][C:13]=34)[O:6][N:5]=2)[CH2:3][CH2:2]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C1COCC1>[C:22]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]2[CH:11]=[N:10][C:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:8]=3)=[C:13]2[CH2:14]1)(=[O:24])[CH3:23]
Reactant: c1ccc2c(c1)NCc1c(-c3nc(C4CC4)no3)ncn1-2
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N1Cc2c(-c3nc(C4CC4)no3)ncn2-c2ccccc21

Procedure:
A mixture of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydroimidazo[1,5-a]quinoxaline (XXXIII, EXAMPLE 101, 0.201 g) and acetic anhydride (3 ml) in THF (0.7 ml) is heated at 80° for 45 min. The reaction mixture is then cooled, concentrated, and partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phase is separated and filtered through sodium surfate and concentrated. The crude product is crystallized from dichloromethane and hexane to give the title compound, which is then recrystallized from ethyl ether/ethyl acetate/hexane, mp 202.0°-202.5°; MS (m/z) at 321; IR (mineral oil) 1674, 1639, 1501, 1358 and 1401 cm-1 ; NMR (CDCl3) 1.15, 2.18, 2.29, 5.32, 7.41, 7.62 and 8.15 δ.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:11][CH:12]1[CH2:15][CH:14]([CH2:16][OH:17])[C:13]1=[O:18])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BH4-]>C(O)(=O)C>[C:3]([O:11][CH:12]1[CH2:15][CH:14]([CH2:16][OH:17])[CH:13]1[OH:18])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OC1CC(CO)C1=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(OC1CC(CO)C1O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.8 %

Procedure:
Glacial acetic acid in (25 mL) a 250 mL 3-neck flask was cooled in an ice bath under a stream of nitrogen. Sodium borohydride was added cautiously in portions over a 5 minute period. The ice bath removed and the reagent was used after stirring for 15 minutes at ambient temperature. 2-Benzoyloxy-4-hydroxymethylcyclobutanone (1.43 g, 6.5 mmol) from Step H was dissolved in 45 mL of glacial actetic acid and immediately treated with the above borohydride reagent. After stirring the reaction mixture for 35 minutes, the reaction was quenched with ~2 mL of methanol and the reaction mixture was concentrated in vacuo to a syrup. The syrup was dissolved in 250 mL of ethyl acetate and the ethyl acetate solution was washed with water and 5% aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated to give 1.47 g of the title compound which was taken on to the next step without purification; MS DCI-NH3M/Z: 221 (M+H)+, 238 (M+NH4)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[CH:11]=[C:10]([CH3:16])[CH:9]=2)=[O:5])C.[OH-].[Li+]>C(O)C>[CH3:15][C:12]1[CH:11]=[C:10]([CH3:16])[CH:9]=[C:8]2[C:13]=1[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2
Reactant: CCOC(=O)c1cc2c(C)cc(C)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)c2cc(C(=O)O)[nH]c2c1
Yield: 95.1 %

Procedure:
A mixture of 4,6-dimethyl-1H-indole-2-carboxylic acid ethyl ester (22 g, 0.1 mol) and lithium hydroxide (4.8 g, 0.2 mol) in 400 ml of ethanol was heated at reflux overnight. The solvent was removed under reduced pressure and the residue was dissolved in water and neutralized with 10% HCl to pH<3. The resulting precipitates were filtered and washed with water and dried in vacuo at 40° C. to give white solids (18 g, 95%). 1H NMR (DMSO-d6, 400 MHz): δ 12.73 (brs, 1H, exchangeable with D2O, NH), 11.55 (brs, 1H, exchangeable with D2O, NH), 7.06 (s, 1H), 7.03 (s, 1H), 6.69 (s, 1H), 2.44 (s, 3H), 2.35 (s, 3H).