Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=2)=O)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C[Si](Cl)(C)C.Cl>C(Cl)Cl>[Br-:1].[C:27]([C:24]1[CH:25]=[CH:26][C:21]([S+:19]([C:16]2[CH:15]=[CH:14][C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:18][CH:17]=2)[C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)=[CH:22][CH:23]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: Fc1ccc(Br)cc1
Reactant: CC(C)(C)c1ccc(S(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc([S+](c2ccc(F)cc2)c2ccc(C(C)(C)C)cc2)cc1
Product: [Br-]
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a Grignard reagent prepared from 79 g of 1-bromo-4-fluorobenzene, 47 g of bis(4-tert-butylphenyl) sulfoxide obtained in Synthesis Example 1-2 and 150 g of methylene chloride were added. Under ice cooling, 49 g of trimethylsilyl chloride was added dropwise. The reaction solution was aged for 30 minutes, after which 105 g of 5 wt % dilute hydrochloric acid was added dropwise to quench the reaction. The organic layer was separated and concentrated in vacuum. Diisopropyl ether was added to the concentrate for recrystallization. The resulting crystals were collected by filtration and dried in vacuum, obtaining 68 g of the target compound, bis(4-tert-butylphenyl)(4-fluorophenyl)sulfonium bromide as white crystals. Yield 96%.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[C:16](=O)[CH2:15][CH2:14][CH2:13][O:12][C:11]=2[CH:18]=1.CN([CH:22]=[O:23])C>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2=[C:11]([CH:18]=1)[O:12][CH2:13][CH2:14][C:15]([CH:22]=[O:23])=[C:16]2[Cl:3]
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCCOc2cc(Br)ccc21
Product: O=CC1=C(Cl)c2ccc(Br)cc2OCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Phosphorus oxychloride, POCl3 (1.88 mL, 20.8 mmol) was added dropwise to DMF (5 mL) at 0° C. After 30 min a solution of 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one 8 (2.0 g, 8.3 mmol) in 8 mL DMF was added dropwise. The reaction mixture was allowed to reach room temperature to stir 2 hr, then poured slowly over rapidly stirred ice water. The aqueous phase was extracted with ethylacetate and the combined organics were washed with brine, dried over sodium sulfate and concentrated to give 9.
Reaction SMILES: ClCCCC([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=O.[CH3:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1>>[CH3:18][C:19]1[N:23]2[CH2:9][CH2:8][CH:7]=[C:12]([C:11]3[CH:12]=[CH:7][C:8]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:9][CH:10]=3)[C:22]2=[CH:21][N:20]=1
Reactant: CS(=O)(=O)Nc1ccccc1C(=O)CCCCl
Reactant: Cc1ncc[nH]1
Product: Cc1ncc2n1CCC=C2c1ccc(NS(C)(=O)=O)cc1

Procedure:
Combine 100 g (0.36 mol) of N-[(4-chloro-l-oxobutyl)phenyl] methanesulfonamide with 400 g (4.88 mol) of 2-methylimidazole and heat to 175° C. for 22 hr under argon. Crystallization from methylene chloride provides the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(#N)C>[Cl-:7].[CH2:11]([O:10][C:8]([N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9])[CH3:12]
Reactant: c1ccncc1
Reactant: CCOC(=O)Cl
Solvent: CC#N
Product: CCOC(=O)[n+]1ccccc1
Product: [Cl-]

Procedure:
A solution of pyridine (320 g, 4.05 mol) in acetonitrile (1600 mL) was cooled to −25° C. and treated with ethyl chloroformate (440 g, 4.05 mol) over about 0.75 hours, keeping the temperature below −15° C. A very thick slurry of the intermediate N-ethoxycarbonylpyridinium chloride salt was formed. This suspension was stirred at −30 to −15° C. for 2 hours. Triethyl phosphite (671.2 g, 4.04 mol) was then added over about 1 hour while keeping the temperature in the same range. A yellow solution results. This was allowed to warm to ambient temperature overnight and the solvent was distilled off under vacuum to a maximum temperature of 60° C. The residual oil was dissolved in dichloromethane (2000 mL) and stirred with a mixture of water (500 mL) and concentrated hydrochloric acid (20 mL) at ambient temperature for 3 hours. The phases were separated and the dichloromethane solution washed with water (500 mL) and then with a solution of 1 g potash in 500 mL water. The pH of this wash is checked after IS minutes agitation and if in the 6-8 range, the dichloromethane solution is water-washed again and the solvent is removed under vacuum to a temperature of 70° C. (oil-pump vacuum was used towards the end of the distillation) to leave 1144 g (98%) of diethyl N-ethoxycarbonyl-1,4-dihydropyridine-4-phosphonate (DHP-Phosphonate). This material was a 91:9 mixture of DHP-Phosphonate and its 1,2-isomer.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.O.N1(O)C2C=CC=CC=2N=N1.Cl.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][CH:36]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37]([OH:39])=[O:38].[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48]([O:38][C:37](=[O:39])[CH:36]([NH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[F:28])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:47]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1ccccc1F)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1F)c1ccccc1
Yield: 16.3 %

Procedure:
A solution of DCC (534 mg, 0.71 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (217 mg, 1.42 mmol), (2-fluoro-phenylamino)-phenyl-acetic acid hydrochloride (I247) (200 mg, 0.71 mmol) and (R)-quinuclidin-3-ol (271 mg, 2.13 mmol) in THF (10 mL) is stirred at RT for 2 days. The solvent is evaporated and the residue is taken up with EtOAc, washed with sat NaHCO3, water and brine. The organic layer is collected, dried over Na2SO4, filtered and evaporated to dryness. The residue is purified by preparative HPLC. The organic solvent is evaporated and the acid aqueous phase is basified with Na2CO3 and extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and evaporated to afford the title compound as yellow oil (41 mg, 16% yield).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][O:12][C:9]2=[CH:10][N:11]=1)(=O)C.O.[OH-].[Na+]>O1CCOCC1>[O:12]1[C:9]2=[CH:10][N:11]=[C:6]([CH2:5][OH:4])[CH:7]=[C:8]2[CH:14]=[CH:13]1
Reactant: CC(=O)OCc1cc2ccoc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: OCc1cc2ccoc2cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.4 %

Procedure:
Also to yield the desired compound: Furo[2,3-c]pyridin-5-ylmethyl acetate (1.15 g, 6 mmol) was dissolved in 1,4-dioxane (30 ml) and water (10 ml) and treated with 2N sodium hydroxide solution (12 ml) and stirred at RT for 18 h. The mixture was then partitioned between ethyl acetate and water, the organic layer was dried and evaporated to dryness to provide the desired compound (0.63 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([O:17][CH3:18])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].C(O)(=[O:21])C>>[CH3:18][O:17][C:15]([C:7]12[CH2:8][C:9]3([OH:21])[CH2:10][CH:11]([CH2:12][C:5]([C:3]([O:2][CH3:1])=[O:4])([CH2:14]3)[CH2:6]1)[CH2:13]2)=[O:16]
Reactant: COC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2
Reactant: CC(=O)O
Product: COC(=O)C12CC3CC(O)(C1)CC(C(=O)OC)(C3)C2
Yield: 42 %

Procedure:
To 25 mL of acetic acid were added the 10 mmole of the 1,3-dimethoxycarbonyladamantane, 1 mmole of NHPI and 0.05 mmole of V(AA)3, and the resultant mixture was stirred for 8 hours at 85° C., under an oxygen atmosphere. As a result, 1,3-dimethoxycarbonyl-5-adamantanol (yield 42%) and 1,3-methoxycarbonyl-5,7-adamantanediol (yield 36%) were formed. The conversion of 1,3-dimethoxycarbonyladamantane was 92%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:16]([O:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])([CH3:15])[CH3:14])/[C:8]([OH:10])=O)[N:6]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.FC(F)(F)C(O)=O.[NH2:64][C@H:65]1[CH2:68][N:67]([C:69]([NH:71][S:72]([N:75]2[CH2:79][CH2:78][N:77]([NH:80][C:81](=[O:90])[C:82]3[CH:87]=[CH:86][C:85]([OH:88])=[C:84]([OH:89])[CH:83]=3)[C:76]2=[O:91])(=[O:74])=[O:73])=[O:70])[C:66]1=[O:92]>CN(C)C=O.C(N(CC)CC)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][C:13]([CH3:14])([CH3:15])[C:16]([O:18][CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:17])[C:8]([NH:64][CH:65]2[CH2:68][N:67]([C:69]([NH:71][S:72]([N:75]3[CH2:79][CH2:78][N:77]([NH:80][C:81](=[O:90])[C:82]4[CH:87]=[CH:86][C:85]([OH:88])=[C:84]([OH:89])[CH:83]=4)[C:76]3=[O:91])(=[O:73])=[O:74])=[O:70])[C:66]2=[O:92])=[O:10])[N:6]=1
Reactant: CC(C)(O/N=C(\C(=O)O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: N[C@H]1CN(C(=O)NS(=O)(=O)N2CCN(NC(=O)c3ccc(O)c(O)c3)C2=O)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(ON=C(C(=O)NC1CN(C(=O)NS(=O)(=O)N2CCN(NC(=O)c3ccc(O)c(O)c3)C2=O)C1=O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
(Z)-2-Amino-α-[[1-(diphenylmethoxycarbonyl)-1-methylethoxy]imino]-4-thiazoleacetic acid (0.88 g, 0.002 mol) was dissolved in 20 ml of dimethylformamide followed by 0.3 g of N-hydroxybenzotriazole (containing 13% water), followed by 0.5 g of dicyclohexylcarbodiimide and 0.28 ml of triethylamine. The mixture was stirred at room temperature for 1 hour, then 1.08 g (0.002 mol) of (S)-3-amino-N-[[3-[(3,4-dihydroxybenzoyl)amino]-2-oxo-1-imidazolidinyl]sulfonyl]-2-oxo-1-azetidinecarboxamide, trifluoroacetate salt (see Example 1D) was added. The mixture was stirred at room temperature overnight. The precipitate (dicyclohexylurea) was filtered off and the filtrate evaporated in vacuo. Trituration of the remaining syrup with ether yielded 1.8 g of the title compound in crude form.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:11])=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.[CH:12](O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][CH:12]=[N:10][C:5]=2[C:4]=1[CH3:11]
Reactant: COc1ccc(N)c(N)c1C
Reactant: O=CO
Product: COc1ccc2[nH]cnc2c1C
Temperature: 60 °C
Yield: 84 %

Procedure:
A mixture of 4-methoxy-3-methyl-l,2-benzenediamine (2.8 g, 18A mmol) and formic acid (30 mL) was heated at 60° C. for 30 minutes. The formic acid was removed under reduced pressure and the product was partitioned between chloroform and water containing sufficient sodium hydroxide to basify the solution. After evaporation of the solvent the crude product was chromatographed (methanol:chloroform) to give 2.55 g (84%) of 5-methoxy-4-methyl-1H-benzimidazole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C)C=O.[H-].[Na+].C1(=O)O[CH2:32][CH2:31][O:30]1>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH2:32][CH2:31][OH:30])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Reactant: O=C1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c(=O)n1CCO
Temperature: 150 °C
Yield: 86.6 %

Procedure:
To a solution of 2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione and 30 ml of dimethylformamide was added 0.53 g of 55 % sodium hydride, and the solution was heated up to 150°C. To this was added 0.97 g of ethylene carbonate, and the mixture was reacted for one hour at 150°C. After the reaction was complete, the solvent was distilled off from the resulting mixture under reduced pressure. To the residue obtained was added water to precipitate a crude product. This product was recrystallized from methanol to yield 2.8 g of 1-(m-nitrophenyl)-3-(2-hydroxyethyl)pyrido[2,3-d] pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 212°-213°C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.Br[CH2:32][CH2:33][OH:34].C([O-])(O)=O.[Na+]>CC#N>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:32][CH2:33][OH:34])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 70.2 %

Procedure:
To a solution of COMPOUND 249 (0.1189 g, 0.38 mmol) in CH3CN (4 mL) was added Et3N (0.08 mL, 0.57 mmol), KI (0.0063 g, 0.04 mmol), and 2-bromoethanol (0.03 mL, 0.46 mmol), and stirred at room temperature for 23 hours. Saturated NaHCO3 (10 mL) was added and extracted with CH2Cl2 (3×30 mL), and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (25:1:1 CH2Cl2-MeOH—NH4OH) provided 0.0946 g (66%) of COMPOUND 339 as a pale yellow oil. 1H NMR (CDCl3) δ 1.71-1.98 (m, 6H), 2.09 (s, 6H), 2.46 (t, 3H, J=5.1 Hz), 2.94 (d, 3H, J=10.8 Hz), 3.56 (t, 2H, J=5.1 Hz), 3.82 (s, 4H), 7.04-7.08 (m, 2H), 7.34 (d, 2H, J=7.5 Hz), 8.33 (d, 2H, J=4.2 Hz). 13C NMR (CDCl3) δ 18.35, 27.34, 53.93, 55.13, 57.82, 58.52, 59.74, 122.63, 133.76, 138.29, 146.15, 157.80. ES-MS m/z 355.5 (M+H). Anal. Calcd. for C21H30N4O.0.3CH2Cl2: C, 67.33; H, 8.12; N, 14.74. Found: C, 67.46; H, 8.43; N, 14.93.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[C:3]=1[F:10].C(NC(C)C)(C)C.[Li].[C:19](=[O:21])=[O:20]>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([F:9])[C:5]([F:8])=[C:6]([CH:7]=1)[C:19]([OH:21])=[O:20]
Reactant: Fc1ccc(Br)c(F)c1F
Reactant: O=C=O
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(Br)c(F)c(F)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 1-bromo-2,3,4-trifluorobenzene (1) (5.0 mL, 41.7 mmol) in THF (120 mL) was added lithium diisopropylamine (2.0 M solution, 21 mL, 42 mmol) at −78° C. After stirring for 1 hour at −78° C., the mixture was added to a solution of CO2 in THF (1 L). The dry-ice bath was removed and the reaction mixture stirred overnight at room temperature. The reaction mixture was quenched with 10% aqueous HCl (835 mL), concentrated, and washed with ether (250 mL). The combined organics were washed with 5% aqueous NaOH (300 mL) and water (100 mL, pH 12). The aqueous layer was acidified (pH 0) with concentrated HCl. The resulting suspension was extracted with ether (2×300 mL), dried over MgSO4, filtered, concentrated under reduced pressure to afford 7.70 g (72% yield) of the desired product (2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[Br:10][C:11]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:12]=1[O:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CC(O)C.C(N(CC)C(C)C)(C)C>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:17]2[CH2:16][CH2:15][CH:14]([O:13][C:12]3[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:11]=3[Br:10])[CH2:19][CH2:18]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)c(OC2CCNCC2)c1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1ccc(Br)c(OC2CCN(c3ncc(Br)cn3)CC2)c1
Temperature: 120 °C

Procedure:
Into a 100-mL sealable pressure flask equipped with a magnetic stirbar was added 5-bromo-2-chloropyrimidine (2.50 g, 12.9 mmol), 4-(2-bromo-5-fluorophenoxy)piperidine hydrochloride (4.00 g, 12.9 mmol), 2-propanol (30 mL) and N,N-diisopropylethylamine (4.50 mL, 25.8 mmol). The vial was sealed and heated to 120° C. for 3 h. The reaction mixture was cooled and poured into a 500 mL separatory funnel containing water (250 mL) and the mixture was extracted with ethyl acetate (3×75 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The resulting oil was recrystallized from diethyl ether/hexanes and cooled to −40° C. to cause precipitation, then filtered through Whatman#1 filter paper to give a beige solid, which was dried overnight on the vacuum pump. MS (ESI, Q+) m/z 432, 434, 437 (M+1 for 2×35Br and 37Br).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([I:14])[CH:12]=2)[O:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:33]([N:36]([CH2:49][CH2:50]Br)[S:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[N+:46]([O-:48])=[O:47])(=[O:39])=[O:38])[CH:34]=[CH2:35]>CC(N(C)C)=O>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:15]([CH2:50][CH2:49][N:36]([CH2:33][CH:34]=[CH2:35])[S:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[N+:46]([O-:48])=[O:47])(=[O:38])=[O:39])[S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([I:14])[CH:12]=2)[O:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:4]
Reactant: C=CCN(CCBr)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: C=CCN(CCN(c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1I)S(C)(=O)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
2-(4-Fluoro-phenyl)-5-iodo-6-methanesulfonylamino-furo[2,3-b]pyridine-3-carboxylic acid methylamide (150 mg, 0.31 mmol) is dissolved in DMA (4 mL) and Cs2CO3 (110 mg, 0.34 mmol) and N-Allyl-N-(2-bromo-ethyl)-2-nitro-benzenesulfonamide (214 mg, 0.61 mmol) is added and the mixture is placed in the microwave for 30 min at 150° C. The mixture is then filtered and the solid is washed with EtOAc (30 mL). The organic is washed with H2O (10 mL) then Brine (20 mL) and then dried over Na2SO4 then concentrated to dryness. HPLC (CH3CN/H2O/0.1% TFA) provides 6-({2-[Allyl-(2-nitro-benzenesulfonyl)-amino]-ethyl}-methanesulfonyl-amino)-2-(4-fluoro-phenyl)-5-iodo-furo[2,3-b]pyridine-3-carboxylic acid methylamide (45 mg, 19%). MS-ES [M+H]+=758.3.
Reaction SMILES: [S:1]([Cl:3])Cl.[CH3:4][NH:5][C:6](=[O:12])[O:7][CH2:8][CH2:9][CH2:10][CH3:11].C(N(CC)CC)C>C(Cl)Cl>[Cl:3][S:1][N:5]([CH3:4])[C:6](=[O:12])[O:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: ClSCl
Reactant: CCCCOC(=O)NC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)N(C)SCl
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To a solution of 45.2 g (0.44 mole) of sulfur dichloride in 200 ml of methylene chloride cooled to -5° C. under a nitrogen atmosphere was added a solution made up of 50.9 g (0.4 mole) of n-butyl N-methylcarbamate, 44.5 g (0.44 mole) of triethylamine and 100 ml of methylene chloride. The addition took 2 hours while the temperature was maintained at -15° C. to 0° C. After stirring for 1 hour the mixture was filtered under a positive nitrogen atmosphere, and the filtrate was concentrated. Solid was removed by extracting the product with hexanes. After filtration the hexane solution was concentrated to give 57.3 g of n-butyl N-chlorothio-N-methylcarbamate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[N:13]=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8].O>C(O)(=O)C.[Zn]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[C:7](=[O:8])[NH:9][C:10](=[O:11])[CH2:12][NH:13]1
Reactant: Cc1cccc(Cn2ncc(=O)[nH]c2=O)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(CN2NCC(=O)NC2=O)c1
Reaction time: 8 h
Yield: 59.4 %

Procedure:
Into a three-necked flask equipped with a mechanical stirrer and a reflux condenser was placed 1 g of 1-(3-methylbenzyl)-6-aza-uracil, 100 ml of water was added and a vigorous stirring commenced. 1.1 g of zinc powder was added in one portion, and was followed by dropping in 20 ml of glacial acetic acid. The mixture was then vigorously stirred and refluxed for 24 hours. The mixture was thereafter cooled and the precipitate was filtered off with suction. The mass of crystals was dissolved in hot methanol, the solution filtered and the filtrate was left to stand overnight and filtered to yield 0.6 g of 2-(3'-methylbenzyl)-hexahydro-1,2,4-triazine-3,5-dione; m.p. 158°.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:21]([OH:23])=[O:22])[CH2:4][CH2:5][C:6]([NH:8][C@@H:9]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10]([SH:13])([CH3:12])[CH3:11])=[O:7].[N:24](OCC)=[O:25].Cl.CO>CO.C(O)C>[ClH:1].[NH2:2][C@H:3]([C:21]([OH:23])=[O:22])[CH2:4][CH2:5][C:6]([NH:8][C@H:9]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10]([S:13][N:24]=[O:25])([CH3:11])[CH3:12])=[O:7]
Reactant: CC(C)(S)[C@@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Reactant: CCON=O
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CC(C)(SN=O)[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Reaction time: 0.5 h

Procedure:
To the solution of (N-γ-L-glutamyl-D-penicillamyl)glycine hydrochloride (0.5 g) in methanol (5 ml), was added at 0° C. the solution of ethyl nitrite in ethanol (10%) (1.1 ml). At the same temperature a drop of 4N-hydrochloric acid-methanol solution was added, and the mixture was stirred for 30 minutes. The solvent was evaporated off under reduced pressure, and the resultant crystals were washed with diethyl ether, to give (N-γ-L-glutamyl-S-nitroso-L-penicillamyl)glycine hydrochloride (0.5 g).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[N:11]=[C:12]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[C:29]([C:36]([F:39])([F:38])[F:37])[CH:28]=2)[C:13]2[CH:18]=[CH:17][N:16]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:14]=2[N:15]=1)#[N:9]>C(Cl)Cl>[C:8]([C:10]1[N:11]=[C:12]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[C:29]([C:36]([F:39])([F:38])[F:37])[CH:28]=2)[C:13]2[CH:18]=[CH:17][N:16]([CH2:19][C:20]([OH:22])=[O:21])[C:14]=2[N:15]=1)#[N:9]
Reactant: CCOc1ccc(-c2nc(C#N)nc3c2ccn3CC(=O)OC(C)(C)C)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(-c2nc(C#N)nc3c2ccn3CC(=O)O)cc1C(F)(F)F
Reaction time: 5 h
Yield: 97.9 %

Procedure:
Trifluoroacetic acid (0.41 mL) was added to a solution of tert-butyl {2-cyano-4-[4-ethoxy-3-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}acetate (160 mg) in CH2Cl2 (1.6 mL) at room temperature, and the mixture was stirred at the same temperature for 5 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (CHCl3:MeOH=100:0 to 80:20), whereby {2-cyano-4-[4-ethoxy-3-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}acetic acid (137 mg) was obtained as a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].[NH2:19][C@@:20]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][C:24](=[CH2:26])[C@@H:23]2[C@H:21]1[C@H:22]2[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH:17]1[C:18]2[CH:6]([CH2:5][O:4][C:2]([NH:19][C@@:20]3([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][C:24](=[CH2:26])[C@@H:23]4[C@H:21]3[C@H:22]4[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:3])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: C=C1C[C@@](N)(C(=O)OCC)[C@H]2[C@@H]1[C@@H]2C(=O)OCC
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1C[C@@](NC(=O)OCC2c3ccccc3-c3ccccc32)(C(=O)OCC)[C@H]2[C@@H]1[C@@H]2C(=O)OCC
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Add solid 9-fluorenylmethyl chloroformate (3.15 g, 12.2 mmol) portion wise over 5 minutes to a stirred solution of diethyl (1S,2S,5R,6S)-2-amino-4-methylene-bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.8 g, 11.1 mmol) and sodium bicarbonate (2.04 g, 24.3 mmol) in tetrahydrofuran (28 mL) and water (8.4 mL) cooled to 0-5° C. After 1 hour, add water (10 mL) and extract with ethyl acetate (50 mL). Wash the extract with brine solution (20 mL), dry, filter and evaporate to a pale yellow oil (6.5 g). Purify by flash chromatography eluting with ethyl acetate:iso-hexane (10:90 to 20:80) to give a viscous colorless oil (4.58 g). Repurify by flash chromatography eluting with ethyl acetate:iso-hexane (20:80) to give a white semi-solid foam of title compound (4.22 g, 80%). MS (m/z): 476 (M+1).