Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[C:10]([NH:16][C:17](=[O:19])[CH3:18])[CH:9]=2)=[C:4]([F:20])[C:3]=1[O:21][CH3:22].[BH4-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[C:10]([NH:16][C:17](=[O:19])[CH3:18])[CH:9]=2)=[C:4]([F:20])[C:3]=1[O:21][CH3:22]
Reactant: COc1c(Cl)ccc(-c2cc(NC(C)=O)ncc2C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(Cl)ccc(-c2cc(NC(C)=O)ncc2CO)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a stirred solution of N-(4-(4-chloro-2-fluoro-3-methoxyphenyl)-5-formylpyridin-2-yl)acetamide (1.7 g, 2.370 mmol) in a mixture of THF (15 mL) and methanol (5 mL) was added sodium borohydride (0.090 g, 2.370 mmol) in two portions and the reaction mixture was stirred at room temperature for 30 min. The volatiles were removed, water (15 mL) was added and the solution extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulphate, and concentrated under reduced pressure to afford N-(4-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(hydroxymethyl)pyridin-2-yl)acetamide (1.6 g, 1.88 mmol, 38% yield) as a brown solid. The compound was carried into the next step without further purification. LCMS (ESI) m/e 324.9 [(M+H)+, calcd for C15H15ClFN2O3 325.1]; LC/MS retention time (Method F): tR=0.97 min.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+].Cl[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21]>C1COCC1>[C:12]([O:11][C:10]([NH:9][CH2:8][C@H:3]1[C@@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][N:4]1[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: C[C@H]1CCCN[C@H]1CNC(=O)OC(C)(C)C
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CCC[C@H](C)[C@@H]1CNC(=O)OC(C)(C)C

Procedure:
To the mixture of rac-cis-tert-butyl ((3-methylpiperidin-2-yl)methyl)carbamate (9.48 g, 41.53 mmol) in THF (25 mL) was added NaOH (2 M, 25 mL), followed by allyl chloroformate (6.65 mL, 62.3 mmol).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:35])[CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21](O)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:36].O>C(O)CCC>[ClH:36].[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:35])[CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][C:18](=[C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: CC(C)(C)c1ccc(C(=O)CCCN2CCC(=C(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
A mixture of 30 g (0.059 mole) of 4'-tert-butyl-4-[4-(α-hydroxy-α-phenylbenzyl)piperidino]butyrophenone, 400 ml of 37% HCl, 200 ml of water and 100 ml of n-butanol was refluxed for one and one-half hours after which the solvent and excess acid were removed. The remaining residue was recrystallized from toluene to give the desired product, M.P. 223.5°-225.5° C.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[O:12][CH2:13][C:14]3[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H][H]>O1CCCC1.[Ni]>[C@H:1]1([NH:10][C:11]2[O:12][CH2:13][C:14]3[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 106.2 %

Procedure:
To a solution of (R)-indan-1-yl-(5-nitro-4H-benzo[d][1,3]oxazin-2-yl)-amine (example 1) (1.90 g, 6.1 mmol) in tetrahydrofuran (250 mL) at 23° C. were added three Pasteur pipettes of Raney-Nickel (ready to use 10% suspension in water) and the mixture was vigourously stirred under an atmospheric pressure of hydrogen for 23 h. The catalyst was filtered off, washed with tetrahydrofuran, the solvent was removed in vacuum to give the title compound as a light yellow foam (1.81 g, 99%), MS (ISP) m/e=280.4 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9](F)[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:14]Br>>[Br:14][C:9]1[C:8]([F:13])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[C:10]=1[F:11]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Reactant: BrBr
Product: O=C(O)c1cc(F)c(Br)c(F)c1F

Procedure:
The 4-fluoro substituent of 2,3,4,5-tetrafluorobenzoic acid was replaced by bromine by a series of reactions analogous to the sequence VIII→IX→X→II in Flow Sheet C, to produce 4-bromo-2,3,5-trifluorobenzoic acid (XI). The latter is then converted to a series of reactions analogous to the sequence IV→V→VI→VII of Flow Sheet A to yield an alkyl N-(1-hydroxy-2-alkyl)-3-amino-2-(4-bromo-2,3,5-trifluorobenzoyl)propenoate (XII). Selective cyclization of XII with lithium carbonate affords an alkyl 7-bromo-6,8-difluoro-1,4-dihydro-1-(2-hydroxy-2-alkyl)quinoline-3-carboxylate (XIII). Coupling with 2,6-dimethyl-4-(trialkylstannyl)pyridine then yields alkyl 6,8-difluoro-7-(2,6-dimethyl-4-pyridinyl)-1,4-dihydro-1-(2-hydroxy-2-alkyl)quinoline-3-carboxylate (XIV). The latter is then converted to its mesylate (XV) with methanesulfonyl chloride. The mesylate is cyclized with hydrogen sulfide and sodium hydride to form the ester I (R'=H, X=S) which by hydrolysis is converted to the free acid (I; R and R'=H, X=S). The cyclization takes place by saturating a solution or suspension of XV with hydrogen sulfide, then treating it with excess sodium hydride while cooling the reaction in a Dry Ice bath and then allowing the reaction to warm to ambient temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:15][C:16]1[CH:33]=[CH:32][C:19]2[O:20][C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[CH2:23][N:24]([C:25](Cl)=[O:26])[C:18]=2[CH:17]=1>C(Cl)Cl>[Cl:15][C:16]1[CH:33]=[CH:32][C:19]2[O:20][C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[CH2:23][N:24]([C:25]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)=[O:26])[C:18]=2[CH:17]=1
Reactant: Nc1ccncc1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccncc1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 89.3 %

Procedure:
By the method described in Example 18, 4-aminopyridine (1.3 g, 14.0 mmol) in 40 mL of CH2Cl2 with molecular sieves #5A (5 g) and Et3N (1.4 g, 15.0 mmol) was reacted with the title compound of Example 2 (4.1 g, 14.0 mmol) to produce 4.4 g of the title product after HPLC purification on silica gel.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[C:6]1[CH:11]=[C:10]([S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[N:9]=[C:8]([NH:18][C@H:19]([CH2:21][CH3:22])[CH3:20])[CH:7]=1>CO>[C@@H:19]([NH:18][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[N:9]=1)[C:5]([OH:23])=[O:4])([CH2:21][CH3:22])[CH3:20]
Reactant: CCCS(=O)(=O)c1cc(C(=O)OC)cc(N[C@@H](C)CC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)c1cc(C(=O)O)cc(N[C@@H](C)CC)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
Add 2 N NaOH (6.0 mL, 12.0 mmol) to a solution of (S)-2-sec-butylamino-6-propanesulfonyl-isonicotinic acid methyl ester (2.47 g, 7.87 mmol) in methanol (10 mL) at 0° C. Stir the mixture at room temperature for 3 h, acidify the solution to about pH=2 and concentrate to one half of the solvent. Partition the residue between ethyl acetate and water. Extract the aqueous layer with ethyl acetate (2×50 mL). Wash the combined extracts with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound (90%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[Br:12][CH2:13][CH2:14][CH2:15]Br>C(#N)C>[Br:12][CH2:13][CH2:14][CH2:15][O:11][C:3]1[CH:4]=[CH:5][C:6]([C:8](=[O:9])[CH3:10])=[CH:7][C:2]=1[CH3:1]
Reactant: BrCCCBr
Reactant: CC(=O)c1ccc(O)c(C)c1
Solvent: CC#N
Product: CC(=O)c1ccc(OCCCBr)c(C)c1

Procedure:
A mixture of 4-hydroxy-3-methylacetophenone (14.5 g, 96 mmol), K2O3 (17.5 g, 144 mmol), and 1,3-dibromopropane (30 g, 144 mmol) in acetonitrile (400 ml) was heated at reflux for 6 hours. At the end of the reaction, the solvent was removed on a rotary evaporator, and the crude solid was extracted into dichloromethane (750 ml). The insoluble inorganics were filtered off. The dichloromethane solution was concentrated again to a crude oil (34.5 g). Purification was effected by flash chromatography over a silica gel column (SiO2, 150 g; eluted with 7:3 hexane:dichloromethane, 2 l; and dichloromethane 2 l). The material thus purified weighed 14.6 g (56%) and was recrystallized from ethanol. Recrystallization again from ethanol gave analytically pure 1-[4-(3-bromopropoxy)-3-methylphenyl]-ethanone, m.p.=59°-61° C.
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[Cl:15][C:16]1[CH:17]=[C:18]([C@@H:22]2[C@@H:27]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[N:26]([C@@H:35]([CH:39]3[CH2:41][CH2:40]3)[C:36](=[O:38])[CH3:37])[C:25](=[O:42])[C@:24]([CH2:44][C:45]([OH:47])=[O:46])([CH3:43])[CH2:23]2)[CH:19]=[CH:20][CH:21]=1>C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([C@@H:22]2[C@@H:27]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[N:26]([C@@H:35]([CH:39]3[CH2:41][CH2:40]3)[C@@H:36]([OH:38])[CH3:37])[C:25](=[O:42])[C@:24]([CH2:44][C:45]([OH:47])=[O:46])([CH3:43])[CH2:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](O)[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
L-Selectride (Aldrich, St. Louis, Mo.), (1M in THF, 5.0 ml, 5.00 mmol) was added dropwise over the course of 5 minutes to a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-oxopropyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
Reaction SMILES: [NH2-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.Br[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1>O1CCCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][N:10]([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[NH2:11])=[CH:16][CH:17]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: NNc1ccc(F)cc1
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NN(CCc1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
A flask containing tetrahydrofuran (6.0 mL; Aldrich) was charged with sodium amide (0.488 g, 11.89 mmol; Acros) and chilled to 0° C. (4-Fluorophenyl)hydrazine (1.0 g, 7.9 mmol; Aldrich) was added in portions. After 5 minutes the solid had completely dissolved. The ice bath was removed and stirring was continued for 1 hour. The solution was chilled again in an ice bath and 1-(2-bromoethyl)-4-fluorobenzene (1.731 ml, 8.72 mmol; Aldrich) was added dropwise. After 10 minutes the ice bath was removed and stirring was continued for 1.5 hours. The mixture was poured into water (5 mL). The tetrahydrofuran was removed under reduce pressure and the residue was diluted with water (20 mL). The aqueous layer was extracted with diisopropyl ether (2×25 mL) and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product which was carried on without further purification: MS (DCI/NH3) m/z 248.9 (M+H)+.
Reaction SMILES: [Cl:1]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.[Cl:13][C:14]1[N:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1>C(Cl)(Cl)Cl>[Cl:13][C:14]1[N:15]=[N:16][C:17]([CH2:20][Cl:1])=[CH:18][CH:19]=1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: Cc1ccc(Cl)nn1
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(Cl)nn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Trichloroisocyanuric acid (3.62 g) was added to a solution of 3-chloro-6-methyl-pyridazine (5.00 g) in chloroform (130 mL) heated to 60° C. The mixture was stirred at 60° C. for 2 h and then at room temperature overnight. The mixture was filtered over Celite and the filtrate was concentrated. The residue was chromatographed on silica gel (cyclohexane/ethyl acetate 98:2→70:30) to give the title compound as a colorless oil that solidified on standing. Yield: 2.48 g (39% of theory); Mass spectrum (ESI+): m/z=163/165/167 (2 Cl) [M+H]+.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:29][O:30][NH2:31].CC([O-])=O.[Na+]>CCO>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[C:9]([C:1](=[N:31][O:30][CH2:29][C:28]2[CH:32]=[CH:33][C:34]([Cl:35])=[C:26]([Cl:25])[CH:27]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1
Reactant: NOCc1ccc(Cl)c(Cl)c1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(Nc1ccc(Cl)cc1C(=NOCc1ccc(Cl)c(Cl)c1)c1ccccc1)C(F)(F)F
Yield: 51 %

Procedure:
A solution of N-(2-benzoyl-4-chlorophenyl)trifluoromethanesulfonamide 25 (710 mg, 1.95 mmol), O-(3,4-dichlorobenzyl)hydroxylamine hydrochloride (468 .mg, 2.05 mmol) and anhydrous NaOAc (168 mg, 2.05 mmol) in EtOH (50 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 3:2) and the solvent removed under reduced pressure. An isomeric mixture of E- and Z-oxime ether derivatives was obtained, which were separated by radial thin layer chromatography (eluting with CH2Cl2/PE, 7.5:92.5 to 1:5). The major isomer was obtained as a pale yellow solid which was recrystallized from CH2Cl2/PE to give N-{4-chloro-2-[(3,4-dichlorobenzyloxyimino)phenylmethyl]phenyl}trifluoromethanesulfonamide 87 (535 mg, 51%), as pale yellow crystals. M.p. 87-88° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.18, br s, 1H; 7.65, d, J=8.8 Hz, 1H; 7.55-7.40, m, 5H; 7.34-7.14, m, 4H; 6.88, d, J=2.2 Hz, 1H; 5.09, s, 2H. The minor isomer was obtained as a pale yellow solid (315 mg, 30%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[F:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][NH:23]2>CN1C(=O)CCC1>[F:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][N:23]2[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: Fc1cccc2c1CCCN2
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4c(F)cccc43)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (1.0 g, 4.19 mmol) in NMP (10.0 mL) was added 5-fluoro-1,2,3,4-tetrahydroquinoline (1.5 g, 9.92 mmol) with stifling for 1 h at 150° C. in an oil bath. The reaction mixture was cooled to room temperature, precipitated with water (100 mL). The solids were collected by filtration and dried in an oven under reduced pressure to afford methyl 3-(5-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a gray solid (1.0 g, crude).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][S:6]([C:9]2[CH:26]=[CH:25][C:12]3[N:13]([CH2:21][CH:22]4[CH2:24][CH2:23]4)[C:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:15][C:11]=3[CH:10]=2)(=[O:8])=[O:7])[CH2:2]1.C(N(CC)CC)C.C[Si]([N:38]=[C:39]=[O:40])(C)C>ClCCl>[CH:22]1([CH2:21][N:13]2[C:12]3[CH:25]=[CH:26][C:9]([S:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:39]([NH2:38])=[O:40])[CH2:4]4)(=[O:8])=[O:7])=[CH:10][C:11]=3[N:15]=[C:14]2[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:23][CH2:24]1
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CNC3)ccc2n1CC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CN(C(N)=O)C3)ccc2n1CC1CC1
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To the solution of 5-(azetidin-3-ylmethylsulfonyl)-1-(cyclopropylmethyl)-2-neopentyl-1H-benzo[d]imidazole (STEP F, 350 mg, 0.780 mmol) and triethylamine (395 microL, 2.81 mmol) in dichloromethane (5 mL) was added trimethylsilyl isocyanate (162 microL, 1.02 mmol) at room temperature. The resulting solution was stirred for 1 h. The reaction mixture was concentrated in vacuo. The residue was extracted with ethyl acetate (15 mL) and washed with water (30 mL). The organic layer was dried over magnesium sulfate. The crude product was purified with silica gel column chromatography (ethyl acetate-methanol=100:1 to 100:8) to give the title compound (198 mg, 61%).
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[CH:7]2[CH2:10][C:5]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)([CH2:6]2)[C:4]1=[O:20])[CH3:2]>CO.[Pd]>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:5]23[CH2:6][CH:7]([CH2:10]2)[C:8](=[O:9])[N:3]([CH2:1][CH3:2])[C:4]3=[O:20])=[CH:16][CH:15]=1
Reactant: CCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CO
Product: CCN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 1a, 2.33 g of 3-ethyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 70 ml of methanol are hydrogenated in the presence of 0.15 g of palladium-on-carbon and worked up. Melting point 159°-162° (from ethyl acetate/petroleum ether).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH:14]1[N:19]=[C:18](Cl)[C:17]2[N:21]=[CH:22][N:23]([C@@H:24]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:26]([OH:31])[C@H:25]3[OH:32])[C:16]=2[N:15]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][O:12][NH:13][C:18]2[C:17]3[N:21]=[CH:22][N:23]([C:16]=3[N:15]=[CH:14][N:19]=2)[C@@H:24]2[O:28][C@H:27]([CH2:29][OH:30])[C@@H:26]([OH:31])[C@H:25]2[OH:32])=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CONc2ncnc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1

Procedure:
The title compound was prepared according to Method A described above (R2, R3 =H) by reacting O-[(4-nitrophenyl)methyl]hydroxylamine hydrochloride (1.43 g, 7 mmol) with 6-chloropurine riboside (i.e. 9-β-D-ribofuranosyl-6-chloro-9H-purine) (1.0 g, 3.5 mmol) in DMF (40 ml) at 110° C. for 2 h with diisopropylethylamine (1.80 g, 14 mmol) present. The reaction mixture was evaporated and to the resultant residue was added saturated sodium bicarbonate solution (20 ml) and water (20 ml). Methanol was gradually added until the residue dissolved, and the solid which gradually precipitated was removed by filtration. The flitrate was concentrated to a residue which was purified by flash chromatography on silica gel. Elution with ethyl acetate/ethanol (30/1) initially, followed by a (8/1) mixture of these solvents provided a solid which was recrystallized from ethanol. The first crop of material was discarded, but the second crop was confirmed as the title compound (70 mg, 7%) mp 115°-117 ° C. TLC rf 0.20 [SiO2, ethyl acetate/methanol (9/1)]; 1H NMR (DMSO-d6)γ 3.46-3.57 (2H, m, H-5'a and H-5'b), 3.90 (1H, q, H-4'), 4.08 (1H, q, H-3'), 4.43 (1H, q, H-2'), 5.07 (1H, t, 5'-OH), 5.44, 5.74 (2H, 2d, 2'and 3'-OH), 5.82 (1H, d, H-1'), 7.67 (2H, d, Ar-H), 8.08 (1h, s, H-8), 8.22 (2H, d, Ar-H), 9.34 (1H, br s, N-H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][C@@H:6]1[C@H:9]([NH:10][C:11](=[O:38])/[C:12](=[N:26]\[O:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])/[C:13]2[N:14]=[C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[S:16][CH:17]=2)[C:8](=[O:39])[NH:7]1.C1N=CN([C:45](N2C=NC=C2)=[O:46])C=1>C(Cl)(Cl)Cl.CCOC(C)=O>[C:22]([O:21][C:19]([NH:18][C:15]1[S:16][CH:17]=[C:13](/[C:12](=[N:26]/[O:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])/[C:11](=[O:38])[NH:10][C@H:9]2[C@@H:6]([CH2:5][N:4]3[CH2:3][CH2:2][NH:1][C:45]3=[O:46])[NH:7][C:8]2=[O:39])[N:14]=1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CNCCN)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CN2CCNC2=O)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of tert-Butyl 2-(((Z)-(2-(((2R,3S)-2-(((2-aminoethyl)amino)methyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (100 mg, 0.151 mmol) in chloroform (756 μl) was added CDI (98 mg, 0.604 mmol) followed by TEA (105 μl, 0.756 mmol). After stirring at rt for 1 h it was diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound (73 mg, 81%) as a white solid. It was used as crude in step 4. LCMS: Rt=0.70 min, m/z=596.2 (M+1) Method 2m_acidic.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Br:9])=[CH:4][C:3]=1[CH2:10]O.[CH3:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:21])=O)[CH:16]=[C:15]([CH3:22])[CH:14]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[Br:9][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[Cl:8])[N:1]=[C:19]([C:17]1[CH:18]=[C:13]([CH3:12])[CH:14]=[C:15]([CH3:22])[CH:16]=1)[CH:21]=[CH:10]2
Reactant: Nc1cc(Cl)c(Br)cc1CO
Reactant: CC(=O)c1cc(C)cc(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(-c2ccc3cc(Br)c(Cl)cc3n2)c1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
(2-amino-5-bromo-4-chlorophenyl)methanol (8.2 g, 34.7 mmol), 3,5-dimethylacetophenone (8.22 g, 55.5 mmol), RuCl2(PPh3)3 (0.15 g, 0.173 mmol), and KOH (1.31 g, 23.4 mmol) was refluxed in 90 mL of toluene for 18 hours. Water was collected from the reaction using a Dean-Stark trap. The reaction mixture was allowed to cool to room temperature and filtered through a silica gel plug and eluted with DCM and purified by column chromatography, eluting with 2:1 (v/v) hexanes:DCM, to give 6-bromo-7-chloro-2-(3,5-dimethylphenyl)quinoline (5.2 g, 43.3%).
Reaction SMILES: [CH2:1]([NH:3][S:4]([CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)(=[O:6])=[O:5])[CH3:2].[S-:21][C:22]#[N:23].[K+].BrBr.[ClH:27]>C(O)(=O)C.C(O)C>[ClH:27].[CH2:1]([NH:3][S:4]([CH2:7][CH2:8][N:9]1[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][C:11]=2[S:21][C:22]1=[NH:23])(=[O:5])=[O:6])[CH3:2]
Reactant: CCNS(=O)(=O)CCNc1ccc(OC(F)(F)F)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCNS(=O)(=O)CCn1c(=N)sc2cc(OC(F)(F)F)ccc21

Procedure:
The procedure is as in Example 3, starting with N-ethyl-2-(p-trifluoromethoxyanilino)ethanesulphonamide (6.1 g), potassium thiocyanate (7.6 g) and bromine (3.6 g) in acetic acid (60 cc). After 18 hours at a temperature in the region of 20° C., neutralization with 30% strength sodium hydroxide and extraction with ethyl acetate, a crude product is obtained, which product is converted to a hydrochloride by adding 4.2N ethereal hydrogen chloride (5 cc) in ethanol (30 cc) and recrystallized in absolute ethanol (50 cc). N-Ethyl-2-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanesulphonamide hydrochloride (3.0 g), m.p. 240° C., is thereby obtained.