Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:13]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])C(=O)[C:5]=2[N:4]=[CH:3][CH:2]=1.Cl>[OH-].[Na+]>[N:9]1[C:8]2[C:7](=[O:15])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][N:4]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1C(=O)c2ncccc2-c2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1c2ncccc2-c2cccnc21
Reaction time: 2 h
Yield: 30.4 %

Procedure:
To a solution of 200 ml of 10% sodium hydroxide was added 10 g (47 mmole) of 4,7-phenanthrolin-5,6-quinone. This was heated in a water bath at 70°-80° with magnetic stirring for 2 hours. Then the reaction was cooled in an ice bath and acidified with concentrated hydrochloric acid to pH 4-5, keeping the mixture below 20°. The precipitate of side product, 5,7-dihydroxy-4,7-phenanthroline was filtered off and the filtrate was extracted with 5×50 ml of chloroform. After drying with sodium sulfate, the solvent was evaporated, yielding 2.6 g of 1.8-diazafluoren-9-one, m.p. 233°-234.5°.
Reaction SMILES: [CH:1]12[N:8]([C:9]3[CH:14]=[C:13]([CH2:15][N:16]([CH3:18])[CH3:17])[N:12]=[C:11]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH:29]5[CH2:31][CH2:30]5)=[O:27])=[CH:21][CH:20]=4)[N:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.[CH3:32][N:33]([CH2:35][C:36]1C=CC(NC(NC2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=O)=[CH:38][CH:37]=1)[CH3:34]>>[CH:5]12[N:8]([C:9]3[CH:14]=[C:13]([CH2:15][N:16]([CH3:17])[CH3:18])[N:12]=[C:11]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]5[CH:38]=[CH:37][C:36]([CH2:35][N:33]([CH3:34])[CH3:32])=[CH:30][CH:31]=5)=[O:27])=[CH:21][CH:20]=4)[N:10]=3)[CH:1]([CH2:7][CH2:6]1)[CH2:2][O:3][CH2:4]2
Reactant: CN(C)Cc1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: CN(C)Cc1cc(N2C3CCC2COC3)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Product: CN(C)Cc1ccc(NC(=O)Nc2ccc(-c3nc(CN(C)C)cc(N4C5CCC4COC5)n3)cc2)cc1

Procedure:
A procedure analogous to that used for the preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-cyclopropylurea was used, using 1-(4-((dimethylamino)methyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as the boronic ester component. Yield=0.070 g, 39%. MS; 516.5, M+H.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[C:6](OCC)=[O:7])C.[Li+].[BH4-].Cl>C1COCC1.C1(C)C=CC=CC=1>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([CH:5]([CH2:4][OH:3])[CH2:6][OH:7])[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C(C(=O)OCC)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C(CO)CO)CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
To a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)malonic acid diethyl ester (14.6 g, 0.043 mol) in anhydrous THF (100 mL) and anhydrous toluene (100 mL), LiBH4 (2.1 g. 0.96 mol) was added portion wise. The resulting mixture was heated at 60° C. for 17 h, then stirred at ambient temperature for 24 h. The reaction mixture was slowly added to aqueous HCl (0.1 M, 350 mL) and then extracted with EtOAc. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc: MeOH 100:0 to 98:2 to 95:5 to 90:10 to 80:20) to afford the title compound as a colourless oil (6.91 g, 63%). 1H NMR (CDCl3, 400 MHz) δ 3.90-3.75 (m, 4H); 2.75-2.58 (m, 4H); 1.77-1.61 (m, 4H); 1.52 (m, 1H); 1.45 (s, 9H) and 1.26-1.13 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:7][S:8]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:4]([OH:6])=[O:5].[ClH:21].[CH2:22](O)[CH3:23]>>[ClH:21].[NH2:1][CH2:2][C@H:3]([NH:7][S:8]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:4]([O:6][CH2:22][CH3:23])=[O:5]
Reactant: CCO
Reactant: NC[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)O
Agent: Cl
Product: CCOC(=O)[C@H](CN)NS(=O)(=O)c1cccc2ccccc12
Temperature: 35 °C

Procedure:
147.2 g (0.5 mol) of (2S)-3-amino-2-(naphthalene-1-sulfonylamino)propionic acid were suspended in 1 l of ethanol and hydrogen chloride gas was introduced into the mixture for about 2 h whereupon the temperature increased to about 35° C. and a clear solution was obtained. Then the mixture was evaporated in vacuo in a rotary evaporator. The residue was dissolved in hot ethanol and diisopropyl ether was added until precipitation of the product started. The product was allowed to crystallize overnight at room temperature. The title hydrochloride was filtered off, washed with diisopropyl ether and dried in vacuo. Yield: 148 g (83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C@H:12]1[N:20]([C:21](=[O:43])[C@@H:22]([NH:29][C:30](=[O:42])[C@@H:31]([N:33](C)[C:34](=O)OC(C)(C)C)[CH3:32])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C@H:12]1[N:20]([C:21](=[O:43])[C@@H:22]([NH:29][C:30](=[O:42])[C@@H:31]([NH:33][CH3:34])[CH3:32])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11]
Reactant: Cc1cccc(F)c1NC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1c(C)cccc1F)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
In a 50 mL round-bottomed flask, tert-butyl (S)-1-((S)-2-((S)-2-(2-fluoro-6-methylphenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylamino)-1-oxopropan-2-yl(methyl)carbamate (30 mg, 50.2 μmol, Eq: 1.00) was combined with DCM (3 mL) to give a colorless solution. TFA (1 mL, 13.0 mmol, Eq: 259) was added and the reaction was stirred at rt for 30 min. The reaction mixture was concentrated in vacuo and the residue was treated with saturated aqueous NaHCO3 (10 mL). The resulting mixture was extracted with DCM (2×10 mL), the combined organic layers dried over Na2SO4, and then concentrated in vacuo to give (S)-1-[(S)-2-((S)-2-methylamino-propionylamino)-2-(tetrahydro-pyran-4-yl)-acetyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2-fluoro-6-methyl-phenyl)-amide (13 mg), m/z=498 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]([OH:30])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Br[CH:32]([CH:34](Br)[CH3:35])[CH3:33]>C(O)(C)C>[OH:30][C:9]1[C:10]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:2]([N:1]2[CH2:35][CH2:34][CH2:32][CH2:33]2)=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: Nc1cc(C(NC(=O)COc2ccccc2)c2ccccc2)c(O)c2ncccc12
Reactant: CC(Br)C(C)Br
Solvent: CC(C)O
Product: O=C(COc1ccccc1)NC(c1ccccc1)c1cc(N2CCCC2)c2cccnc2c1O

Procedure:
N-[(5-amino-8-hydroxyquinolin-7-yl)(phenyl)methyl]-2-phenoxyacetamide (200 mg, 0.5 mmol), dibromobutane (0.1 ml), TEA (0.2 ml) in isopropanol were heated at reflux for 16 h. The reaction mixture was concentrated in vacuo, the residue dissolved in methylene chloride, washed with brine. The organic layer was dried over sodium sulfate and filtered. To the filtrate was added 1M HCl/ether, the solids filtered, washed with ether to give N-[(8-hydroxy-5-pyrrolidin-1-ylquinolin-7-yl)(phenyl)methyl]-2-phenoxyacetamide as a purple solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[NH:8])[NH2:7])[CH3:2].C(N(CC)CC)C.Br[CH:18]([CH3:22])[C:19](=O)[CH3:20]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:19]([CH3:20])=[C:18]([CH3:22])[NH:8][C:6]=1[NH2:7])=[O:9])[CH3:2]
Reactant: CC(=O)C(C)Br
Reactant: CCOC(=O)CC(=N)N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(N)[nH]c(C)c1C
Temperature: 5 °C
Yield: 35 %

Procedure:
To a solution of Carbamimidoyl-acetic acid ethyl ester (0.5 g) in ethyl acetate (6 mL) was added triethylamine (0.5 mL) and mixture was stirred at 5° C. Than 3-Bromo-butan-2-one (0.4 mL) was added under a nitrogen atmosphere and the mixture was refluxed for 1 h. The reaction mixture was then filtered through a medium porosity fitted glass funnel containing a thin layer of silica gel. The filtrate was washed with 100 mL of ethyl acetate and the combined washes were then evaporated under reduced pressure to give (0.25 g, 35%) of 2-Amino-4,5-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester [MH]+=183.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:23]=1.ClCCl.[I-].C(OC([N:35]1[CH2:38][CH:37]([Zn+])[CH2:36]1)=O)(C)(C)C.Cl>CN(C)C(=O)C.[Cu]I>[NH:35]1[CH2:38][CH:37]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[N:19]([CH:20]([CH3:21])[CH3:22])[N:18]=[CH:17][N:16]=5)=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:23]=2)[CH2:36]1
Reactant: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)(C)OC(=O)N1CC([Zn+])C1
Agent: [Cu]I
Agent: Cl
Agent: [I-]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(C3CNC3)cc1OCC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 11.4 %

Procedure:
Following the procedure for 419, 5-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-1-isopropyl-1H-1,2,4-triazole (313.4 mg, 0.803 mmol) was dissolved in N,N-dimethyacetamide and purged with nitrogen. Added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (32.8 mg, 0.04 mmol) and copper(I)iodide (15.3 mg, 0.08 mmol). Bubbled in nitrogen for 10 minutes. Added (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide (279.8 mg, 0.80 mmol) in 2.8 mL DMA. Heated at 80° C. overnight. Complete reaction was confirmed by LCMS. Diluted reaction mixture with 1 M HCl and extracted tert-butyl 3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)azetidine-1-carboxylate with ethyl acetate. Dried over magnesium sulfate and concentrated in vacuo. Purified by flash chromatography (0 to 50% ethyl acetate in hexanes). Concentrated in vacuo and re-dissolved the residue in 10 mL 1,4-dioxane. Added 5 mL 4 N HCl in dioxane and let stir for 2 hours. Complete deprotection was confirmed by LCMS. Concentrated in vacuo purified by HPLC to give 370 (33.3 mg, 11% yield, M=1 367.1)
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([C:27]#[N:28])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:33]([NH2:36])([CH3:35])[CH3:34]>C(#N)C.O>[CH:33]([NH:36][C:21]([C:20]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:29]([F:30])([F:31])[F:32])[CH:11]=2)=[O:22])=[C:16]([C:27]#[N:28])[CH:17]=[C:18]2[C:19]=1[NH:24][N:25]=[CH:26]2)=[O:23])([CH3:35])[CH3:34]
Reactant: CC(C)N
Reactant: N#Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: CC#N
Solvent: O
Product: CC(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)c(C#N)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 600 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-9-oxo-1,9-dihydro-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalene-5-carbonitrile in 5 mL of acetonitrile/water (4:1, v/v) is added 1.1 mL (12.9 mmol) of isopropylamine. The reaction mixture is stirred during 4 hours at ambient temperature and then concentrated in vacuo. After purification by flash chromatography (SiO2, hexanes/ethyl acetate 4:1), 250 mg (38%) of a white solid are obtained; LC/MS:518/520 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.Br[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2=O
Reactant: BrCCCc1ccccc1
Product: COc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O

Procedure:
6-Methoxy-1-oxo-1,2,3,4-tetrahydroisoquinoline (example 1 ) is condensed with 1-bromo-3-phenylpropane under N-alkylation conditions described in example 1 to yield 6-methoxy-2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[SH:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:17]([CH2:21][CH3:22])[C:18](Br)=[O:19]>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:18](=[O:19])[CH:17]([CH2:21][CH3:22])[S:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1S
Reactant: CCC(Br)C(=O)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC1Sc2cc(Br)ccc2NC1=O
Temperature: 25 °C
Yield: 13.6 %

Procedure:
To a mixture of 2-amino-5-bromo-benzenethiol (20 g, 0.1 mol) and cesium carbonate (33 g, 0.1 mol) in DMF (500 ml) at −35° C. was added dropwise 2-bromobutyrylbromide (23 g, 0.1 mol). The mixture was allowed to warm to room temperature, poured into ice/water, and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with water, then brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, ethyl acetate:hexane/1:6) to afford 7-bromo-2-ethyl-4H-benzo[1,4]thiazin-3-one (3.7 g, 14%): mp 100° C.; MS (EI) m/z 271/273(M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45]2[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=2)=[CH:27][CH:26]=1>CCOCC>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45]2[CH:46]=[CH:47][C:48]([C:49]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:50])=[CH:52][CH:53]=2)=[CH:29][CH:30]=1
Reactant: C1CCNCC1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1)N1CCCCC1
Temperature: 25 °C

Procedure:
To a chilled solution of 35 ml. of piperidine, 2.5 ml. of triethylamine and 0.6 g. of dimethylaminopyridine in 100 ml. of diethyl ether is added (1/2 hour) a solution of 8.3 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl chloride hydrochloride in 50 ml. of ether. The solution is warmed to room temperature and maintained there for two hours. The solution is heated to reflux for an additional 2 hours at which time the reaction is complete. The solution is cooled, extracted twice with water and dried. The solvent is removed in vacuo and the solid is recrystallized from diethyl ether to yield 1-{4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl}piperidine.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[C:23]2[C:5]([CH2:6][C:7]3([C:16]42[NH:20][C:19](=S)[C:18]([CH3:22])=[N:17]4)[CH2:12][CH2:11][CH:10]([CH:13]([F:15])[F:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:25]>>[Br:1][C:2]1[CH:24]=[C:23]2[C:5]([CH2:6][C:7]3([C:16]42[N:20]=[C:19]([NH2:25])[C:18]([CH3:22])=[N:17]4)[CH2:12][CH2:11][CH:10]([CH:13]([F:15])[F:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: N
Reactant: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCC(C(F)F)CC1
Product: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC(C(F)F)CC1
Temperature: 110 °C
Yield: 41.5 %

Procedure:
6′-Bromo-4-(difluoromethyl)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 128 Step 3, 0.3 g, 0.73 mmol) was taken up in ammonia (7 M in MeOH) (6.22 mL, 43.6 mmol) and the resulting mixture was heated in the microwave reactor at 110° C. for 30 min. The solvent was evaporated. The same amount of ammonia was added and the mixture was heated and concentrated (5 times). The crude material was dissolved in EtOAc. Aq. citric acid solution (0.1 M) was added and the phases were separated. The citric acid phase was basified with 1 M NaOH and extracted with DCM twice. The combined DCM extracts were concentrated to give the title compound (0.120 g, 42% yield). 20 mg of the product was purified by preparative chromatography to give 11 mg of the title compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.19-1.31 (m, 3 H), 1.34-1.48 (m, 3 H), 1.66-1.82 (m, 2 H), 1.90 (d, 1 H), 2.20 (s, 3 H), 2.80-2.95 (m, 2 H), 5.53-5.97 (m, 1 H), 6.53 (s, 2 H), 6.59 (s, 1 H), 7.21 (d, 1 H), 7.33 (d, 1 H); MS (ES+) m/z 396 [M+H]+.
Reaction SMILES: [C:1](O)(=O)[CH3:2].[NH2:5]/[C:6](=[N:18]\[OH:19])/[C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:9])[CH3:8]>CN(C=O)C>[CH3:1][C:2]1[O:19][N:18]=[C:6]([C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])([CH3:9])[CH3:8])[N:5]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)/C(N)=N/O
Reactant: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1nc(C(C)(C)NC(=O)OC(C)(C)C)no1
Temperature: 120 °C
Reaction time: 10 h
Yield: 79.8 %

Procedure:
To a solution of acetic acid (1.8 g) in DMF (50 mL) was added N,N′-carbonyldiimidazole (CAN 530-62-1, 4.865 g, mmol). The solution was stirred at ambient temperature for 0.5 h. (Z)-tert-butyl 1-amino-1-(hydroxyimino)-2-methylpropan-2-ylcarbamate (6.07 g) was added and the reaction mixture was stirred at 120° C. for 10 h. Removal of the solvent under reduced pressure left a yellow oil which was purified by column chromatography (silica gel 120 g, eluting with 30% ethyl acetate in petroleum ether) to give the title compound (5.38 g, 80%) as colorless oil; MS: m/e=264.1 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[C:15](=[O:16])[CH2:14][CH:13]2[CH2:12][NH:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[CH:17]1([CH2:20]Br)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH:17]1([CH2:20][N:11]2[CH2:10][C:9]3([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:13]([CH2:14][C:15]3=[O:16])[CH2:12]2)[CH2:19][CH2:18]1
Reactant: COc1cccc(C23CNCC2CC3=O)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc(C23CN(CC4CC4)CC2CC3=O)c1

Procedure:
In the manner of Example 8, 5-(m-methoxyphenyl)-3-azabicyclo[3.2.0]heptan-6-one, dimethyl acetal, can be reacted with cyclopropylmethyl bromide and sodium carbonate in toluene to give 3-cyclopropylmethyl-5-(m-methoxyphenyl)-3-azabicyclo[3.2.0]heptan-6-one, dimethyl acetal.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[I:12]Cl.O>CC(O)=O>[I:12][C:9]1[CH:10]=[C:4]([O:3][CH:2]([F:11])[F:1])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: ClI
Reactant: Nc1ccc(OC(F)F)cc1
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(OC(F)F)cc1I
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 22.3 %

Procedure:
A solution of 4-(difluoromethoxy)aniline (1.0 g, 6.30 mmol) in AcOH (6 mL) was heated to 60° C. and iodine monochloride (1.07 g, 6.6 mmol) in AcOH (15 mL) was added dropwise. The reaction mixture was then heated to 85° C. and stirred for 1.5 h. The reaction mixture was cooled to r.t. and poured into cold water and the resulting suspension filtered. The filtrate was concentrated in vacuo to give a dark brown oil. Purification by column chromatography (SiO2, 10-20% EtOAc/hexanes) gave the title compound (0.40 g, 22%) as a dark brown oil. δH (DMSO-d6) 7.38 (1H, d, J 2.7 Hz), 6.98-6.94 (1H, m), 6.97 (1H, t, J 74.8 Hz), 6.75 (1H, d, J 8.8 Hz), 5.20 (2H, br. s). LCMS (ES+) 286.0 (M+H)+, RT 3.28 minutes (Method 5).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[Cl:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3Cl)[C@H:12]([OH:25])[C@@H:11]1[OH:26]>C(O)(C)C>[OH:14][C@@H:13]1[CH2:12][CH2:11][CH2:7][C@H:6]1[NH:3][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[C:21]=1[N:22]=[CH:23][N:15]2[CH:13]1[C@H:12]([OH:25])[C@H:11]([OH:26])[C@@H:10]([CH2:9][Cl:8])[O:14]1
Reactant: O[C@@H]1[C@H](O)[C@@H](CCl)O[C@H]1n1cnc2c(Cl)ncnc21
Reactant: CCN(CC)CC
Solvent: CC(C)O
Product: O[C@@H]1[C@@H](CCl)OC(n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 309.8 %

Procedure:
To a suspension of (R,R)-2-aminopentanol hydrochloride (34.2 g, 249 mmol) in degassed isopropanol (100 ml) and distilled triethylamine (dried over calcium hydride, 95 ml, 69 g, 226 mmol) was added dropwise a solution of (4S,5S,2R,3R)-5-(chloromethyl)-2-(6-chloropurin-9-yl)oxolane-3,4-diol (36.3 g, 118.7 mmol) in 400 ml of isopropanol. The reaction mixture was stirred at room temperature for 30 minutes, and then refluxed (oil bath temperature: ˜80° C.) for 20 hours. After cooling the reaction mixture to ambient temperature, the solvent was removed under reduced pressure, and 1000 ml of water was added to the residue. The suspension was stirred at room temperature for 3.5 hours, and the solid material filtered off, washed with water (1×60 ml and 1×90 ml), and dried under vacuum over P2O5 for 3 days to yield 68.0 g (81%) of 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]purin-9-yl}(4S,5S,3R)-5-(chloromethyl)oxolane-3,4-diol as a light brown powder.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].[O:7](C(OC(C)(C)C)=O)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=O>ClCCl>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:8](=[O:7])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: NCCCBr
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCBr

Procedure:
Prepared from 3-bromopropylamine hydrobromide and BOC2O in the presence of base in dichloromethane, 9.89 mmol: 1H NMR (CDCl3) δ 5.07 (br, 1H), 3.31 (t, 2H, J=6.6 Hz), 3.12 (apparent br q, 2H, J=6.0 Hz), 1.92 (p, 2H; J=6.6 Hz), 1.30 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][C:18]1([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O>CS(C)=O>[CH3:17][C:18]1([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COC(=O)CC1(C)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CC1(C)CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 60 °C
Yield: 67.2 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (2.97 g, 18.77 mmol) in DMSO (30 mL) was added sodium carbonate (6.4 g, 60.38 mmol) followed by methyl (4-methylpiperidin-4-yl)acetate (3.21 g, 18.77 mmol) (prepared according to the procedures described by Janet Ralbovsky, Joseph Lisko and Wei He, Synthetic Communications, 2005, 35 (12), 1613-1625 and Gerhard Hund, and Woldemar Schneider, Chem Ber 1980,113 (2), 401-7). The reaction mixture was heated to 60° C. for 1.5 hours, then allowed to cool and water (100 mL) was added. The suspension filtered, and dried to leave a yellow solid (3.70 g, 12.62 mmol, 67%). 1H NMR δ 1.08 (s, 3H), 1.45-1.48 (m, 2H), 1.55-1.61 (m, 2H), 2.38 (s, 2H), 3.59 (s, 3H), 3.64-3.70 (m, 2H), 3.85-3.91 (m, 2H), 6.95 (d, 1H), 8.19 (d, 1H), 8.95 (s, 1H); MS m/e MH+ 294.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[F:12])=[O:4].CCN(CC)CC.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[S:22]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH:2]([F:1])[F:13])=[C:6]([F:12])[CH:7]=1)(=[O:23])=[O:21]
Reactant: O=C(c1ccc(O)cc1F)C(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(OS(=O)(=O)C(F)(F)F)cc1F)C(F)F

Procedure:
To 2,2-difluoro-1-(2-fluoro-4-hydroxyphenyl)ethanone (39.0 g, 0.2 mol) and Et3N (20.7 g, 0.2 mol) in CH2Cl2 at 0° C. was added Tf2O (58 g, 0.2 mol) dropwise while keeping the temperature at 0° C. The ice-salt bath was removed, and when the temperature rose to 25° C., a solution of saturated NaHCO3 was added. The aqueous phase was extracted with CH2Cl2 and the combined extracts were dried over MgSO4, and concentrated, and the residue was purified by column chromatography (PE/EA 10:1) to afford 4-(difluoroacetyl)-3-fluorophenyl trifluoromethanesulfonate as an brown oil.