Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][OH:23].O>CC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:21][CH2:22][OH:23])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: OCCBr
Reactant: Brc1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: OCCN1CCN(c2ncc(Br)cn2)CC1
Yield: 46.2 %

Procedure:
To a solution of 5-bromo-2-(piperazin-1-yl)pyrimidine (0.20 g, 0.83 mmol) in acetone (10.0 mL) was added K2CO3 (0.58 g, 4.17 mmol) followed by the addition of 2-bromoethanol (0.01 g, 1.66 mmol). The resulting reaction mixture was heated to reflux for 3 h. After the completion of reaction (TLC monitoring), the reaction mixture was cooled, added water and extracted with EtOAc (2×100 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (100-200 M, 2% MeOH-DCM) to obtain the desired product (0.11 g, 47%). MS: 287.10 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.Cl.[CH:38]1([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:44]4[CH2:45][CH2:46][N:41]([CH:38]5[CH2:40][CH2:39]5)[CH2:42][CH2:43]4)=[CH:19][C:18]=3[C:24]([F:25])([F:26])[F:27])(=[O:15])=[O:16])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:31][C:32]([F:35])([F:34])[CH2:33]2)=[O:29])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: C1CN(C2CC2)CCN1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(N4CCN(C5CC5)CC4)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to Example 127 using (1R,2R,4R)-2-(3,3-Difluoro-azetidine-1-carbonyl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 118) and 1-cyclopropylpiperazine-bis-hydrochloric acid. White solid. MS (EI): 630.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[C:11]([NH:14][C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[N:21]1([C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH:28]=O)[CH:25]=[N:24][CH:23]=[N:22]1.N1CCC[C@H]1C(O)=O>CO>[CH3:18][C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:20]=[C:28]1[C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)([CH3:19])[CH2:16][CH3:17]
Reactant: CCC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: O=Cc1ccccc1-n1cncn1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CO
Product: CCC(C)(C)n1c(-c2ccccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 25 °C

Procedure:
A reaction mixture of 4-(2-amino-pyrimidin-5-yl)-N1-(1,1-dimethyl-propyl)-benzene-1,2-diamine (130 mg, 0.48 mmol), 2-1,2,4-triazol-1-yl-benzaldehyde (110 mg, 0.64 mmol) and L-proline (5 mg) in MeOH (25 mL) is refluxed for 16 hours. The reaction mixture is allowed to cool to room temperature and is concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography with 8% MeOH in CH2Cl2 as the eluent to afford 5-[1-(1,1-dimethyl-propyl)-2-(2-1,2,4-triazol-1-yl-phenyl)-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine. LCMS (ESMS): m/z 425.20 (M++1)
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.[Cl-].[NH4+]>CS(C)=O>[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][C:2]([CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([Br:14])[CH:16]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCc1cccc(Br)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CCOC(=O)C(Cc1cccc(Br)c1)(Cc1cccc(Br)c1)C(=O)OCC
Yield: 85 %

Procedure:
Diethyl malonate (4.53 mL, 30.0 mmol) was added gradually at 0° C. to a mixed liquid containing sodium hydride (55 wt % in oil, 2.95 g, 67.5 mmol) and anhydrous dimethylsulfoxide (60 mL). Following stirring of the resulting mixed liquid at this temperature for 30 minutes, 3-bromobenzyl bromide (15.7 g, 63.0 mmol) was added. The resulting mixed liquid was stirred at room temperature for 2 hours, and a saturated aqueous solution of ammonium chloride was then added to halt the reaction. The organic layer was separated from the mixed liquid, and the water layer was extracted with ethyl acetate. The thus obtained organic layer was washed with a saturated saline solution and then dried using anhydrous magnesium sulfate. The organic layer was then filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:1), yielding the title compound (4c) (12.7 g, 25.5 mmol) as a white solid in a yield of 85%.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:26])=[CH:5][C:6](F)=[C:7]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH:17]3[CH2:19][CH2:18]3)[C:13]3=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:12]3[N:11]=2)[CH:8]=1)#[N:2].[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]1>>[C:1]([C:3]1[C:4]([F:26])=[CH:5][C:6]([O:35][CH2:34][CH2:33][N:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)=[C:7]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH:17]3[CH2:18][CH2:19]3)[C:13]3=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:12]3[N:11]=2)[CH:8]=1)#[N:2]
Reactant: OCCN1CCOCC1
Reactant: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(F)cc1F
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(OCCN2CCOCC2)cc1F

Procedure:
The title compound was obtained as the major product (34% yield) from the reaction between 2-((5-cyano-2,4-difluorophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 414) and 2-morpholinoethanol according to the procedure described in Example 419.
Reaction SMILES: [O-]CC.[Na+].[N+:5]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6].C1(C)C=CC(S(O[CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)(=O)=O)=CC=1>CN(C)C=O.O>[CH:28]1([O:27][CH2:26][CH2:25][O:14][C:10]2[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:13]=[CH:12][CH:11]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CCCCC2)cc1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(OCCOC2CCCCC2)c1
Temperature: 100 °C
Yield: 95.6 %

Procedure:
To a solution of 6.8 g of sodium ethoxide and 15 g of m-nitrophenol in 250 ml of dimethylformamide, 28 g of cyclohexyloxyethyl p-toluenesulfonate were added. After heating at 100° C. for 2 hours, the resulting mixture was diluted with water and extracted with benzene. The solvent was removed under reduced pressure, and the residue was purified by vacuum distillation to give 23.8 g of 3-[2-(cyclohexyloxy)ethoxy]nitrobenzene. B.P., 118°-124° C./0.1 mmHg. nD27 1.5380.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21]>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]([OH:21])[CH2:7][C:5]2[O:4][N:3]=[C:2]([CH3:1])[CH:6]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: Cc1cc(C)on1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CC(O)c2cccc(Cl)c2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-dimethylisoxazole (104 g, 1.07 mol, 1 eq) in THF (1 L) cooled to −78° C. under nitrogen, a solution of lithiumdiisopropylamide (1.8 M ethylbenzene in THF) (630 mL, 1.134 mol, 1.06 eq) was added dropwise. After 1 hr, a solution of 3-chlorobenzaldehyde 100 g, 0.711 mole, 0.66 eq) in THF (300 mL) was added drop wise at −78° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. It was cooled to 0° C., and quenched by saturated ammonium chloride solution (130 mL). The organic layer was concentrated to dryness. Water (1 L) was added to the residue was extracted with ethyl acetate (2×1 L). Combined organic extracts were washed with brine (700 mL) dried over anhydrous sodium sulfate. Concentrated and purified by column chromatography (50% ethyl acetate in hexane) over silica gel using a mixture of ethyl acetate and hexanes as eluant. The title compound was obtained as viscous brown oil (120 g, 0.507 mol, 48%).
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:17]=[C:16]2[C:7]([C:8](=[O:18])[O:9][C:10]32[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:6][CH:5]=1)[CH3:3].[C:19]1([C:25]2[N:26]=[CH:27][C:28]([NH:31][C:32](=O)[O:33]C3C=CC=CC=3)=[N:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>CS(C)=O>[CH2:2]([C:4]1[CH:17]=[C:16]2[C:7]([C:8](=[O:18])[O:9][C:10]32[CH2:11][CH2:12][N:13]([C:32]([NH:31][C:28]2[CH:27]=[N:26][C:25]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:30][N:29]=2)=[O:33])[CH2:14][CH2:15]3)=[CH:6][CH:5]=1)[CH3:3]
Reactant: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Reactant: CCc1ccc2c(c1)C1(CCNCC1)OC2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCc1ccc2c(c1)C1(CCN(C(=O)Nc3cnc(-c4ccccc4)cn3)CC1)OC2=O
Reaction time: 0.08 h
Yield: 54.2 %

Procedure:
To a suspension of 6-ethylspiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (53 mg) and phenyl N-(5-phenyl-2-pyrazinyl)carbamate (58 mg) in dimethyl sulfoxide (1 mL) was added 10 M sodium hydroxide aqueous solution (0.02 mL). The mixture was vigorously stirred for 5 minutes followed by partition between water and ethyl acetate. The organic layer was separated and then washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the organic solvent left a residue, which was subjected to the crystallization from ethyl acetate to give the subject compound (46 mg) as crystals (melting point 176-178° C.).
Reaction SMILES: [CH2:1]([N:5]([CH2:11][CH:12]=O)[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH:2]=[CH:3][CH3:4].C([O-])(=O)C.[Na+].Cl.[CH3:20][NH:21][OH:22]>O1CCOCC1.O>[CH3:20][N:21]1[O:22][CH:3]([CH3:4])[CH:2]2[CH:12]1[CH2:11][N:5]([C:6]([O:7][CH2:8][CH3:9])=[O:10])[CH2:1]2
Reactant: CC=CCN(CC=O)C(=O)OCC
Reactant: CNO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)N1CC2C(C)ON(C)C2C1

Procedure:
18.4 g (0.1 mol) of ethyl N-(but-2-enyl)-N-(2-oxoethyl)-carbamate are dissolved in 100 ml of dioxane, and 9 g of anhydrous sodium acetate and 9 g (0.108 mol) of N-methylhydroxylamine hydrochloride in 10 ml of water are added. The mixture is heated under reflux overnight and cooled and the salts are filtered off with suction and washed with dioxane. The filtrate is concentrated, the residue is taken up in 100 ml of water and K2CO3 is added. The mixture is extracted with CHCl3, the extract is dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:38]1[CH2:41][CH:40]([C:42]2[C:47]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:46][CH:45]=[CH:44][N:43]=2)[CH2:39]1>CN(C=O)C.O>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]([N:38]1[CH2:39][CH:40]([C:42]2[C:47]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:46][CH:45]=[CH:44][N:43]=2)[CH2:41]1)=[O:12]
Reactant: c1ccc(-c2cccnc2C2CNC2)cc1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1nc2ccccc2[nH]1)N1CC(c2ncccc2-c2ccccc2)C1
Reaction time: 0.08 h
Yield: 36.8 %

Procedure:
To a mixture of 1H-benzoimidazole-2-carboxylic acid (124 mg, 0.76 mmol) in DMF (5 mL) was added TEA (152 mg, 1.5 mmol) and HATU (347 mg, 0.92 mmol). The reaction mixture was stirred for 5 min and 2-azetidin-3-yl-3-phenyl-pyridine hydrochloride (100 mg, 0.76 mmol) was added. The reaction mixture was stirred at RT overnight. The mixture was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography to give (1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyridin-2-yl)-azetidin-1-yl]-methanone (100 mg, 0.28 mmol, 59% yield) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH2:20])=[CH:7]2.Cl[C:22]1[N:27]=[C:26]([O:28][CH3:29])[NH:25][C:24]2=[N:30][CH:31]=[CH:32][C:23]=12.CCN(C(C)C)C(C)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH:20][C:22]1[C:23]3[CH:32]=[CH:31][NH:30][C:24]=3[N:25]=[C:26]([O:28][CH3:29])[N:27]=1)=[CH:7]2
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Reactant: COc1nc(Cl)c2ccnc-2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1nc(NCc2cc3cccc(Cl)c3nc2-c2ccccc2Cl)c2cc[nH]c2n1

Procedure:
Prepared according to Procedure H using (8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methanamine (0.100 g, 0.33 mmol), 4-chloro-2-methoxy-pyrrolo[2,3-d]pyr-imidine (0.061 g, 0.33 mmol, 1 eq) and DIEA (0.07 mL, 0.4 mmol, 1.2 eq) in ethanol (3 mL). N-((8-Chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-2-meth-oxy-7H-pyrrolo[2,3-d]pyrimidin-4-amine [PI3Kδ IC50=5420 nM] was obtained after purification as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.28 (1 H, s), 8.37 (1 H, s), 8.03 (1 H, dd, J=8.4, 1.0 Hz), 7.94-7.99 (1 H, m), 7.94 (1 H, dd, J=7.6, 1.4 Hz), 7.40-7.65 (5 H, m), 6.88 (1 H, dd, J=3.3, 2.2 Hz), 6.47 (1 H, s), 4.59 (2 H, s), 3.67 (3 H, s) Mass Spectrum (ESI) m/e=450.1 and 452.0 (M+1)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)[CH3:2].Br[C:13]1[S:17][C:16]([S:18]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)(=[O:20])=[O:19])=[CH:15][CH:14]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:13]2[S:17][C:16]([S:18]([N:21]3[CH:25]=[CH:24][CH:23]=[CH:22]3)(=[O:19])=[O:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)cc1
Yield: 81 %

Procedure:
N-[5-(4-ethylphenyl)thiophene-2-sulfonyl]pyrrole was prepared, in the same manner as described in Example 13C, from 4-ethylphenylboronic acid and N-(5-bromothiophenesulfonyl)pyrrole. Purification by column chromatography using 10% ethyl acetate/hexanes gave the pure sulfonamide as a tan solid in 81% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5]2.C([Li])CCC.[CH3:35][N:36]1[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]1>C1COCC1>[CH3:35][N:36]1[CH2:41][CH2:40][C:39]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][N:6]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5]3)([OH:42])[CH2:38][CH2:37]1
Reactant: Brc1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccc3c(c2)CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C3)CC1
Reaction time: 0.17 h
Yield: 57 %

Procedure:
Under nitrogen, a solution of 5-bromo-2-trityl-2,3-dihydro-1H-isoindole (2.03 g, 4.6 mmol) in THF (20 mL) was cooled to −78° C. n-Butyllithium solution (2.5M in hexanes, 2.0 mL, 5 mmol) was added over 5 minutes, then after 10 minutes, 1-methyl-4-piperidone was added dropwise. After a further hour, the cooling bath was removed and the reaction quenched with sodium bicarbonate solution. The mixture was extracted with ethyl acetate then the organic phase washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica (gradient elution with 2M methanolic ammonia/dichloromethane, 0% to 5%) to afford 1-methyl-4-(2-trityl-2,3-dihydro-1H-isoindol-5-yl)-piperidin-4-ol as a pink foam (1.25 g, 57%). 1H NMR (MeOH-d4) 7.56 (6H, dd), 7.28 (6H, t), 7.25-7.21 (2H, m), 7.15 (3H, t), 7.03 (1H, d), 3.92 (2H, s), 3.91 (2H, s), 2.70 (2H, d), 2.53 (2H, td), 2.33 (3H, s), 2.06 (2H, td), 1.70 (2H, d). MS: [M+H]+ 475.
Reaction SMILES: [CH:1]1([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:18]/[C:19](/[CH3:25])=[CH:20]/C(OC)=O>>[CH:1]1([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[CH3:15])=[CH:20]/[C:19](=[O:18])[CH3:25])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)/C=C(\C)OC
Reactant: CC(=O)c1ccc(C2CCCCCC2)cc1
Product: CC(=O)/C=C(\C)c1ccc(C2CCCCCC2)cc1
Yield: 28 %

Procedure:
(E)-4-(4-cycloheptyl-phenyl)-3-pentene-2-one was prepared analogous to Example 52 from 4'-cycloheptyl-acetophenone (b.p. 120°-125°C at 0.03 mm Hg) and methyl (E)-3-methoxy-crotonate with a yield of 28% of theory. B.p. 132°-135°C at 0.1 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=[O:8].[N+:15]([O-])([OH:17])=[O:16].S(=O)(=O)(O)O>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[NH:5][C:6]=1[CH:7]=[O:8]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Agent: O=S(=O)(O)O
Product: O=Cc1[nH]c(-c2ccc([N+](=O)[O-])cc2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g of 4-chloro-5-formyl-2-phenylimidazole was added little by little to a mixture of 25 ml each of fuming nitric acid (specific gravity of 1.52) and concentrated sulfuric acid. After addition was completed, the mixture was stirred at room temperature for 1 hour, and poured into 400 ml of ice-water. Recrystallization of the resultant precipitate from 100 ml of dimethylformamide yielded 9 g of 4-chloro-5-formyl-2-(4-nitrophenyl)imidazole as slightly yellow, needle-formed crystals, m.p. of not lower than 300° C.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:24]>>[ClH:24].[ClH:24].[N:17]1([C:14]2[CH:13]=[CH:12][C:11]([C:10]([CH:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[O:23])=[CH:16][CH:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(N3CCCCC3)cc2)CC1
Agent: Cl
Product: O=C(c1ccc(N2CCCCC2)cc1)C1CCNCC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
The 1-acetyl-4-(4-piperidinobenzoyl)piperidine (0.63 g) prepared in Example 1 was dissolved in 10 ml of concentrated hydrochloric acid and the solution was stirred at 100° C. for 3 hours. The solvent was then distilled off under reduced pressure and the residue was recrystallized from ethanol to give 0.5 g of colorless crystals melting at 256°-264° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[NH:4][C:5](=[O:19])[N:6]([C@H:8]2[C@@:12]([F:14])([CH3:13])[C@H:11]([OH:15])[C@@:10]([F:18])([CH2:16][OH:17])[O:9]2)[CH:7]=1.C([Mg]Cl)(C)(C)C.Cl[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[O:38][P:39](=[N:41][C@@H:42]([CH3:49])[C:43]([O:45][CH:46]([CH3:48])[CH3:47])=[O:44])=[O:40].CO>C1COCC1>[CH:46]([O:45][C:43](=[O:44])[C@@H:42]([N:41]=[P:39]([O:38][C:29]1[CH:30]=[CH:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]=1[O:17][CH2:16][C@:10]1([F:18])[C@@H:11]([OH:15])[C@:12]([F:14])([CH3:13])[C@H:8]([N:6]2[CH:7]=[C:2]([Br:1])[C:3](=[O:20])[NH:4][C:5]2=[O:19])[O:9]1)=[O:40])[CH3:49])([CH3:47])[CH3:48]
Reactant: C[C@]1(F)[C@H](n2cc(Br)c(=O)[nH]c2=O)O[C@](F)(CO)[C@H]1O
Reactant: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1ccc2ccccc2c1Cl
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1ccc2ccccc2c1OC[C@@]1(F)O[C@@H](n2cc(Br)c(=O)[nH]c2=O)[C@](C)(F)[C@@H]1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31.9 %

Procedure:
To a solution of chiral 5-bromo-1-((2R,3R,4S,5S)-3,5-difluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidine-2,4-dione (92 mg, 0.26 mmol) prepared in Preparation 7 in THF (3 ml) at 0° C. was added a THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (0.64 mL, 0.64 mmol) dropwise. The mixture was stirred at 0° C. for 15 min, followed by the addition of THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(naphthalen-2-yloxy)phosphorylamino)propanoate prepared in Example 3 Step B (1.29 mL, 0.64 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. Methanol (2 mL) was added to quench the reaction. The mixture was purified by flash chromatography (5-10% MeOH in DCM) to give the title compound as a white solid (56 mg, 32%).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:8]=2[CH2:17][OH:18])([CH3:4])([CH3:3])[CH3:2]>[Ni].CO>[NH2:14][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([CH2:17][OH:18])[CH:9]=1)[NH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13]2
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])cc(CO)c2[nH]1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1cc2cc(N)cc(CO)c2[nH]1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
A mixture of (2-tert-butyl-5-nitro-1H-indol-7-yl)methanol (4.0 g, 16 mmol) and Raney Nickel (400 mg) in CH3OH (100 mL) was stirred for 5 g at room temperature under H2. The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum to give (5-amino-2-tert-butyl-1H-indol-7-yl)methanol (3.4g, 80%). 1H NMR (CDCl3, 400 MHz) δ 8.53 (br s, 1H), 6.80 (d, J=2.0 Hz, 1 H), 6.38 (d, J=1.6 Hz, 1 H), 4.89 (s, 2 H), 1.37 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[C:19]([O:22][CH3:23])[C:18]([F:24])=[C:17]([F:25])[C:3]=1[C:4](=[O:16])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:7]1>C(O)(=O)C>[F:1][C:2]1[C:20]([F:21])=[C:19]([O:22][CH3:23])[C:18]([F:24])=[C:17]([F:25])[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:7]1
Reactant: COc1c(F)c(F)c(C(=O)CC2OC(=O)c3ccccc32)c(F)c1F
Solvent: CC(=O)O
Product: COc1c(F)c(F)c(C(=O)C=C2OC(=O)c3ccccc32)c(F)c1F
Temperature: 0 °C
Yield: 39 %

Procedure:
A mixture of 3 gm (8 mmol) of 3-(2',3',5',6'-tetrafluoro-4'-methoxyphenacyl)phthalide in 40 ml of glacial acetic acid was heated and stirred at 55°-60° C., and 3 gm of molecular bromine in 20 ml of glacial acetic acid was added dropwise. The colorless solution of the α-brominated starting material was thereafter added to 260 ml of ice cold water with vigorous stirring. The white precipitate was filtered and dried, dissolved in 150 ml of methylene chloride and refluxed for 2 hours in the presence of 3 ml of triethylamine. Dilute acid washing, followed by concentration and recrystallization from ethanol gave 1.1 gm (45%) of 3-(2',3',5',6'-tetrafluoro-4'-methoxyphenacylidene)phthalide, mp 199°-200° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.CC([O-])(C)C.[K+].[SiH:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19]>O1CCCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19]
Reactant: CC[SiH](CC)CC
Reactant: Cn1ccc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc2ccccc2n1C
Yield: 71.7 %

Procedure:
The reaction was conducted according to the General Procedure by heating N-methylindole (66 mg, 0.5 mmol, 1 equiv.), KOt-Bu (8.4 mg, 0.08 mmol, 0.15 equiv.) and Et3SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL of tetrahydrofuran for 48 hours at 23° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica eluting with hexanes (isochratic) to obtain 88 mg (72%) of the title compound as a colourless oil. 1H NMR (500 MHz, THF-d8) δ 7.50 (dt, J=7.9, 1.0 Hz, 1H), 7.32 (dq, J=8.3, 0.9 Hz, 1H), 7.11 (ddd, J=8.2, 6.9, 1.2 Hz, 1H), 6.97 (ddd, J=7.9, 7.0, 0.9 Hz, 1H), 6.68 (d, J=0.9 Hz, 1H), 3.84 (s, 3H), 1.06-0.98 (m, 9H), 0.98-0.92 (m, 6H). 13C NMR (126 MHz, THF-d8) δ 140.48, 136.86, 128.70, 121.44, 120.05, 118.51, 112.96, 108.71, 32.18, 6.83, 3.63. The HSQC spectrum of this reaction product as provided in FIG. 8.