Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=O)[S:5][C:6]=1[CH2:7][CH3:8].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:39][C@H:40]1[C:45]([F:47])([F:46])[CH2:44][CH2:43][CH2:42][C@H:41]1[NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:51]([O:50][C:49](=[O:55])[NH:48][C@@H:41]1[CH2:42][CH2:43][CH2:44][C:45]([F:47])([F:46])[C@@H:40]1[NH:39][C:9]([C:4]1[S:5][C:6]([CH2:7][CH3:8])=[C:2]([Br:1])[CH:3]=1)=[O:11])([CH3:54])([CH3:52])[CH3:53]
Reactant: CCc1sc(C(=O)O)cc1Br
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@@H]1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
4-Bromo-5-ethylthiophene-2-carboxylic acid (1.00 g, 4.25 mmol) and BOP (5.64 g, 12.8 mmol) were dissolved in DMF (42.5 mL) and stirred at room temperature for 5 min. To the reaction solution was added tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (1.07 g, 4.25 mmol) and diisopropylethyl amine (1.11 mL, 6.38 mmol) and the reaction stirred at room temperature for 64 h. The reaction mixture was diluted with ethyl acetate and washed with water 3×. The organic layer was collected, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-50% EtOAc/Hex) to give the title compound (1.56 g, 3.34 mmol). LRMS (APCI) calc'd for (C18H25BrF2N2O3S) [M+H]+, 467.1; found 466.9. 1H NMR (CDCl3, 500 MHz) δ 7.32 (s, 1H), 6.28 (s, 1H), 4.90 (s, 1H), 4.54 (s, 1H), 4.29 (s, 1H), 2.81 (q, J=7.5, 2H), 2.22 (m, 1H), 1.88 (m, 1H), 1.81 (m, 1H), 1.69 (m, 1H), 1.59 (m, 1H), 1.46 (s, 9H), 1.41 (m, 1H), 1.28 (t, J=7.3, 3H)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH2:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[CH2:22][CH3:23].C(N(CC)C(C)C)(C)C.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:28][C:27]3[CH:29]=[CH:30][C:24]([CH2:21][CH2:22][CH3:23])=[CH:25][CH:26]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Reactant: CCCc1ccc(N)cc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCc1ccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)c2)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 31 %

Procedure:
To a mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (41 mg, 0.15 mmol), 4-propylaniline (0.029 mL, 0.20 mmol), and N,N-diisopropylethylamine (0.052 mL, 0.30 mmol) in 1.5 mL DMF at room temperature was added COMU (68 mg, 0.158 mmol). The reaction was briefly warmed to approx. 60° C. and then continued at room temperature for 15 hours. The reaction was added drop wise to a stirring mixture of 35 mL water containing 5 mL brine at room temperature, and the resulting precipitate filtered and rinsed with water. The filtrate was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was combined with the filtered precipitate and then chromatographed eluting with portions of CHCl3, then 1:1 CHCl3:EtOAc, and then 5% MeOH/CHCl3. The obtained solid was then triturated with an EtOAc/hexane mixture to give the title compound as a light beige solid (18 mg, 32%). 1H NMR (DMSO-d6) δ: 10.07 (s, 1H), 8.13 (s, 1H), 7.62-7.69 (m, 2H), 7.48-7.51 (m, 1H), 7.31-7.40 (m, 2H), 7.21 (dt, J=7.7, 2.0 Hz, 1H), 7.13-7.19 (m, 2H), 6.40 (s, 2H), 4.29 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H), 2.50-2.56 (m, 2H), 1.58 (sxt, J=7.4 Hz, 2H), 0.89 (t, J=7.3 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:6]=[N:5][C:4]=1[C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]1[CH2:23][C@@H:22]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19]1)=[O:16].[P:43](OCC)([O:48][CH2:49][CH3:50])([O:45][CH2:46][CH3:47])=[O:44]>CN(C=O)C.C(OCC)(=O)C>[CH2:46]([O:45][P:43]([CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:6]=[N:5][C:4]=1[C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]1[CH2:23][C@@H:22]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19]1)=[O:16])([O:48][CH2:49][CH3:50])=[O:44])[CH3:47]
Reactant: CCOP(=O)(OCC)OCC
Reactant: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1CBr)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F)OCC
Temperature: 110 °C
Reaction time: 12 h

Procedure:
tert-Butyl (3S,5R)-3-[{[5-(bromomethyl)-1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (440 mg) was dissolved in DMF (4 ml), triethyl phosphate (295 μl) was added and the mixture was stirred at 110° C. for 12 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (473 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=[O:13].[OH-:15].[Na+].Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:15][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:24])=[CH:4][C:3]=1[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C(C)Br
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: [OH-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1cc(C(=O)O)c(O)c2ccccc12
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
0.05 mole of 1-hydroxy-2-naphthoic acid was dissolved in 70 ml of DMF, and 10 ml of a 40% aqueous solution of sodium hydroxide was added dropwise to the solution while introducing nitrogen gas. Then, 0.05 mole of ethyl α-bromo-propionate was added dropwise and the mixture was agitated at 40° C. for 3 to 4 hours to effect reaction. After completion of the reaction, the reaction mixture was poured into ice-hydrochloric acid, and crystals were recovered by filtration and recrystallized from acetonitrile to obtain a compound having a melting point of 178° C. Then, 0.01 mole of 1-hydroxy-4-[1-(ethoxycarbonyl)-ethoxy]-2-naphthoic acid so obtained and 0.01 mole of N-(δ-2,4-di-tert-amylphenoxy)butylamine were dissolved in 60 ml of dry dioxane, and 0.01 mole of dicyclohexylcarbodiimide was added to the solution. The reaction was conducted at room temperature under agitation for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and separated by column chromatography to obtain a compound having a melting point of 75° C. (the yield being 52%). From the results of the elementary analysis, it was confirmed that this compound was the compound (1) illustrated above.
Reaction SMILES: [O:1]1[CH2:27][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH3:28][NH:29][CH3:30]>C(O)C>[C:17]1([CH:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:27][N:29]([CH3:30])[CH3:28])=[CH:6][CH:7]=3)[O:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CNC
Reactant: CC1(C)CC(c2cccc3ccccc23)c2ccc(OCC3CO3)cc2O1
Solvent: CCO
Product: CN(C)CC(O)COc1ccc2c(c1)OC(C)(C)CC2c1cccc2ccccc12
Reaction time: 48 h

Procedure:
7-(2,3-Epoxypropoxy)-2,2-dimethyl-4-(1-napthyl)chroman (3.15 g., 0.0088 moles) was dissolved in a solution of dimethylamine in ethanol (20 ml., ~40%) and left to stand at room temperature for 48 hours. Removal of solvent gave the title compound as a dark coloured oil which was converted to the succinate salt. Recrystallization from acetone gave a white solid (1.72g., 49%) m.p. 123-125° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl[C:11](Cl)(Cl)[CH:12]([OH:14])O.Cl.[NH2:18][OH:19].S([O-])([O-])(=O)=O.[Na+].[Na+].Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:12](=[O:14])[CH:11]=[N:18][OH:19])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: NO
Reactant: Nc1ccc(F)c(Br)c1
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C=NO)Nc1ccc(F)c(Br)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
To a 500 mL round bottom flask, 3-bromo-4-fluoraniline (5 g, 0.0261 mol), water (300 mL), chloral hydrate (5.19 g, 0.0314 mol), hydroxylamine hydrochloride (5.8 g, 0.0835 mol) and sodium sulphate (25 g) were added. To this reaction mixture, concentrated HCl (7.5 mL) was slowly added. The reaction mixture was stirred at 90° C. for 3 hours. A precipitate formed and was collected by filtration. The solid was dried to provide the title compound (4.2 g, 61%). 1H NMR (300 MHz, DMSO-d6): δ 12.28 (s, 1H), 10.51 (s, 1H), 8.12 (dd, J=2.4 Hz, J=2.7 Hz, 1H), 7.68 (m, 2H), 7.36 (t, J=8.7 Hz, 1H).
Reaction SMILES: [N+:1]([O:4][C@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:29]=[CH:28][C:23]([NH:24]C(=O)C)=[N:22][C:20]1=[O:21])([O-:3])=[O:2].C[O-].[Ba+2].C[O-].O>CO>[N+:1]([O:4][C@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:14][OH:15])[O:7][C@H:6]1[N:19]1[CH:29]=[CH:28][C:23]([NH2:24])=[N:22][C:20]1=[O:21])([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccn([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]2O[N+](=O)[O-])c(=O)n1
Agent: C[O-]
Agent: [Ba+2]
Solvent: CO
Solvent: O
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O[N+](=O)[O-])c(=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution of 1-(2-O-nitro-3,5-di-O-acetyl-β-D-arabinofuranosyl)-N4 -acetylcytosine (10 g., 24 mmol) in anhydrous methanol (425 ml) under an atmosphere of dry nitrogen was added 1.9N barium methoxide (5 ml., 9.5 meq) in methanol. The reaction mixture was stirred at room temperature under an inert atmosphere for one hour and was then neutralized with a cation exchange resin (90 g., Bio-Rex 70/H+, 100-200 mesh )in the presence of water (5 ml). The resin was separated by filtration and washed with methanol. The combined filtrate and washings were evaporated under reduced pressure to yield crude 1-(2-O-nitro-β-D-arabinofuranosyl)cytosine (6.60 g., 95%), which was crystallized from H2O to yield pure 1-(2-O-nitro-β-D-arabinofuranosyl)cytosine (5.97 g., 86%): m.p. 151.3°-152.7° C.;
Reaction SMILES: Br[CH:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[N-:23]=[N+:24]=[N-:25].[Na+].CO>CN(C)C=O>[N:23]([C:18]1[C:17](=[O:20])[CH2:16][CH2:15][C@@:14]2([CH3:21])[C:19]=1[CH2:2][CH2:3][C@@H:4]1[C@@H:13]2[CH2:12][CH2:11][C@@:9]2([CH3:10])[C@H:5]1[CH2:6][CH2:7][C:8]2=[O:22])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@]12CCC(=O)C=C1C(Br)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@]12CCC(=O)C(N=[N+]=[N-])=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 48.3 %

Procedure:
To a stirred solution of 1.1 g of 6-bromoandrost-4-en-3,17-dione in 57.4 ml of dimethylformamide are added 0.250 g of sodium azide. The resulting mixture is heated at 30°-35° C. for 72 hours, cooled and worked up as described in the example 3. There are obtained 0.476 g of the title compound, m.p. (MeOH) 143°-144° C. (dec.);
Reaction SMILES: [CH:1]1N=CN(C(N2C=NC=C2)=O)C=1.O.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]([OH:48])([C:42]4[N:46]([CH3:47])[CH:45]=[N:44][CH:43]=4)[C:33]4[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=4)[CH:30]=3)[NH:25][C:24](=[O:49])[CH:23]=2)[CH:19]=[CH:20][CH:21]=1.N12CCN(CC1)CC2.CO>C1COCC1.O>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]([OH:48])([C:42]4[N:46]([CH3:47])[CH:45]=[N:44][CH:43]=4)[C:33]4[CH:34]=[CH:35][C:36]([C:37]([O:39][CH3:1])=[O:38])=[CH:40][CH:41]=4)[CH:30]=3)[NH:25][C:24](=[O:49])[CH:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Cn1cncc1C(O)(c1ccc(C(=O)O)cc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)(c2ccc3[nH]c(=O)cc(-c4cccc(Cl)c4)c3c2)c2cncn2C)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
CDI (0.00925 mol) was added to a mixture of (±)-4-[[4-(3-chlorophenyl)-1,2-dihydro-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]benzoic acid monohydrochloride monohydrate (described in Example B3) (0.00185 mol) in THF (10 ml). The mixture was stirred at 40° C. for 1 hour.1,4 diazabicyclo[2,2,2]octane (0.00185 mol) and methanol (5 ml) were added. The mixture was stirred at 40° C. for 18 hours, poured out into H2O and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 0.44 g (48%) of (±-methyl 4-[[4-(3-chlorophenyl)-1,2-dihydro-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]benzoate, mp. 255° C.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[CH:22])[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6])([CH3:3])[CH3:2].[CH3:23][O:24][C:25](=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[C:22][C:30]2[CH:31]=[CH:32][C:27]([CH2:26][C:25]([O:24][CH3:23])=[O:34])=[CH:28][CH:29]=2)[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cc(C(=O)OC(C)C)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(C(=O)OC(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 6-ethynyl-2,2,4,4-tetramethylchroman-8-carboxylic acid isopropyl ester (Intermediate 44 0.025 g, 0.08 mmol), 4-iodo phenyl acetic acid methyl ester (0.027 g, 0.1 mmol), triethyl amine (2 mL), copper(I)iodide (0.008 g, 0.04 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.017 g, 0.024 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 40% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow oil (0.019 g, 53%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:30][C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([CH3:40])[C:38]=1[F:39])[CH2:34]Br>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH2:34][C:33]1[CH:36]=[C:37]([CH3:40])[C:38]([F:39])=[C:31]([CH3:30])[CH:32]=1)[CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: Cc1cc(CBr)cc(C)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H](Cc1cc(C)c(F)c(C)c1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To a cooled (−78° C.) solution of (R)-4-benzyl-3-pent-4-enoyl-oxazolidin-2-one (0.500 g, 1.928 mmol) in 15 mL of THF, was added LiHMDS (2.9 mL, 2.9 mmol, 1.0 M in THF). The resulting mixture was stirred at −78° C. under N2 for 1 h and then a solution of 3,5-dimethyl-4-fluorobenzyl bromide (0.460 g, 2.121 mmol) in 5 mL of THF was added. After being stirred at −78° C. for 1 h followed by warming to room temperature over 2 h, the reaction mixture was quenched with 50 mL of aqueous NH4Cl solution and extracted with dichloromethane (50 mL×3). The combined organic extracts were dried, filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel) eluting with 0-100% dichloromethane/hexanes to give the title compound as colorless oil (0.221 g, 56% yield). GC-MS: tR=7.0 min; m/z 395 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13](Cl)=[N:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.Cl[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31].[O:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][NH2:42])[CH2:36][CH2:35]1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:42][CH2:41][CH2:40][N:37]4[CH2:38][CH2:39][O:34][CH2:35][CH2:36]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: NCCN1CCOCC1
Reactant: Clc1ncc2c(-c3cccc(Br)c3)n[nH]c2n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)c2)c2cnc(NCCN3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(3-bromo-phenyl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidine (from Example 38 supra) (3.0 g, 9.7 mmol), Et3N (5.4 mL, 38.8 mmol) in DMF (50 mL), (2-(chloromethoxy)-ethyl)trimethylsilane (SEM-Cl, 2.0 mL, 11.6 mmol) was added in one portion. The resultant mixture was stirred for 30 minutes at room temperature. To this solution, 2-morpholino-ethanamine (1.51 g, 11.6 mmol) was added. The resulting mixture was stirred for one hour at room temperature. The reaction was poured into water (200 mL), extracted with EtOAc (3×200 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography (silica gel, 200-300 mesh, EtOAc) to give [3-(3-bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine as yellow oil. (Yield 1.7 g, 32.7%).
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[N+:14]([O-:16])=[O:15])=[CH:8][CH:7]=1.CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([C@H:12]([CH2:13][N+:14]([O-:16])=[O:15])[C@H:2]([CH3:3])[CH:1]=[O:4])=[CH:10][CH:11]=1
Reactant: CCC=O
Reactant: O=[N+]([O-])/C=C/c1ccc(Br)cc1
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: C[C@H](C=O)[C@@H](C[N+](=O)[O-])c1ccc(Br)cc1

Procedure:
The title compound was prepared from propionaldehyde and (E)-1-bromo-4-(2-nitrovinyl)benzene according to the general procedure. Both enantiomeric excess and diastereomeric ratio were determined by HPLC with an AD-H column at 230 nm (2-propanol:hexane=5:95), 1.0 mL/min; major enantiomer tmajor=18.59 min, tminor=13.77 min. [α]D20=−24.6 (c=2.1, CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH:20]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]5[O:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:27]=5[CH:37]=4)[CH2:19][N:18](C(OCC4C=CC=CC=4)=O)[CH2:17][CH:16]3[OH:48])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.B(F)(F)F.CCOCC.C(S)C>ClCCl>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH:20]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]5[O:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:27]=5[CH:37]=4)[CH2:19][NH:18][CH2:17][CH:16]3[OH:48])=[CH:11][CH:10]=2)=[N:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CC(O)C3c3ccc(Oc4ncc(Br)cn4)cc3)cc21
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCS
Solvent: ClCCl
Product: COCCCN1CCOc2ccc(COC3CNCC(O)C3c3ccc(Oc4ncc(Br)cn4)cc3)cc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 139.8 mg of benzyl 4-[4-(5-bromopyrimidin-2-yloxy)phenyl]-3-hydroxy-5-[4 -(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 0.5 ml of dichloromethane is added to a mixture of 0.232 ml of boron trifiuoride etherate and 0.4 ml of ethanethiol. The reaction mixture is stirred at room temperature under argon for 20 hours. The solvent is then evaporated off, and 2 ml of water are added to the residue. The aqueous phase is extracted three times with 5 ml of ethyl acetate each time. The combined organic phases are dried with sodium sulphate, filtered and evaporated. The title compound is obtained as a beige wax from the residue by flash chromatography (SiO2 60F).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].COC(=O)/C=C/C1C=C2C(=CC=1)OC1(CCNCC1)CC2=O>>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][C:22]2([CH2:9][C:8](=[O:10])[C:5]3[C:4](=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[O:11]2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(=O)c1ccc(Br)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccc(Br)cc1O2

Procedure:
1-(4-Bromo-2-hydroxy-phenyl)ethanone (10.1 g, 47.0 mmol) was coupled with N—BOC-4-piperidone according to the procedure for preparation of Intermediate 1, Step A, giving 7-bromo-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylic acid tert-butyl ester (18 g) as an orange solid.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[Cl:17][CH2:18][C:19](Cl)=O.[NH:22]1[CH2:27][CH2:26][C:25]2([C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28]2)[CH2:24][CH2:23]1>>[ClH:17].[CH:12]1[C:7]2[CH2:6][CH2:5][C:4]3[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=3[CH:2]([NH:1][CH2:18][CH2:19][N:22]3[CH2:27][CH2:26][C:25]4([C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH2:29][CH2:28]4)[CH2:24][CH2:23]3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)CCl
Reactant: c1ccc2c(c1)CCC21CCNCC1
Reactant: NC1c2ccccc2CCc2ccccc21
Product: Cl
Product: c1ccc2c(c1)CCc1ccccc1C2NCCN1CCC2(CCc3ccccc32)CC1

Procedure:
The title compound, m.p. 170° C. and MS: m/e=423.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-amino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, chloroacetyl chloride, 2,3-dihydro-spiro[1H-indene-1,4'-piperidine] and Hcl.