Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=O.[CH3:14]C([O-])(C)C.[K+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH2:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: C=Cc1cc(Br)cc(C(F)(F)F)c1
Yield: 78.7 %

Procedure:
3-Bromo-5-trifluoromethylbenzaldehyde (1.10 g, 4.3 mmol) was reacted with CH3PPh3I (2.2 g, 5.4 mmol) and t-BuOK (710 mg, 6.3 mmol) as described above to give 1-bromo-3-trifluoromethyl-5-vinyl-benzene (850 mg, 79%) after purification by flash chromatography on silica gel
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([SH:18])[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[S:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CS(C)=O>[CH2:26]([S:18][C:4]1[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[S:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nc(S)c2nc(-c3ccc(F)cc3)sc2n1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1nc(SCc2ccccc2)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.3 %

Procedure:
To a solution of 5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidine-7-thiol (50 mg, 0.18 mmol) and triethylamine (63 μl, 0.45 mmol) in DMSO (1 ml) was added benzyl bromide (43 μl, 0.36 mmol). The reaction mixture was stirred under N2 at 25° C. for 3 hours. The mixture was poured onto water and extracted with EtOAc. The organic extracts were dried over Na2SO4 and the solvents were removed under reduced pressure. The residue was purified by flash chromatography on silica (CH2Cl2/MeOH 100:1) to yield the title compound as a light yellow solid (40 mg, 60%).
Reaction SMILES: [C:1](O)(=O)C.C([BH3-])#N.[Na+].[N:9]1([CH2:15][CH2:16][NH:17][C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[C:23]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[NH:24][C:25]3=[O:28])=[CH:20][CH:19]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(=O)(O)[O-].[Na+]>CO>[CH3:1][N:17]([CH2:16][CH2:15][N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)[C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:24][C:25]2=[O:28])=[CH:20][CH:19]=1
Reactant: CC(=O)O
Reactant: O=c1[nH]c(-c2ccccc2)cc2ccc(NCCN3CCOCC3)cc12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(CCN1CCOCC1)c1ccc2cc(-c3ccccc3)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
0.05 ml of acetic acid and 13.2 mg (0.168 mmol) of sodium cyanoborohydride were added to 0.5 ml of a methanol solution containing 14.7 mg (0.0241 mmol) of the 7-(2-morpholin-4-ylethylamino)-3-phenyl-2H-isoquinolin-1-one obtained in Example 15. The obtained mixture was stirred at a room temperature for 6 hours. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and was then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=20:1), so as to obtain 12.8 mg (84%) of 7-[methyl(2-morpholin-4-ylethyl)amino]-3-phenyl-2H-isoquinolin-1-one in the form of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5](=[O:12])[NH:4][CH:3]=1.[CH3:13]I>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+].[Ag+]>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][CH3:13])=[N:4][CH:3]=1
Reactant: CI
Reactant: O=c1[nH]cc(Br)c2c1CCCC2
Agent: [Ag+]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1ncc(Br)c2c1CCCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
47.7 g (209 mmol) of 4-bromo-5,6,7,8-tetrahydro-2H-isoquinolin-1-one are dissolved in 1 l of chloroform and, after addition of 77.8 g (282 mmol) of silver(I) carbonate and 53.5 ml (118.7 g, 836 mmol) of methyl iodide, stirred at 50° C. for 3 h. After cooling, the suspension is filtered through Celite, concentrated and chromatographed on silica gel using n-heptane with addition of 2% ethyl acetate. A colorless oil (42.5 g, 84% yield) is obtained.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1([C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10])[OH:8].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O>[C:15]([O:8][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[OH:10])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Oc1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Oc1ccccc1O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium carbonate (63.6 g) was added to a solution of pyrocatechol (55 g) in water (230 mL), and to the resulting mixture was added dropwise benzoyl chloride (58 mL) over a period of 2 hours with vigorous stirring. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was acidified carefully by dropwise addition of 2N hydrochloric acid (350 mL) and then extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from a mixed solvent of ethyl acetate (100 mL) and n-hexane (400 mL) to give the title compound (64.6 g) having the following physical data.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH:6]=[N+:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21]2>>[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24]([CH:6]([C:5]1[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=1[O:3][CH3:2])[N:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1)=[C:23]([OH:28])[CH:22]=[CH:21]2
Reactant: COc1ccccc1C=[N+]1CCOCC1
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [Cl-]
Product: COc1ccccc1C(c1c(O)ccc2cc(Br)ccc12)N1CCOCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-(2-methoxy-benzylidene)-morpholin-4-ium chloride and 6-bromo-2-naphthol.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:22]=[CH:21][CH:20]=[CH:19][C:16]=2[C:17]#[N:18])[CH2:11][CH2:10]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:1][C:20]1[CH:21]=[N:22][C:15]([N:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)=[C:16]([CH:19]=1)[C:17]#[N:18]
Reactant: N#Cc1cccnc1N1CCOCC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)cnc1N1CCOCC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
N-bromosuccinimide (141 mg) was added to a DMF (3 ml) solution containing 2-morpholinonicotinonitrile (100 mg), followed by stirring at 80° C. for 5 hours. The reaction solution was adjusted to room temperature. Then, aqueous saturated sodium thiosulfate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1 to 7:3), and a light yellow solid of 5-bromo-2-morpholinonicotinonitrile (120 mg) was thus obtained.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[O:17][C:16]3=[O:25])=[CH:11][CH:10]=2)[CH2:5][CH:4]1[F:26].CSC.C(Cl)(=O)C>[Cl-].[Zn+2].[Cl-]>[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[O:17][C:16]3=[O:25])=[CH:11][CH:10]=2)[CH2:5][CH:4]1[F:26]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@H](CCC(N)=O)OC3=O)cc2)CC1F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)Cl
Solvent: CSC
Product: NC(=O)CC[C@H]1CN(c2ccc(N3CCC(=O)C(F)C3)cc2)C(=O)O1
Yield: 65 %

Procedure:
The compound was prepared by reacting (S)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide with zinc chloride, dimethyl sulphide and acetyl chloride as per procedure described in Example E in 65% yield.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[BrH:11].O.C(=O)(O)[O-].[Na+]>C1CCCCC1>[Br:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: OCCCCCCCCO
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Product: OCCCCCCCCBr

Procedure:
25 g of octane-1,8-diol was boiled in 250 ml of cyclohexane with 22.6 ml of 47% aqueous hydrobromic acid for six hours in a water separator. The reaction mixture was then poured onto saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated, aqueous sodium chloride solution, dried on sodium sulfate, filtered and concentrated by evaporation in a vacuum. Column chromatography on silica gel with a mixture that consists of hexane/ethyl acetate yielded 21.6 g of the title compound as a yellowish oil.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:15]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[NH:17][CH:18]=1.O>N1C=CC=CC=1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[NH:17][CH:18]=[C:14]([CH2:13][CH2:12][CH2:11][NH:10][S:2]([CH3:1])(=[O:5])=[O:3])[C:15]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:24][CH:23]=1
Reactant: NCCCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)NCCCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Reaction time: 8 h
Yield: 56.7 %

Procedure:
188 mg (1.08 mmol) of methanesulfonic anhydride were added to a solution of 290 mg (0.982 mmol) of 4-(3-aminopropyl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole (prepared as described in Example 1 above) in 5 ml of pyridine and the resulting mixture was allowed to stand overnight. At the end of this time, water was added to the reaction mixture, giving a precipitate which was collected by filtration and washed with ethyl acetate to give 208 mg (yield 57%) of the title compound as a pale brown powder.
Reaction SMILES: C([O:5][C:6](=[O:44])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C@H:16]1[C@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[F:28])[C@:19]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17]1)=[O:15])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:27][C:23]1[C:22]([F:28])=[C:21]([C@@H:20]2[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17][C@H:16]2[C:14]([NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([OH:44])=[O:5])=[O:15])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccccc2C(=O)OC(C)(C)C)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccccc2C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F

Procedure:
rac 2-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid t-butyl ester (50 mg, 0.031 mmol) was treated with 30% TFA/methylene chloride (10 mL) overnight. Removal of solvent and freeze drying of the residue give a white powder. 15 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][OH:9])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][OH:9])[CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CCO)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-Nitrophenethyl alcohol (5.80 g, 34.7 mmol) was dissolved in ethanol (80 mL), and 10% palladium on carbon (0.90 g) was added thereto, and then, the resulting mixture was stirred under a hydrogen atmosphere at room temperature for 1.5 hours.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][NH:13][C:12]3[N:16]=[CH:17][C:18](I)=[CH:19][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][N:29]=2)[CH2:24][CH2:23]1>>[C:1]1([S:7]([N:10]2[CH2:15][CH2:14][NH:13][C:12]3[N:16]=[CH:17][C:18]([C:31]4[CH:30]=[N:29][C:28]([N:25]5[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]5)=[CH:33][CH:32]=4)=[CH:19][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)N1CCNc2ncc(I)cc21
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(S(=O)(=O)c3ccccc3)CCN4)cn2)CC1
Yield: 72 %

Procedure:
1-Benzenesulfonyl-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (88 mg) was reacted with 1-Methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4A to give the title compound as a yellow foam (72% yield). M.p. (foam), LCMS: m/z=450-98 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.39 (s, 3H), 2.60 (t, J=5.0 Hz, 4H), 2.98-3.03 (m, 2H), 3.64 (t, J=5.0 Hz, 4H), 3.80 (t, J=5.0 Hz, 2H), 5.16 (bs, 1H), 6.73 (d, J=8.8 Hz, 1H), 7.40-7.45 (m, 2H), 7.51-7.54 (m, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.67 (dd, J=8.8 Hz, 2.5 Hz, 1H), 8.08 (s, 1H), 8.40 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([CH2:17][CH2:18][N+:19]([O-:21])=[O:20])[N:5]([S:7]([C:10]2[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=1.[CH3:23][O:24][CH:25]([O:32][CH3:33])[C:26](=[O:31])[CH:27]=[C:28]([CH3:30])[CH3:29].C1CCN2C(=NCCC2)CC1>[NH4+].[Cl-]>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([CH2:17][CH:18]([N+:19]([O-:21])=[O:20])[C:28]([CH3:30])([CH3:29])[CH2:27][C:26](=[O:31])[CH:25]([O:24][CH3:23])[O:32][CH3:33])[N:5]([S:7]([C:10]2[CH:11]=[CH:12][C:13]([CH3:14])=[CH:15][CH:16]=2)(=[O:8])=[O:9])[CH:6]=1
Reactant: COC(OC)C(=O)C=C(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c(C)c2CC[N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Product: COC(OC)C(=O)CC(C)(C)C(Cc1c(C)c(Br)cn1S(=O)(=O)c1ccc(C)cc1)[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
Following a general procedure,50 a mixture of 4-Ts (9.00 g, 23.3 mmol) and 1,1-dimethoxy-4-methyl-3-penten-2-one (11.1 g, 69.9 mmol, 3 equiv) was treated with DBU (10.5 mL, 69.9 mmol). The reaction mixture was stirred for 15 min under argon. A saturated solution of cold aqueous NH4Cl (50 mL, 0° C.) was added. The mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried (Na2SO4), concentrated and dried overnight under high vacuum. Addition of diethyl ether (50 mL) to the resulting solid, trituration, and filtration afforded a pale brown solid (11.0 g, 86%): mp 114-115° C.; 1H-NMR δ 1.22 (s, 3H), 1.27 (s, 3H), 1.85 (s, 3H), 2.42 (s, 3H), 2.64, 2.74 (AB, 2J=19.0 Hz, 2H), 3.15 (ABX, 2JAB=15.4 Hz, 3JBX=1.8 Hz, 1H), 3.32 (ABX, 2JAB=15.4 Hz, 3JAX=11.7 Hz, 1H), 3.41 (s, 3H), 3.43 (s, 3H), 4.37 (s, 1H), 5.19 (ABX, 3JAX=11.7 Hz, 3JBX=1.8 Hz, 1H), 7.28 (s, 1H), 7.31 (d, J=8.1 Hz, 2H), 7.59 (d, J=8.1 Hz, 2H); 13C NMR δ 0.7, 21.9, 23.8, 24.0, 25.9, 36.8, 44.2, 55.28, 55.29, 94.4, 104.9, 105.9, 122.6, 125.1, 125.9, 126.7, 130.5, 135.9, 145.6, 203.2; Anal. Calcd for C22H29BrN2O7S: C, 48.44; H, 5.36; N, 5.14. Found: C, 48.70; H, 5.30; N, 5.17.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][Si:19]([CH2:22][Mg]Cl)([CH3:21])[CH3:20].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C[Mg]Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C[Si](C)(C)C)c([N+](=O)[O-])c1

Procedure:
The resultant (3-nitro-phenyl)-carbamic acid tert-butyl ester 2 can then be placed into solution with THF and reacted with ((trimethylsilyl)methyl)magnesiumchloride. A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in THF can then be added and allowed to react under conditions known to a skilled artisan to afford (3-nitro-4-trimethylsilanylmethyl-phenyl)-carbamic acid tert-butyl ester 3. Tetra-butylammonium fluoride can then be added to a solution of ester 3 and 4-iodo-2-methoxynicotinaldehyde in THF to afford {4-[2-hydroxy-2-(4-iodo-2-methoxy-pyridin-3-yl)-ethyl]-3-nitro-phenyl}-carbamic acid tert-butyl ester 4. A solution of compound 4, in turn, can be added to 2,2,2-trifluoroacetic anhydride and allowed to react to afford trifluoro-acetic acid 2-(4-tert-butoxycarbonyl-amino-2-nitro-phenyl)-1-(4-iodo-2-methoxy-pyridin-3-yl)-ethyl ester 5.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[C:19]([CH2:22][NH:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)(=[O:21])[CH3:20].C(N(CC)CC)C>C(O)C>[C:19]([CH2:22][NH:23][CH:24]1[CH2:28][CH2:27][N:26]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:25]1)(=[O:21])[CH3:20]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: CC(=O)CNC1CCNC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NCC(C)=O)C3)nc21
Yield: 98.4 %

Procedure:
A mixture containing 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (5.41 g), 3-(N-acetylmethylamino)pyrrolidine (4.26 g), triethylamine (6.06 g), and ethanol (100 ml) was heated under reflux for 2 hours with stirring. The reaction mixture was concentrated to dryness under reduced pressure. To the residue was added water (70 ml) and acetic acid (15 ml). After cooling the mixture, the precipitate was collected, washed with water, and recrystallized from dimethylformamide. There were obtained 7.4 g of 7-[3-(N-acetylmethylamino)-1-pyrrolidinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 287°-289° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]3[CH:14]=[CH:15][N:16]=[C:10]3[CH:9]=2)[N:5]=[N:6][CH:7]=1.[I:17]NC(=O)CCC(N)=O.C(OCC)C>CN(C)C=O>[I:17][C:14]1[N:11]2[CH:12]=[CH:13][C:8]([C:4]3[N:5]=[N:6][CH:7]=[C:2]([CH3:1])[N:3]=3)=[CH:9][C:10]2=[N:16][CH:15]=1
Reactant: Cc1cnnc(-c2ccn3ccnc3c2)n1
Reactant: NC(=O)CCC(=O)NI
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cnnc(-c2ccn3c(I)cnc3c2)n1
Yield: 39.6 %

Procedure:
7-(5-Methyl-[1,2,4]triazin-3-yl)-imidazo[1,2-a]pyridine (200 mg, 0.9 mmol, 1 equiv) and N-iodosuccinamide (300 mg, 1.3 mmol, 1.4 equiv) in dimethylformamide (5 ml) was stirred at room temperature. After 3 hours diethyl ether was added and the resultant solid was isolated by vacuum filtration furnishing 120 mg of a yellow solid. MS: [M+H]+338
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[Li]CCCC.CN(OC)[C:30](=[O:32])[CH3:31].Cl>C1COCC1.O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:30](=[O:32])[CH3:31])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: CON(C)C(C)=O
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 82.9 %

Procedure:
A solution of 2-Chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purine (0.50 g, 1.55 mmol) and N,N,N′,N-tetramethylethylenediamine (0.35 mL, 2.33 mmol) in dry THF (14 mL) was cooled to −78° C. n-BuLi (2.5M in hexanes, 1.22 mL, 3.05 mmol) was added dropwise and the mixture was stirred at −78° C. for 40 min. N-methyl-N-methoxyacetamide (0.25 mL, 2.33 mmol) was added dropwise and the mixture was stirred at −78° C. for 1.5 h, then allowed to warm to −30° C. Water was added followed by 1M aqueous HCl and the mixture was extracted seven times with ethyl acetate. The combined organic extracts were dried (Na2 SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2), gradient 0-50% ethyl acetate in cyclohexane to give 1-[2-Chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-ethanone (0.47 g, 83%). LCMS RT=3.57 min, [M+H]+=366/368
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10]C)=[O:9])[C:4]([O:12][CH2:13][C:14]2[O:18][N:17]=[C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])[CH:15]=2)=[N:3]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4]([O:12][CH2:13][C:14]2[O:18][N:17]=[C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[O:24][C:25]=3[CH3:26])[CH:15]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1OCc1cc(OCc2nc(-c3ccccc3)oc2C)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1cc(COc2nn(C)cc2CC(=O)O)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
A mixture of methyl [1-methyl-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethoxy]-1H-pyrazol-4-yl]acetate (701 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-methyl-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethoxy]-1H-pyrazol-4-yl]acetic acid (547 mg, yield 81%), which was then recrystallized from acetone-hexane. melting point: 149–150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10](Br)[CH:11]1[O:15][CH2:14][CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][O:15]1
Reactant: BrCC1CCCO1
Reactant: Oc1ccc(Br)cc1Cl
Product: Clc1cc(Br)ccc1OCC1CCCO1

Procedure:
Prepared by the method of Example 42 (b) using 2-chloro-4-bromophenol and tetrahydrofurfuryl bromide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C:25]([C:26](=[O:34])[NH:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][C:23]([CH3:35])=[N:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:28]1([NH:27][C:26]([C:25]2[N:21]([C:18]3[CH:17]=[CH:16][C:15]([O:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:20][CH:19]=3)[N:22]=[C:23]([CH3:35])[CH:24]=2)=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Cc1cc(C(=O)NC2CCCCC2)n(-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)NC2CCCCC2)n(-c2ccc(OC3CCNCC3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[4-(5-cyclohexylcarbamoyl-3-methylpyrazol-1-yl)phenoxy]piperidine-1-carboxylic acid tert-butyl ester (482 mg, 1.00 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (2 mL). After the reaction was stirred at room temperature for 2 hours, it was quenched with saturated sodium bicarbonate and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried (MgSO4) and concentrated to give the crude product in quantitative yield. LC-MS (C22H30N4O2 calculated 382) m/z 383 (M+H).