Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cu]C#N.[CH2:4]([Mg]Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:13]([O:15][C:16](=[O:38])[C:17](=[CH:23][C:24]1[CH:25]=[N:26][C:27]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:28][CH:29]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:14].[Cl-].[NH4+]>C1COCC1>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([CH:23]([C:24]1[CH:25]=[N:26][C:27]([NH:30][C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])=[CH:28][CH:29]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:16]([O:15][CH2:13][CH3:14])=[O:38])[CH3:22]
Reactant: Br[Mg]Cc1ccccc1
Reactant: CCOC(=O)C(=Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(Cc1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To a vigorously stirred suspensin of copper(I)cyanide (0.66 g, 7.32 mmol) in dry THF (5 mL) was added a solution of benzylmagnesium bromide (5 mL 2.93 M in ether, 14.64 mmol) at 0° C. under argon. The mixture was allowed to warm to room temperature, giving a dark brown solution. After 60 minutes a solution of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethylene)-malonic acid diethyl ester (0.67 g, 1.83 mmol) in dry THF (4 mL) was added at 0° C. The mixture was stirred overnight at room temperature then aqueous ammonium chloride was added. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with brine and dried. Removal of the solvent in vacuo gave a residue which was purified by flash chromatography (CH2Cl2/ethyl acetate, 1:0→100:15) to give 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-phenyl-ethyl]-malonic acid diethyl ester (0.44 g, 53%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]OS(C)(=O)=O)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O:20]1[C:24]2([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:23][NH:22][C:21]1=[O:30]>C(#N)C.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:22]2[CH2:23][C:24]3([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[O:20][C:21]2=[O:30])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)OCc1ccc(Br)cn1
Reactant: O=C1NCC2(CCCCC2)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C1OC2(CCCCC2)CN1Cc1ccc(Br)cn1
Temperature: 70 °C
Yield: 57.8 %

Procedure:
Methanesulfonic acid 5-bromo-pyridin-2-ylmethyl ester (85 mg, 0.319 mmol), cesium carbonate (312 mg, 0.957 mmol) and 1-oxa-3-aza-spiro[4.5]decan-2-one (49.5 mg, 0.319 mmol) were mixed in acetonitrile (2 mL). The reaction mixture was heated at 70° C. for 5 hours and then diluted with dichloromethane (8 mL). The mixture was washed with water (3 mL) and brine (3 mL). The combined organic phase was dried over sodium sulfate and concentrated. The residue was purified on silica gel eluting with 10 to 20% ethyl acetate in hexanes to give the product as an off-white solid (60 mg, 58%). 1H NMR (300 MHz, CDCl3): δ 8.6 (d, 1H), 7.81 (dd, 1H), 7.23 (d, 1H), 4.49 (s, 2H), 3.27 (s, 2H), 1.79 (m, 4H), 1.47 (m, 6H).
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]1[O:6][C:7]([CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:8][C:9](=[O:12])[C:10]=1[OH:11].I[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(O)C.O>[OH:3][CH2:4][C:5]1[O:6][C:7]([CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])=[CH:8][C:9](=[O:12])[C:10]=1[O:11][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CCCCCI
Reactant: CC(C)(C)C(=O)OCc1cc(=O)c(O)c(CO)o1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCCOc1c(CO)oc(COC(=O)C(C)(C)C)cc1=O
Yield: 27 %

Procedure:
To a solution of 1.84 g (0.028 mole) of potassium hydroxide in 38 ml of ethanol and 10 ml of water was added 6.76 g (0.026 mole) of 2-hydroxymethyl-3-hydroxy-6-(trimethylacetoxymethyl)-4-pyrone, and the resulting mixture heated to 50°. An 8.3 g (0.03 mole) portion of ethyl 6-iodohexanoate was then added and the resulting clear solution heated at reflux for 7 hr under a nitrogen atmosphere. Removal of the ethanol under reduced pressure left a residue which was dissolved in methylene chloride. The organic solution was washed successively with aqueous NaHCO3 and saturated brine, was dried over magnesium sulfate, and was evaporated to afford a viscous oil. This material was chromatographed on silica gel eluting with ethyl acetate to give 2.9 g (27%) of oily product, 2-hydroxy-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone. NMR (CDCl3): δ1.22 (3H, t, J = 7 Hz), 1.23 (9H, s), 2.30 (2H, t, J = 5.5 Hz), 6.32 (1H, s).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[CH:3]=1.[CH2:15](Br)[C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CC(C)=O>[CH2:17]([O:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[CH:3]=1)[C:16]#[CH:15]
Reactant: CCCc1cc(OC)c(OC)cc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: C#CCOc1cc(OC)c(OC)cc1CCC

Procedure:
Following the same procedure as in Example 3 b), 3.92 g (0.02 moles) of 1-hydroxy-6-propyl-3,4-dimethoxybenzene were reacted with 3.0 g (0.02 moles) of a solution of propargyl bromide in toluene (80% w/w) and 2.8 g (0.02 moles) of anhydrous potassium carbonate in 20 ml of acetone.
Reaction SMILES: C(Cl)Cl.[F:4][C:5]1[N:10]=[C:9]([F:11])[C:8]([F:12])=[C:7](F)[C:6]=1[F:14].[CH2:15]([NH:17][CH2:18]C)C>O>[CH3:15][N:17]([CH3:18])[C:7]1[C:6]([F:14])=[C:5]([F:4])[N:10]=[C:9]([F:11])[C:8]=1[F:12]
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: CCNCC
Solvent: O
Solvent: ClCCl
Product: CN(C)c1c(F)c(F)nc(F)c1F
Reaction time: 0.5 h

Procedure:
To methylene chloride (50 mL) cooled in an ice bath was added pentafluoropyridine (2.0 g, 11.8 mmol) and diethylamine (2.97 mL of a 40% solution in water, 24 mmol). After stirring for 30 minutes the solution was washed with water, and dried over basic alumina. The solvent was removed in vacuo to give 4-dimethylamino-2,3,5,6-tetra-fluoropyridine; NMR (CDCl3) 3.13 (m,6) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1>>[Cl:21][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([CH3:22])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:27]4[CH:28]=[CH:29][C:24]([NH2:23])=[N:25][CH:26]=4)[CH:7]=[CH:6][CH:5]=3)[CH:13]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(3,4-dichloro-phenyl)-6-methyl-pyridine (example E.85) (0.20 g, 0.509 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.123 g, 0.56 mmol) according to the general procedure VI. Obtained as an off-white solid (0.050 g, 21%). MS (ISP) 406.0 [(M+H)+], 408.1 [(M+2+H)+] and 410 [(M+4+H)+]; mp 99° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[N+:17]([O-])=O)[CH3:2].[H][H]>CO.[Pt]=O>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[NH2:17])[CH3:2]
Reactant: CCOC(=O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: CCOC(=O)c1cc(N2CCCCC2)ccc1N
Reaction time: 12 h

Procedure:
Subsequently, the crude 2-nitro-5-piperidin-1-yl-benzoic acid ethyl ester (3.8 g) was dissolved in methanol (35 ml). Platinum oxide (300 mg) was added to the solution at room temperature, the air in the reaction system was replaced by hydrogen, and the mixture was then stirred for 12 hr. After the completion of the reaction, the atmosphere in the reaction system was replaced by nitrogen, and the reaction solution was then filtered through Celite to remove platinum oxide and was then concentrated under the reduced pressure to give crude 2-amino-5-piperidin-1-yl-benzoic acid ethyl ester (compound A) as a useful intermediate (3.4 g, crude yield 100%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>CC(O)C.O>[N:17]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNC1
Reactant: O=C1CCc2cc(OCCCCl)ccc2N1
Solvent: O
Solvent: CC(C)O
Product: O=C1CCc2cc(OCCCN3CCCC3)ccc2N1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A solution of 6-(3-chloropropoxy)-3,4-dihydroquinolin-2(1H)-one prepared in Example 10-(1) (10 g) and pyrrolidine (15 g) in 2-propanol (15 mL) was stirred at 90° C. for 2 days. The reaction mixture was cooled to room temperature, diluted with water and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform→chloroform/methanol=4/1), and the resulting solid was subjected to recrystallization from ethyl acetate to give the titled compound (7.5 g, 65%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[O-]S(C(F)(F)[F:20])(=O)=O.F[N+]1C(Cl)=CC=CC=1Cl>C(#N)C.O1CCCC1.C(=O)([O-])O.[Na+]>[F:20][C:9]1[C:10]([CH:13]=[O:14])=[CH:11][NH:12][C:8]=1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1c[nH]c(-c2cccnc2F)c1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: O=Cc1c[nH]c(-c2cccnc2F)c1F
Reaction time: 2 h
Yield: 15.2 %

Procedure:
5-(2-Fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (660 mg) was dissolved in acetonitrile (30 mL) and tetrahydrofuran (30 mL), 1-fluoro-2,6-dichloropyridinium triflate (1.32 g) was added, and the mixture was stirred for 2 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:2→3:7) to give the title compound as pale-yellow crystals (yield 110 mg, 15%).
Reaction SMILES: O.[SH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.O.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)([O-:15])=[O:14]>CN(C=O)C>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][S:2][C:3]2[N:11]=[CH:10][N:9]=[C:8]3[C:4]=2[NH:5][CH:6]=[N:7]3)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: Sc1ncnc2nc[nH]c12
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CSc2ncnc3nc[nH]c23)cc1
Yield: 91 %

Procedure:
After stirring a mixture of 30 mmol of 6-mercaptopurine monohydrate (5.12 g) and 30 mmol of water-free K2CO3 (4.12 g) in 25 mL of dry DMF for 5 minutes, 30 mmol of 4-nitrobenzylbromide (6.48 g) was added. After stirring for 4 h, 200 mL of H2O was added. The obtained solid was filtered and washed with EtOAc and CH2Cl2, followed by drying under vacuum. Yield: 91%.—White powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:30][C:31](=[NH:50])[C:32]1[CH:49]=[CH:48][C:35]2[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40][C:34]=2[CH:33]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:30]=[C:31]([C:32]3[CH:49]=[CH:48][C:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:39][CH2:40][C:34]=4[CH:33]=3)[N:50]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=N)NO)cc2CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)no2)cc1Cl
Temperature: 80 °C
Yield: 28.5 %

Procedure:
To a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (Preparation 6) (1.406 g, 6.55 mmol) in DMF was added HOBT (1.103 g, 7.20 mmol) and EDC (1.381 g, 7.20 mmol), the resultant solution was stirred under argon for 10 mins at room temp. 1,1-dimethylethyl 7-[(hydroxyamino)(imino)methyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 41)(2 g, 6.55 mmol) was then added to the reaction mixture and the solution heated at 80° C. overnight. The solvent was removed in vacuo and the residue dissolved in methanol for purification by Biotage Horizon, reverse phase cartridge, eluting 5-100% acetonitrile in water. The product containing fractions (last 5) were concentrated in vacuo to yield the title compound as a yellow oil (950 mg, 1.87 mmol, 29% yield). δH (d6DMSO, 400 MHz): 8.19 (1H, d), 8.11 (1H, dd), 7.83-7.89 (2H, m), 7.45 (1H, d), 7.37 (1H, d), 4.89 (1H, sept), 3.50 (4H, br.s), 2.96 (4H, br.s), 1.41 (9H, s), 1.36 (6H, d). MS (ES): C26H3035ClN3O4 requires 483; found 384 [M+H−100]+.
Reaction SMILES: N(OCCCC)=O.[C:8]([O:16][C@@H:17]1[C@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:20]([C:31]([NH:33][CH2:34][CH3:35])=[O:32])[O:19][C@H:18]1[N:36]1[CH:44]=[N:43][C:42]2[C:37]1=[N:38][C:39](N)=[N:40][C:41]=2[Cl:45])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.II.[I:49]CI>C1COCC1.[Cu]I>[C:8]([O:16][CH:17]1[CH:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]([C:31]([NH:33][CH2:34][CH3:35])=[O:32])[O:19][CH:18]1[N:36]1[CH:44]=[N:43][C:42]2[C:37]1=[N:38][C:39]([I:49])=[N:40][C:41]=2[Cl:45])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ICI
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: [Cu]I
Agent: CCCCON=O
Agent: II
Solvent: C1CCOC1
Product: CCNC(=O)C1OC(n2cnc3c(Cl)nc(I)nc32)C(OC(=O)c2ccccc2)C1OC(=O)c1ccccc1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
n-Butyl nitrite (4.65 ml, 39.7 mmol) was added to a suspension of (2R,3R,4S,5S)-2-(2-amino-6-chloro-9H-purin-9-yl)-4-(benzoyloxy)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 46) (8.10 g, 14.7 mmol), iodine (3.73 g, 14.7 mmol), copper(1) iodide (6.16 g, 32.3 mmol) and diiodomethane (12.55 ml, 155.8 mmol) in THF (100 ml) and the mixture was heated under reflux for 2.5 hours. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between aqueous sodium metabisulfite solution (5% w/v, 100 ml) and dichloromethane (100 ml). The organic layer was separated, filtered through Arbocel (trade mark), dried over anhydrous magnesium sulfate and solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1, by volume) to afford the title compound as a yellow foam (7.55 g, 78%).
Reaction SMILES: OO.[C:3]([O:23][CH:24]1[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([OH:32])[C:26]([CH3:34])([CH3:33])[CH2:25]1)(=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([OH:19])[C:13]([CH3:21])([CH3:20])[CH2:12]1)=[O:9].S([O-])([O-])=O.[Na+].[Na+].[C:41]([OH:45])([CH3:44])([CH3:43])[CH3:42]>>[OH:45][C:41]([CH3:44])([CH3:43])[CH2:42][O:19][N:14]1[C:15]([CH3:18])([CH3:17])[CH2:16][CH:11]([O:10][C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:23][CH:24]2[CH2:25][C:26]([CH3:34])([CH3:33])[N:27]([O:32][CH2:42][C:41]([OH:45])([CH3:44])[CH3:43])[C:28]([CH3:31])([CH3:30])[CH2:29]2)=[O:22])[CH2:12][C:13]1([CH3:21])[CH3:20]
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(OC(=O)CCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CC(C)(O)CON1C(C)(C)CC(OC(=O)CCCCC(=O)OC2CC(C)(C)N(OCC(C)(C)O)C(C)(C)C2)CC1(C)C

Procedure:
Aqueous hydrogen peroxide is added to a mixture of bis(1-oxyl-2,2,6,6-tetramethyl-pieridin-4-yl) adipate and ferrous chloride tetrahydrate in tert-butyl alcohol at 30-50° C. Excess peroxide is decomposed with aqueous sodium sulfite solution. The organic layer is concentrated and the crude product is purified by flash chromatography on silica gel to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[NH2:17][NH2:18]>C(Cl)Cl>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:15][CH3:16])[N:3]=[C:2]([Cl:1])[N:11]=[C:10]2[NH:17][NH2:18]
Reactant: NN
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Solvent: ClCCl
Product: COc1cc2nc(Cl)nc(NN)c2cc1OC
Reaction time: 0.75 h

Procedure:
To a solution of 20.8 g. of 2,4-dichloro-6,7-dimethoxyquinazoline in 400 ml. of methylene chloride is added dropwise 20 g. of hydrazine while maintaining the temperature below 30° C. with cooling. The resulting mixture was stirred for 45 minutes and then allowed to stand overnight at a temperature of 0° C. The mixture is then filtered and the solids washed first with water and then with methanol. The resulting solid material is then taken up in ice-water and stirred for 20 minutes. The mixture is then filtered and the resulting solid is recrystallized from methanol/methylene chloride to obtain 6,7-dimethoxy-2-chloro-4-hydrazino-quinazoline, m.p. 312°-315° C. (decomp.).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@H:15]([CH2:19][S:20](Cl)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:26]1[C:31]2[S:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:30]=2[CH2:29][CH2:28][NH:27]1.C(N(CC)CC)C>ClCCl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@H:15]([CH2:19][S:20]([N:27]1[CH2:28][CH2:29][C:30]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[S:32][C:31]=2[CH2:26]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c3c(sc2c1)CNCC3
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCc2c(sc3ccccc23)C1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.5 %

Procedure:
4-(R)-Benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)oxazolidin-2-one (370 mg) was added to a solution of 1,2,3,4-tetrahydro-benzo[4,5]thieno[2,3-c]pyridine hydrochloride (230 mg) and triethylamine (0.30 ml) in dichloromethane (20 ml) and the reaction stirred at room temperature for 18 h. The mixture was washed with water (30 ml) and brine (20 ml), dried (MgSO4), filtered and evaporated under reduced pressure to give the title compound (180 mg) in crude form.
Reaction SMILES: [Na].[Cl:2][C:3]1[N:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[OH2:11]>>[Cl:2][C:3]1[C:4]([CH2:5][OH:11])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O
Reactant: ClCc1cccnc1Cl
Agent: [Na]
Product: OCc1cccnc1Cl

Procedure:
In 100 ml of cold water was dissolved 8.98 g of sodium horohydride and with ice-cooling and stirring, 11.7 g (0.0665 mole) of 2-chloronicotinyl chloride was added in small portions. The mixture was further stirred at the same temperature for 30 minutes and, then, extracted with Et2O (100 ml×3). The extract was dried over MgSO4 and distilled to remove Et2O. The procedure gave 8.75 g of (2-chloro-3-pyridyl)methanol as a pale yellow oil. When left standing at room temperature, this product solidified thoroughly.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:31])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19](Cl)=[N:18][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=[O:7].[CH3:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:31])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19]([C:36]4[CH:35]=[N:34][C:33]([CH3:32])=[CH:38][CH:37]=4)=[N:18][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: COCCN(C)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COCCN(C)C(=O)N1CCN(Cc2cc3nc(-c4ccc(C)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid (2-methoxy-ethyl)-methyl-amide (Example 27) was reacted with 2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine via General Procedure A. Purification on silica yielded 154. NMR (CDCl3): 2.58-2.60 (m, 4H, 2×CH2), 2.65 (s, 3H, CH3), 2.92 (s, 3H, CH3), 3.31-3.33 (m, 4H, 2×CH2), 3.36 (s, 3H, CH3), 3.38-3.41 (m, 4H, 2×CH2), 3.55-3.58 (m, 4H, 2×CH2), 3.87 (s, 2H, CH2), 3.90-3.92 (m, 4H, 2×CH2), 4.06-4.09 (m, 4H, 2×CH2), 7.26 (d, H, ArH, J=8.13 Hz), 7.33 (s, H, ArH), 58.58 (dd, H, ArH, J=8.07 Hz), 9.52 (d, H, ArH, J=1.86 Hz). MS: (ESI+): MH+ 526.45
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.Cl.[NH2:10][C@H:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[O:32][CH3:33])=[CH:21][CH:20]=1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[F:31][C:29]1[CH:28]=[CH:27][C:26]([O:32][CH3:33])=[C:25]([C:22]2[CH:21]=[CH:20][C:19]([CH2:18][C@@H:11]([NH:10][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[O:8])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:24][CH:23]=2)[CH:30]=1
Reactant: O=C(O)c1cnco1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cc(F)ccc2OC)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)c1cnco1
Reaction time: 2 h

Procedure:
To a solution of oxazole-5-carboxylic acid (70 mg, 0.61 mmol) in DMF (1.5 mL) and DCM (1.5 mL) is added (R)-ethyl 3-amino-4-(5′-fluoro-2′-methoxybiphenyl-4-yl)butanoate hydrochloride, intermediate 10, (150 mg, 0.41 mmol), HATU (233 mg, 0.61 mmol), and TEA (284 μL, 2.04 mmol). After stirring for 2 hours, the reaction is quenched with H2O, and the crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN), and then lyophilized to give (R)-ethyl 4-(5′-fluoro-2′-methoxybiphenyl-4-yl)-3-(oxazole-5-carboxamido)butanoate (157 mg). HPLC retention time=1.50 minutes (condition A); MS (m+1)=427.4; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (t, J=7.2 Hz, 3H) 2.46-2.62 (m, 2H) 2.86 (dd, J=13.6, 8.1 Hz, 1H) 3.02 (dd, J=13.6, 6.1 Hz, 1H) 3.67 (s, 3H) 4.05-4.15 (m, 2H) 4.52-4.69 (m, 1H) 6.76-6.82 (m, 1H) 6.83-6.96 (m, 2H) 7.11-7.21 (m, 3H) 7.37 (d, J=8.1 Hz, 2H) 7.61 (s, 1H) 7.80 (s, 1H)
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C(N(CC)CC)C.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C(O)C>[NH:3]([CH2:1][CH3:2])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCN
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCNCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.5 %

Procedure:
To a stirring solution of ethylamine (24 mL, 300 mmol) and triethylamine (14 mL, 100 mmol) in ethanol (200 mL) at 0° C., was added via addition funnel a solution of t-butyl bromoacetate (19.5 mL, 100 mmol) in ethanol (50 mL). The cold bath was left unattended and the mixture was allowed to slowly warm to room temperature. After 24 hours, the solvents were removed in vacuo. The residue was dissolved in ethyl acetate, and extracted twice with 1N citric acid. The combined aqueous layers were basified to pH 10 with solid Na2CO3, and then extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4), filtered, and concentrated in vacuo to give 9.8 g (62%) of a yellow oil.