Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([NH2:12])=[S:11].CCN(C(C)C)C(C)C.Br[CH:25]([C:31](OCC)=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CCO.CCOC(C)=O>[O:32]=[C:31]1[CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:11][C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:13])([F:1])[F:14])=[N:12]1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: NC(=S)Nc1ccccc1C(F)(F)F
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1SC(Nc2ccccc2C(F)(F)F)=NC1=O
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-(trifluoromethyl)phenylthiourea (Menai Organics, 2.36 g, 10.7 mmol), Hunig's base (Aldrich, 1.9 mL, 10.7 mmol) in EtOH (10 mL) was added diethyl bromomalonate (2.0 mL, 10.7 mmol). After 1.5 h at room temperature, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography. MS: 333 (M+1).
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])C(=C)C.[Al].[CH2:14](C1(O)C=CC=CC1O)[C:15](=[CH2:17])[CH3:16]>>[CH2:16]([C:10]1[CH:11]=[C:6]([OH:5])[C:7](=[CH:8][CH:9]=1)[OH:12])[C:15](=[CH2:14])[CH3:17]
Reactant: C=C(C)COc1ccccc1O
Reactant: C=C(C)CC1(O)C=CC=CC1O
Agent: [Al]
Product: C=C(C)Cc1ccc(O)c(O)c1
Yield: 36.6 %

Procedure:
By carrying out the reaction under the temperature and treatment conditions described in Example 1, starting from ortho-methallyloxyphenol (1.043 g), without using an aluminium derivative, a mixture containing unconverted ortho-methallyloxyphenol (0.189 g), DDHB (0.0126 g), ortho-methallylpyrocatechol (0.520 g) and para-methallylpyrocatechol (0.188 g) is obtained, i.e.:
Reaction SMILES: [F-:1].[K+].[C:3]([O:7][C@@H:8]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[C:16]1[CH:21]=[C:20]([CH3:22])[N:19]=[C:18](Cl)[N:17]=1)[CH3:9])([CH3:6])([CH3:5])[CH3:4]>CS(C)=O.C(OCC)(=O)C.O>[C:3]([O:7][C@@H:8]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[C:16]1[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([F:1])[N:17]=1)[CH3:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: [F-]
Reactant: Cc1cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)nc(Cl)n1
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)nc(F)n1
Temperature: 120 °C

Procedure:
Potassium fluoride (0.063 g, 1.08 mmol, 10 equiv) was added to a solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-methylpyrimidin-4-yl)oxazolidin-2-one (34 mg, 0.108 mmol) in DMSO (1.1 mL). The suspension was heated at 120° C. for 3 hours and then cooled to room temperature. The reaction was diluted with ethyl acetate (20 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoro-6-methylpyrimidin-4-yl)oxazolidin-2-one, which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=3.8 Hz, 1H), 4.71 (m, 1H), 4.65 (m, 1H), 4.46 (m, 1H), 4.41 (m, 1H), 2.53 (s, 3H), 1.25 (s, 9H), 1.03 (d, J=6.5 Hz, 3H); MS m/z 298.2 (M+H)+; Rt-0.96 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].C1C(=O)N([Br:21])C(=O)C1>ClC1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:21][CH2:10][C:5]1[CH:4]=[C:3]([N+:11]([O-:13])=[O:12])[C:2]([Cl:1])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: N#Cc1cc(Cl)c([N+](=O)[O-])cc1CBr
Temperature: 130 °C
Yield: 108.9 %

Procedure:
A mixture of 5-chloro-4-nitro-2-methylbenzonitrile (32.0 g, 0.16 mol), NBS (54.0 g, 0.30 mol) and benzoyl peroxide (200 mg, catalytic amount) in chlorobenzene was heated at 130° C. and irradiated with a sunlamp for 15 h. More NBS (30.0 g, 0.17 mol) and benzoyl peroxide (200 mg) were added. The mixture was further reacted for 24 h. After cooling, the precipitate formed was filtered off and washed with CH2Cl2. The combined filtrates were washed with H2O (2×), dried over anhydrous MgSO4 and concentrated in vacuo. The residue was then chromatographed over silica gel and eluted with hexanes:EtOAc (9:1) to give 2-bromomethyl-5-chloro-4-nitrobenzonitrile (48 g, contaminated with starting material and dibrominated product) as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:7][CH:8]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cccc(CCCO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1cccc(CCCBr)c1
Reaction time: 5 h
Yield: 87.9 %

Procedure:
Compound 47-3 (3.53 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (6.19 g) and N-bromosuccinimide (4.20 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (4.29 g) as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][CH2:39][CH:40](Cl)[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[I-].[K+]>C(#N)C>[CH2:22]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([CH2:38][CH2:39][C@@H:40]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[S:4][CH2:3]2)[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36][CH2:37]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Reactant: CCOC(=O)C(Cl)CCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](CCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Yield: 18.1 %

Procedure:
A mixture of 0.4 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, 1 g of ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorobutyrate, 0.2 g of triethylamine, 0.9 g of potassium iodide and 50 ml of acetonitrile is heated under reflux for 2 days. After cooling, the reaction solution is concentrated under reduced pressure, and the residue is purified by silica-gel column chromatography (hexane:ethyl acetate=2:1) to give 0.15 g of tert-butyl 3(R)-[3-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 0.25 g of tert-butyl 3(R)-[3-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpropyl]amino-4-oxy-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oily material, respectively.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[OH:7][CH:8]([CH2:16][NH2:17])[CH2:9][CH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[NH2:12].[CH2:18]([O:25][C:26](ON1C(=O)C2C(C3CC2C=C3)C1=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.C(#N)C>[CH2:18]([O:25][C:26]([NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][CH2:9][CH:8]([OH:7])[CH2:16][NH2:17])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)C2C3C=CC(C3)C2C1=O
Reactant: NCC(O)CC[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NCC(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
Sodium bicarbonate (4.2 g, 0.050 mol) and 5-hydroxylysine hydrochloride (2.50 g, 0.0126 mol) were dissolved in water (70 ml) with stirring at room temperature. Acetonitrile (40 ml) was added, followed by N-benzyloxycarbonyloxy-5-norbornen-2,3-dicarboximide (3.94 g, 0.0126 mol) in acetonitrile (30 ml) over 15 minutes. After 2 hours, most of the acetonitrile was removed in vacuo and the remaining solution was treated with hydrochloric acid to reduce the pH to 2.0. The solution was extracted with ethyl acetate (50 ml), the pH was increased to 5.5 with sodium hydroxide, and the product was purified over Dowex 50W-2X. The product was eluted with 3% pyridine in water, concentrated to a small volume and freeze dried to give III (1.24 g, 0.0042 mol, 33%); nmr (0.5 M NaOD in D2O)δ 1.4-2.1 (m, 4H, --CH2CH2 --), 3.1-3.5 (m, 2H, --NCH2CH ), 3.5-3.9 (m, 1H, --NCHRCO), 3.9-4.2 (m, 1H, --CH2CHOHCH2 --), 5.10 (s, 2H, --CH2O), 7.39 (s, 5H, --CH2O); mass spectrum (FAB): 297 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=O.C([O-])(O)=O.[Na+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[N:8]=2)[CH:7]=1
Reactant: Nc1cnc(Cl)cn1
Reactant: CN(C)c1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)c1ccc(-c2cn3cc(Cl)ncc3n2)cc1
Yield: 7 %

Procedure:
In a double necked round bottomed flask equipped with condenser and under nitrogen flow were introduced 5-chloro-2-amino-pyrazine (61 mg, 0.47 mmol), 2-bromo-4′-dimethylamino-acetophenone (170 mg, 0.71 mmol) and anhydrous acetonitrile (7 mL). The reaction mixture was refluxed for 3 hrs. After it cooled down, NaHCO3 (71 mg, 0.85 mmol) was added. The reaction was refluxed for another 6 hrs. The solvent was removed and the crude product (221 mg) was purified by FCC (hex/DCM/AcOEt=2:2:1), to afford 9 mg (yield 7%) of the product as yellow solid. 1HNMR (270 MHz; CDCl3), δ 8.82 (s, 1H, Ar—H), 8.09 (s, 1H, Ar—H), 7.822 (s, 1H, Ar—H), 7.818 (d, 3JHH=8.9 Hz, 2H, Ar—H), 6.77 (d, 3JHH=8.7 Hz, 2H, Ar—H), 3.02 (s, 6H, NCH3). m/z (CI-MS): 273 ([M+1]+), 261, 239 ([M−Cl+1]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:9])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: COc1cccc(Cc2ncc(Cl)cc2C(=O)O)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cc2cccc(OC)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(3-methoxybenzyl)nicotinic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 9.15 (1H, d, J=7.5 Hz), 8.63 (1H, d, J=2.4 Hz), 7.94–7.90 (3H, m), 7.49 (2H, d, J=8.4 Hz), 7.09 (1H, t, J=7.8 Hz), 6.74–6.63 (3H, m), 5.18–5.08 (1H, m), 4.17 (1H, d, J=13.8 Hz), 4.09 (1H, d, J=13.8 Hz), 3.85 (3H, s), 3.66 (3H, s), 1.41 (3H, d, J=7.0 Hz); MS (ESI) m/z 439 (M+H)+, 437 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([OH:16])[C:8]2[O:9][C:10]([F:13])([F:12])[O:11][C:7]=2[CH:6]=1)=[O:4].Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][CH2:18][CH2:19][C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)[C:8]2[O:9][C:10]([F:13])([F:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: Cc1cccc(CCBr)c1
Reactant: COC(=O)c1cc(O)c2c(c1)OC(F)(F)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCCc2cccc(C)c2)c2c(c1)OC(F)(F)O2
Temperature: 80 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
1.8 g of 2,2-difluoro-7-hydroxy-benzo[1,3]dioxole-5-carboxylic acid methyl ester, 4.6 g of 1-(bromo-ethyl)-3-methyl-benzene, and 3.2 g of K2CO3 were added to 70 ml of anhydrous DMF and the reaction mixture stirred at 80° C. for 3 h. The reaction mixture was then allowed to cool to room temperature, 300 ml of water added and extracted three times using 100 ml of EA each. The organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP 1:4 yielded 2.4 g of the title compound, colorless oil. Rf (EA/HEP 1:4)=0.32
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([NH:11][C:12](=[O:14])[CH3:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:15](Cl)([CH3:18])([CH3:17])[CH3:16].Cl>ClCCCl>[C:15]([C:8]1[CH:9]=[CH:10][C:5]([NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:7]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)Cl
Reactant: CC(=O)Nc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)Nc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
A reactor was charged with 1,2-dichloroethane (50 L), followed by aluminum chloride (6.08 kg, 45.6 mol), The mixture was stirred for ten minutes at room temperature and then cooled to 5° C. N-phenylacetamide (5 kg, 37.0 mol) was added slowly, after which the mixture was cooled to −12° C. A solution of t-butylchloride (5.03 kg, 54.3 mol) in 1,2-dichloroethane (5 L) was added to the reaction over ten minutes and then stirred for 1 hour at that temperature. The reaction mixture was added to ice water (50 L) and concentrated hydrochloric acid (2.5 L) at 5-10° C., over one hour. The mixture was heated slowly to 40° C., held at that temperature for thirty minutes and the layers then allowed to separate. The aqueous was extracted further with dichloroethane (50 L) and the combined extracts concentrated, under vacuum, to low volume. Hexane (5 L) was added and the mixture concentrated in vacuo. The residue was slurried with hexane (25 L), cooled to 5° C. and stirred for thirty minutes. The solids were isolated by filtration and dried at room temperature to provide 6.1 kg of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[Cl:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1.Cl.CCN=C=NCCCN(C)C>ClCCl.CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][N:24]([C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[O:12])[CH2:23][CH2:22]2)=[O:20])=[CH:27][CH:28]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Indole-5-carboxylic acid (18 mg, 0.11 mmole) and 4-(4-chlorobenzoyl) piperidine hydrochloride (26 mg, 0.1 mmole) were dissolved in 5 ml dichloromethane. To this solution was added triethylamine (1 eq. to neutralize the HCl salt) catalytic DMAP and EDCI (33 mg, 0.11 mmole). The reaction mxture was stirred at room temperature overnight and then worked up by washing sequentially with 1N HCl, saturated sodium bicarbonate, and saturated sodium chloride. The compound was then purified by flash chromatography on silica gel (40:1 CHCl3/MeOH). 1H NMR (300 Mhz, CDCl3) δ 8.45 (s, 1H), 7.88 (d, 2H), 7.72 (s, 1H), 7.45 (d, 2H), 7.38 (d, 1H), 7.24 (s, 2H), 6.58 (s, 1H), 3.42 (m, 1H), 3.11 (m, 2H), 1.83 (m, 4H), 1.60 (m, 2H).
Reaction SMILES: [C:1]1([CH3:41])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:24])[CH3:23])[CH2:13][CH:12]([NH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([O:37]CC)=[O:36])[CH:30]=3)=[O:27])[C:11]2=[O:40])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[C:1]1([CH3:41])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:24])[CH3:23])[CH2:13][CH:12]([NH:25][C:26](=[O:27])[NH:28][C:29]3[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=3)[C:35]([OH:37])=[O:36])[C:11]2=[O:40])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(C)=O)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=O)N1CC(NC(=O)Nc2cccc(C(=O)O)c2)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Yield: 58.2 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-acetyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (670 mg) was dissolved in methanol (32 ml), aqueous lithium hydroxide monohydrate (253 mg) solution (16 ml) and tetrahydrofuran (16 ml) were added, and the mixture was refluxed for 45 minutes, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (150 ml), the solution was washed with diethyl ether, acidified with 1N hydrochloric acid, and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, diisoproryl ether was added to the residue for trituration, collected by filtration, to thereby obtain 370 mg of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:30][C:31]1[O:35][C:34]([C:36](O)=[O:37])=[CH:33][CH:32]=1>>[Br:30][C:31]1[O:35][C:34]([C:36]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=[CH:10]3)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[O:37])=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccc(Br)o2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 70 mg, 0.18 mmol) and 5-bromofuran-2-carboxylic acid (41.0 mg, 0.21 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][C:11]2[N:12]=[C:13]([NH2:50])[C:14]3[N:15]=[CH:16][N:17]([C:48]=3[N:49]=2)[C@@H:18]2[O:47][C@H:37]([CH2:38][O:39][Si](C(C)(C)C)(C)C)[C@@H:28]([O:29][Si](C(C)(C)C)(C)C)[C@H:19]2[O:20][Si](C(C)(C)C)(C)C)[CH:5]=[CH:6][CH:7]=1.[F-].[NH4+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][C:11]2[N:12]=[C:13]([NH2:50])[C:14]3[N:15]=[CH:16][N:17]([C:48]=3[N:49]=2)[C@@H:18]2[O:47][C@H:37]([CH2:38][OH:39])[C@@H:28]([OH:29])[C@H:19]2[OH:20])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(CCOc2nc(N)c3ncn([C@@H]4O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]4O[Si](C)(C)C(C)(C)C)c3n2)c1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cccc(CCOc2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of crude 2-[2-(3-methylphenyl)ethoxy]-2′,3′,5′-tri-O-(TERT-butyldimethylsilyl)-adenosine (5 g, Example 8) in anhydrous methanol (70 mL) under a nitrogen atmosphere was added ammonium fluoride (2.5 g, 67.5 mmol). The resulting solution was heated to reflux for 14 hours, at which time HPLC indicated the disappearance of starting material. The reaction was cooled to room temperature, concentrated in vacuo on a rotary evaporator, and the resultant solids partitioned between ethyl acetate (30 mL) and water (30 mL). The mixture was stirred for 30 minutes, the layers separated, and the aqueous portion extracted with additional ethyl acetate (2×30 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to a clear oil. The product was purified by passing the oil through a plug of silica gel, eluting with CH2Cl2, 2% methanol in CH2Cl2, 5% methanol in CH2Cl2, and 10% methanol in CH2Cl2. Fractions containing the product were combined and concentrated at reduced pressure to afford the desired product as a light yellow solid. 1.1 g (35%). m.p.: 102–108° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(O)C>[F:22][C:21]([F:24])([F:23])[C:18]1[CH:17]=[N:16][C:15]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1-c1ccc(C(F)(F)F)cn1
Temperature: 100 °C
Yield: 99.5 %

Procedure:
4-methoxycarbonylphenyl boronic acid (541 mg) and 2-chloro-5-trifluoromethylpyridine (718 mg) were added to a suspension of bisbenzonitriledichloropalladium (119 mg) and 1,4-bisdiphenylphosphinobutane (131 mg) in toluene (10 ml) at ambient temperature and then ethanol (5 ml) and saturated aqueous sodium hydrogencarbonate solution (5 ml) were added to the mixture. This mixture was heated at reflux for 5 hours at 100° C. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue diisopropyl ether was added to afford the desired compound (841 mg) as a white powder which include some impurity.
Reaction SMILES: [F:1][CH:2]([NH:32][CH:33]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34]1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:23]=[CH:22][N:21]=3)[CH:13]=2)=[O:10])=[CH:5][CH:4]=1.[CH2:39]=O>>[F:1][CH:2]([N:32]([CH3:39])[CH:33]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34]1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:23]=[CH:22][N:21]=3)[CH:13]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: Cc1ccc(NC(=O)c2ccc(C(F)NC3CCN(C)C3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: C=O
Product: Cc1ccc(NC(=O)c2ccc(C(F)N(C)C3CCN(C)C3)cc2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
The product from Example 11 was methylated via reductive amination with HCHO/NaBHCN afforded the title compound. Mass: (M+1), 526.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[N:15][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Pt]=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]2[CH2:12][CH2:13][CH2:14][NH:15][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc2ncccc2c1=O
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)(C)n1ncc2c(c1=O)CCCN2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In acetic acid (20 ml) was dissolved 6-t-butyl-pyrido[2,3-d]pyridazin-5(6H)-one (955 mg) followed by addition of platinum oxide (94 mg), and the mixture was stirred under hydrogen at room temperature for 7 hours. The catalyst was then filtered off, the filtrate was concentrated to dryness, and the residue was washed with diethyl ether and dried. White powder, 911 mg. 1H-NMR (CDCl3) δ: 1.63(9H,s), 1.8-2.0(2H,m), 2.54(2H,t,J=6.2Hz), 3.28(2H,t,J=5.4Hz), 4.24(1H,brs), 7.19(1H,s).