Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([C:11]#[C:12][C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[CH:3]1.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([C:11]#[C:12][C:13]3[CH:23]=[CH:22][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[CH:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CC3(C)C)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C2=CC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 10.0 mg (0.025 mmol) of ethyl 4-[2-(1,1-dimethyl-3-(4-methylphenyl)-5-indenyl)ethynyl]benzoate (Compound 47) in 0.5 ml THF/H2O (3:1 v/v) was added 5.2 mg (0.12 mmol) LiOH H2O. After stirring at room temperature for 48 hours the solution was extracted with hexanes and the aqueous layer was acidified with saturated aqueous NH4Cl. Solid NaCl was added and the resulting mixture extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a colorless solid. 1H NMR (300 MHz, d6-DMSO): δ 7.95 (2H, d, J=8.3 Hz), 7.65 (2H, d, J=8.3 Hz), 7.57 (2H, m), 7.49 (3H, m), 7.30 (2H, d, J=7.9 Hz), 6.61 (1H, s), 2.36 (3H, s), 1.36 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][CH:6]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:5]1[CH:6]=[C:2]([CH3:1])[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4]1
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)c1n[nH]cc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1nn(-c2ccccc2OC)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
Ethyl 4-methyl-1H-pyrazole-3-carboxylate (4.0 g) was dissolved in N,N-dimethylacetamide (30 mL), 2-methoxyphenylboronic acid (7.9 g), copper acetate (9.5 g) and pyridine (8.4 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (1.6 g, 25%) as a pale-yellow oil.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C@:20]([CH3:24])([C@@H:21]([CH3:23])[CH:22]=1)[C@@H:19]1[C@H:10]([C@H:11]3[C@@:15]([CH2:17][CH2:18]1)([CH3:16])[C:14](=[O:25])[CH2:13][CH2:12]3)[CH2:9][CH2:8]2)(=O)C.[Br:26]N1C(C)(C)C(=O)N(Br)C1=O>O1CCOCC1.O>[Br:26][C@@H:22]1[C@H:21]([CH3:23])[C@@:20]2([CH3:24])[C:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:25])=[CH:6][C:5]1=[O:4]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(=O)OC1=C[C@H](C)[C@@]2(C)C(=C1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1[C@@H](Br)C(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Temperature: 25 °C
Reaction time: 1 h
Yield: 193.6 %

Procedure:
Under ice cooling, a suspension of 5.18 g of 3-acetoxy-1α-methylandrosta-2,4-dien-17-one in 50 ml of dioxane and 100 ml of water is combined in portions with 2.2 g of 1,3-dibromo-5,5-dimethylhydantoin and stirred for one hour at room temperature. Subsequently, the mixture is precipitated into 1 liter of water saturated with sodium chloride, 2.7 g of sodium sulfite is added, and the mixture is stirred for 60 minutes. The precipitated residue is filtered off, washed free of chloride with water, and dried, thus obtaining 5.65 g of a mixture of 2β-bromo-1α-methyl-4-androstene-3,17-dione and 2β-bromo-1α-methyl-4-androstene-3,17-dione.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:19][C:14]=3[CH2:13][N:12]([S:26]([CH3:29])(=[O:28])=[O:27])[C@H:11]([CH2:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH2:10]2)[N:5]=[CH:4]1.[S:37]1C=[CH:40][CH:39]=[C:38]1S([Cl:45])(=O)=O.Cl.BrC1C=CC2N(CC3N=CNC=3)C[C@@H](CC3C=CC=CC=3)N(S(C)(=O)=O)CC=2C=1>>[ClH:45].[ClH:1].[NH:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][C:18]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:19][C:14]=3[CH2:13][N:12]([S:26]([C:29]3[S:37][CH:38]=[CH:39][CH:40]=3)(=[O:28])=[O:27])[C@H:11]([CH2:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH2:10]2)[N:5]=[CH:4]1
Reactant: CS(=O)(=O)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1cccnc1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: CS(=O)(=O)N1Cc2cc(Br)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Agent: Cl
Product: O=S(=O)(c1cccs1)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1cccnc1

Procedure:
Example 329 was prepared as an off white solid from (R)-2,3,4,5-tetrahydro-7-phenyl-3-(3-pyridinylmethyl)-1H-1,4-benzodiazepine (prepared as described in Example 273) and 2-thiophenesulfonyl chloride by the following sequence: Compound C of Example 224; Compound D of Example 224.
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].Cl.Cl.[NH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C@@H:24]3[CH:29]4[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]4)[CH2:25]3)=[O:23])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1>CN(C=O)C.C(#N)C.O>[ClH:5].[CH3:1][S:2]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([C@@H:24]3[CH:29]4[CH2:28][CH2:27][N:26]([CH2:31][CH2:30]4)[CH2:25]3)=[O:23])=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)Nc1cccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)c1
Reaction time: 18 h

Procedure:
63.6 μl (0.46 mmol) of triethylanaine and 21.2 μl (0.27 mmol) of methanesulfonyl chloride are added to a solution of 60 mg (0.09 mmol) of (3R)—N-(3′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 8A) in 1 ml of DMF at room temperature. After 18 h at room temperature, the reaction mixture is diluted with a 1:1 mixture of acetonitrile and water and purified by preparative HPLC. The product fractions are concentrated, taken up in 1 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 14 mg (35.2% of theory) of the title compound are obtained. HPLC (Method 1): Rt=3.70 min. LC-MS (Method 2): Rt=2.45 min.; m/z=400 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:4][CH:3]=1.Cl.[CH3:18][O:19][C:20](=[O:34])[C:21]1[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][C:22]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33].F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([OH:27])[C:21]=2[C:20]([O:19][CH3:18])=[O:34])=[O:16])=[CH:4][CH:3]=1
Reactant: Nc1ccc(CCC(=O)O)c2ccccc12
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)CCc1ccc(N)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.5 %

Procedure:
A mixture of 3-(4-amino-1-naphthyl)propanoic acid (160 mg, 0.74 mmol), 2-(4-amino-butoxy)-6-hydroxy-benzoic acid methyl ester hydrochloride (200 mg, 0.72 mmol), [(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium tetrafluoroborate (TBTU) (275 mg, 0.857 mmol) and N,N-diisopropylethylamine (0.4 mL, 2.3 mmol) in DMF (3 mL) was stirred at ambient temperature for 1.5 hour, poured into water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers were washed with water (2×5 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to an oil. The product was purified on silica gel, eluting with 75% ethyl acetate/hexanes to provide the titled compound (165 mg, 52%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].[Br:12]Br>C(O)(=O)C.O>[Br:12][C:9]1[CH:10]=[C:2]([F:1])[C:3]([OH:11])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: BrBr
Reactant: O=C(O)c1cccc(F)c1O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(Br)cc(F)c1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5.00 g (32 mmol) of 3-fluorosalicylic acid was suspended in 50 ml of glacial acetic acid. 2.2 ml of bromine were added and the mixture was stirred at ambient temperature for 48 h. The resulting suspension was diluted with 500 ml of water and the precipitate filtered off and dried by suction to afford 9.394 g of 5-bromo-3-fluoro-2-hydroxybenzoic acid as an ivory solid.
Reaction SMILES: OO.FC(F)(F)C(O)=[O:6].[C:10]([C:12]1[C:16]([S:17][C:18]([F:21])([F:20])[F:19])=[C:15]([CH3:22])[N:14]([C:23]2[C:28]([Cl:29])=[CH:27][C:26]([C:30]([F:33])([F:32])[F:31])=[CH:25][C:24]=2[Cl:34])[N:13]=1)#[N:11]>>[C:10]([C:12]1[C:16]([S:17]([C:18]([F:20])([F:19])[F:21])=[O:6])=[C:15]([CH3:22])[N:14]([C:23]2[C:28]([Cl:29])=[CH:27][C:26]([C:30]([F:32])([F:33])[F:31])=[CH:25][C:24]=2[Cl:34])[N:13]=1)#[N:11]
Reactant: Cc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=C(O)C(F)(F)F
Agent: OO
Product: Cc1c(S(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 8 h
Yield: 83 %

Procedure:
A 30 wt % aqueous solution of hydrogen peroxide (29 μL) was added to a trifluoroacetic acid solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylthiopyrazole (116 mg) described in Example 1. The reaction mixture was stirred overnight whereupon solvent was evaporated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (100 mg, 83%). MS (ES): M/Z [M+NH4]=453. 1H NMR: (400 MHz, DMSO-d6): 2.35 (s, 3H) and 8.41 (s, 2H). 19F NMR (376 MHz, DMSO-d6): −62.01 (s, 3F) and −74.18 (s, 3F).
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH2:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>C(O)C.C(N(CC)CC)C>[C:3]([N:6]1[CH2:11][CH2:10][N:9]([N:12]=[CH:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)N1CCN(N)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(N=Cc2ccc(F)cc2)CC1
Temperature: 80 °C

Procedure:
To a solution of 1-acetyl-4-aminopiperazine dihydrochloride (300 mg) in ethanol (10 ml) and triethylamine (0.78 ml) was added p-fluorobenzaldehyde (0.164 ml), and the mixture was heated at 80° C. for 2 hours. After removal of the solvent in vacuo, the residue was triturated with ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, and concentrated. The residue was crystallized from diisopropyl ether to give 1-acetyl-4-(4-fluorobenzylidene)aminopiperazine (0.15 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][C@@H:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=1[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([N:30]2[CH2:36][CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=3[NH:32][C:31]2=[O:41])[CH2:26][CH2:25]1.[Li+].[OH-].C1C[O:47][CH2:46]C1>O>[O:41]=[C:31]1[N:30]([CH:27]2[CH2:26][CH2:25][N:24]([C:46]([O:22][C@@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][C:12]3[CH:13]=[C:14]([CH3:15])[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[C:10]([Cl:23])[CH:11]=3)=[O:47])[CH2:29][CH2:28]2)[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=2[NH:32]1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: COC(=O)[C@H](O)Cc1cc(C)c(OCc2ccccc2)c(Cl)c1
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COC(=O)[C@@H](Cc1cc(C)c(OCc2ccccc2)c(Cl)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-(4-benzyloxy-3-chloro-5-methyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate was prepared analogously to Example 7f from 7.0 g (20.9 mmol) methyl(R)-3-(4-benzyloxy-3-chloro-5-methyl-phenyl)-2-hydroxy-propionate and 5.2 g (21.2 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one. The crude product was dissolved in 150 mL THF and combined with a solution of 0.50 g (20.6 mmol) LiOH in 50 mL water. The reaction mixture was stirred overnight at RT, combined with water and the organic solvent was eliminated i.vac. The aqueous phase was washed twice with EtOAc and acidified with 21 mL 1 M HCl. The resulting oil was exhaustively extracted with EtOAc. The combined organic extracts were dried, filtered and evaporated down i.vac.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][N:16]=1.CO.[BH4-].[Na+].O>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][N:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cn1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine-5-carbaldehyde (13.0 g) in tetrahydrofuran (150 ml)-methanol (10 ml) was gradually added sodium borohydride (835 mg) at 0° C. After stirring for 30 min., water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to give crystals of 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine-5-methanol. Recrystallization from acetone-isopropyl ether gave colorless prism crystals (12.4 g, yield 95%). melting point: 121-122° C.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH:24]1([CH2:29][NH2:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>CCO>[CH:24]1([CH2:29][NH:30][C:2]2[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:9][C:10]([F:12])([F:13])[F:11])[CH2:14][C:15]([F:17])([F:18])[F:16])=[O:7])=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Reactant: NCC1CCCC1
Solvent: CCO
Product: O=C(c1ccc(NCC2CCCC2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (122 mg, 0.350 mmol) and cyclopentylmethyl amine (42 mg, 0.420 mmol) in 3 mL of EtOH containing TEA (0.075 mL, 0.525 mmol). The product was purified by flash chromatography on silica gel using 3:1/hexanes:EtOAc as eluent. Yield: 141 mg (94%); 1H NMR (400 MHz, CHLOROFORM-D) δ 1.30 (m, 2H), 1.64 (m, 4H), 1.89 (m, 2H), 2.26 (m, 1H), 3.24 (dd, J=7.23, 5.04 Hz, 2H), 4.23 (q, J=8.42 Hz, 4H), 6.91 (d, J=8.97 Hz, 1H), 7.50 (dd, J=8.97, 2.20 Hz, 1H), 8.26 (d, J=2.20 Hz, 1H), 8.33 (s, 1H); MS (ESI) 427.82 (MH+).
Reaction SMILES: [OH:1][C@H:2]([C@H:6]([CH3:10])[C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].CO[C:13](OC)([CH3:15])[CH3:14]>CC(C)=O.[Cu](Cl)Cl>[CH3:14][C:13]1([CH3:15])[O:1][C@H:2]([C@H:6]([CH3:10])[C:7]([OH:9])=[O:8])[C:3](=[O:5])[O:4]1
Reactant: C[C@H](C(=O)O)[C@@H](O)C(=O)O
Reactant: COC(C)(C)OC
Agent: Cl[Cu]Cl
Solvent: CC(C)=O
Product: C[C@H](C(=O)O)[C@H]1OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.5 %

Procedure:
To a solution of (2R,3S)-2-hydroxy-3-methylsuccinic acid (2.48 g; 16.8 mmol; 1.0 eq.) in acetone (80.0 mL) was added 2,2-dimethoxypropane (4.13 g; 33.6 mmol; 2.0 eq.) and copper(II) chloride (226 mg; 1.68 mmol; 0.1 eq.). The resulting reaction mixture was stirred for 16 h at RT. The reaction mixture was evaporated and the residue taken up in CHCl3. Activated charcoal is added and the resulting mixture stirred for one hour. Filtration on a pad of celite gave the title product (mixture of diastereoisomers) as a greenish oil (1.85 g, 59%) used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.Br[CH:37]1[CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:39]([N:3]1[C:2](=[O:1])[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:25][CH2:26][CH2:27]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:4]1=2)[CH:37]=[CH2:38]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: BrC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Yield: 11.1 %

Procedure:
In a sealed tube was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.212 mmol) in DMF to give a brown solution. bromocyclopropane (76.9652 mg, 0.636 mmol) and potassium carbonate were added. The reaction mixture was heated at 80 degree for 16 h. The reaction mixture was then heated under microwave 100 degree for 2 h and 130 degree for 8 h. The reaction mixture was partitioned between dichloromethane (20 ml) and water (20 ml). The organic phase was separated using phase separator and concentrated. The crude product was purified by column (biotage, 25 g) eluted with ethyl acetate/cyclohexane to afford product (12 mg). 1H NMR (500 MHz, CDCl3) 7.17-7.23 (m, 8H), 7.07-7.10 (m, 2H), 5.77-5.84 (m, 1H), 5.18-5.24 (m, 2H), 4.51 (d, 2H), 2.2-2.5 (m, 4H), 1.9-2.0 (m, 1H), 1.69-1.79 (m, 1H), 1.1-1.35 (br, 9H). LCMS (Method A): RT=7.9 min, M+H+=512.17.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].Cl[C:7]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[C:12]2[C:8]=1[NH:9][CH:10]=[N:11]2.C1COCC1.O>C(OCC)(=O)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:7]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[C:12]2[C:8]=1[NH:9][CH:10]=[N:11]2)[CH2:2][CH3:3]
Reactant: FC(F)(F)c1nc(Cl)c2[nH]cnc2n1
Reactant: CCC[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1nc(C(F)(F)F)nc2nc[nH]c12
Temperature: 50 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
1-Propyl magnesium bromide (3.0 mmol) was added to a mixture of 6-chloro-2-trifluoromethylpurine 222 mg (1.0 mmol), [1,3-bis(diphenylphosphino)-propane]dichloronickel(II) (0.04 mmol) and THF 15 ml at 20° C. under nitrogen. The reaction mixture was allowed to stirred at 50° C. for 12 hours, then cooled to 20 ° C., and 0.2 ml of water was added to quench the reaction. The mixture was diluted with 20 ml ethyl acetate and filtered over celite. Evaporation under vacuo and chromatography (MeOH:EtOAc:hexane=2:50:50) gave the title compound with 30% yield. 1H NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.27 (t, J=8.37 Hz, 1H), 3.29 (t, J=7.5 Hz, 2H), 1.95 (m,2H), 1.02 (t, 7.5 Hz, 2H).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]2[CH3:32])[C:19]([CH3:33])=[C:18]([CH3:34])[N:17]=1>CN(C)C=O>[ClH:15].[CH3:33][C:19]1[C:20]([N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]2[CH3:32])=[N:21][C:16]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:17][C:18]=1[CH3:34]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Reactant: NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(NC2CCCCC2)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Yield: 81.7 %

Procedure:
After cyclohexylamine(0.30 ml, 2.61 mmol) and triethylamine(0.36 ml, 2.59 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.74 mmol) in dimethylformamide, 550 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].O.[CH2:32]([O:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1)[CH3:33].C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:38]3[CH:37]=[N:36][C:35]([O:34][CH2:32][CH3:33])=[CH:40][CH:39]=3)=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2CN(CC)C(=O)C2CC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2CN(CC)C(=O)C2CC2)c1
Temperature: 80 °C

Procedure:
{4′-Bromo-2′-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester (14.5 g, 30.6 mmol) was dissolved in DME (100 mL) and water (50 mL) along with 2-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (9.1 g, 36.5 mmol) and potassium carbonate (10.7 g, 77.4 mmol) under N2 atmosphere. The mixture was purged with N2, and then tetrakis(triphenylphosphine)palladium(0) (0.500 g, 0.43 mmol) was added and the reaction was heated to 80° C. The reaction was monitored by analytical LCMS and when the starting material was consumed, the mixture was cooled to room temperature and diluted with ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-35% ethyl acetate in hexanes) to afford the title compound.