Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:10][CH2:9][CH2:8][N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[C:6](=[O:28])[NH:5]1.Br[C:38]1[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[OH:1][C:2]([CH3:35])([CH3:36])[CH2:3][C@:4]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:10][CH2:9][CH2:8][N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:38]3[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=3)=[CH:17][CH:18]=2)[CH3:12])[C:6](=[O:28])[NH:5]1
Reactant: Cn1ccc(Br)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Temperature: 130 °C
Yield: 39.1 %

Procedure:
(S)-4-(2-hydroxy-2-methylpropyl)-4-phenyl-1-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-diazepan-2-one (10 mg, 0.02 mmol), 4-bromo-1-methylpyridin-2(1H)-one (7.6 mg, 2 equiv.), Pd(PPh3)2Cl2 (1 mg, cat. amount), 2M aq Na2CO3 solution (200 μL, excess), and 1,4-dioxane (2 mL) were mixed. The mixture was evacuated and refilled with Nitrogen gas 3×, before being heated to 130° C. in the microwave oven for 2 h. After being cooled down, the mixture was concentrated, acidified with 5% aq HCl and purified by prep HPLC to afford (S)-4-(2-hydroxy-2-methylpropyl)-1-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-4-phenyl-1,3-diazepan-2-one (3.7 mg, 38%). LC-MS Method 1 tR=1.53 min., m/z 474 (M+1); H1 NMR (CD3OD) δ 7.63 (d, 1H), 7.51 (d, 2H), 7.43 (d, 2H), 7.32 (t, 2H), 7.22 (t, 1H), 7.14 (d, 2H), 6.74-6.59 (m, 2H), 5.42 (q, 1H), 3.55 (s, 3H), 2.89 (m, 1H), 2.71 (m, 1H), 2.34 (d, 1H), 1.49 (d, 3H), 1.12 (s, 3H), 0.54 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:6]=[CH:7][C:8]([NH:10][C:11]1[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:13]([O-:15])=[O:14])=[O:9].[NH2+]1CCCCC1.Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:6]=[CH:7][C:8]([NH:10][C:11]1[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:13]([OH:15])=[O:14])=[O:9]
Reactant: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)[O-])cc1OC
Agent: C1CC[NH2+]CC1
Agent: Cl
Solvent: O
Product: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 98 %

Procedure:
A 20 g quantity of piperidinium N-(3,4-dimethoxycinnamoyl)anthranilate is dissolved in 60 ml of water with heating, and the resultant aqueous solution is added dropwise to 45 ml of diluted hydrochloric acid (5 ml of conc. hydrochloric acid and 40 ml of water) with stirring. The precipitated crystals which form are collected by filtration, washed with water and then dried at 90°-100° C. under reduced pressure for 3 hours to yield 15.5 g of N-(3,4-dimethoxycinnamoyl)anthranilic acid (98.0% yield), m.p. 208°-208.5° C. The compound structure is confirmed by elemental analysis, and by IR and NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C@H:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:57]([O:59][C:60]([CH2:62][C@@H:63]1[CH2:67][CH2:66][CH2:65][NH:64]1)=[O:61])[CH3:58].ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:64]1[CH2:65][CH2:66][CH2:67][C@H:63]1[CH2:62][C:60]([O:59][CH2:57][CH3:58])=[O:61])=[O:5])[C:11]([NH:13][C@H:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: C[C@H](NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCOC(=O)C[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CCCN1C(=O)c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Yield: 64 %

Procedure:
Prepared analogously to Example 1g from (1S)-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine, and (S)-2-(ethoxycarbonylmethyl)pyrrolidine in tetrahydrofuran. Yield: 64%; Rf value: 0.42 (silica gel: dichloromethane/ethanol=9:1); C25H26C12N4O4 (517.728); mass spectrum: (M−H)-=515/517/519 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12](SC)[N:13]=1.[NH2:26][C@H:27]([CH3:30])[CH2:28][OH:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12]([NH:26][C@H:27]([CH3:30])[CH2:28][OH:29])[N:13]=1
Reactant: C[C@@H](N)CO
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(SC)nc21
Product: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(N[C@H](C)CO)nc21

Procedure:
The product of Example 44, and (R)-2-aminopropan-1-ol were reacted by the procedure of Example 60 to afford the title compound 4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-2-((R)-2-hydroxy-1-methyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 0.81 (m, 6H), 1.30 (m, 2H), 1.96 (m, 2H), 2.36 (m, 2H), 3.71 (m, 2H), 4.25 (m, 1H), 5.31 (m, 0.5H), 5.56 (m, 0.5H), 5.71 (br s, 1H), 6.26 (br d, 1H, J=9.6), 7.12 (d, 1H, J=9.6 Hz), 7.30-7.54 (m, 4H). LC MS (m/e)=401 (MH+). Rt=2.07 min.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([OH:10])=[CH:8][C:7]([Br:11])=[CH:6][N:5]=1.Br[C:13]([CH3:20])([CH3:19])[C:14](OCC)=[O:15].O>CN(C)C=O>[Br:11][C:7]1[CH:6]=[N:5][C:4]2[NH:3][C:14](=[O:15])[C:13]([CH3:20])([CH3:19])[O:10][C:9]=2[CH:8]=1
Reactant: Nc1ncc(Br)cc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)Oc2cc(Br)cnc2NC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20.6 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.68 g) in N,N-dimethylformamide (15 mL) was added dropwise a solution of 2-amino-5-bromopyridin-3-ol (3.22 g) in N,N-dimethylformamide (25 mL) at room temperature over a period of 10 minutes, and the mixture was stirred at room temperature for 20 minutes. To the mixture was added dropwise ethyl α-bromoisobutyrate (3.32 g) over a period of 20 minutes, and the reaction mixture was stirred at room temperature for 1 hour and at 80° C. for 2 hours. After cooling, to the reaction mixture was added cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively water and brine, dried over magnesium sulfate and concentrated in vacuo by a half volume. The precipitates were collected by filtration to give 7-bromo-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (0.90 g) was obtained as a powder.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[CH:18]2.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N+:17]([O-:9])=[CH:18]2
Reactant: Brc1cccc2cnccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc2c(Br)cccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
Aqueous meta-chloroperbenzoic acid (65%, 29 g) was added to a solution of 5-bromoisoquinoline (20.7 g) in chloroform (250 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with an aqueous sodium hydroxide solution with cooling in an ice bath and partitioned into organic and aqueous layers. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and small amounts of chloroform and diethyl ether were added to the residue. The deposit was filtrated to obtain compound (1a) (11.8 g, 50%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([O:19]C)=[O:18])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCCC1.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCCCOC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCCCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 40 h
Yield: 100.2 %

Procedure:
To a solution of 6.65 g (23 mmol) of N-tert-butoxycarbonyl-O-(4-pentenyl)-L-serine, methyl ester in 500 mL of tetrahydrofuran at room temperature was added a solution of 1.95 g (46 mmol) of lithium hydroxide monohydrate in 100 mL of water. The resulting mixture was stirred at room temperature for 40 hours. To the reaction mixture then was added 46 mL of 1.00N hydrochloric acid. The mixture was diluted with ethyl acetate, washed with water (3×) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 6.30 g of N-tert-butoxycarbonyl-O-(4-pentenyl)-L-serine as a colorless oil. NMR (300 MHz, CDCl3): δ 5.77 (d of d of t, 1H, J=17.2, 10.2, 6.6 Hz), 5.37 (br d, 1H, J=8.0 Hz), 5.03-4.92 (m, 2H), 4.42 (m, 1H), 3.87 (d of d, 1H, J=9.5, 2.6 Hz), 3.63 (d of d, 1H, J=9.5, 4.0 Hz), 3.45 (t, 2H, J=6.6 Hz), 2.07 (quart., 2H, J=7.3 Hz), 1.64 (quint., 2H, J=7.3 Hz), 1.44 (s, 9H).
Reaction SMILES: Br[C:2]1[N:3]([C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH2:21])[C:19]=2[N:20]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@@:5]1([CH3:13])[OH:6].[NH3:22]>>[NH2:22][C:2]1[N:3]([C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH2:21])[C:19]=2[N:20]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@@:5]1([CH3:13])[OH:6]
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1c(Br)nc2c(N)ncnc21
Reactant: N
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1c(N)nc2c(N)ncnc21

Procedure:
A solution of the compound from Step A (38 mg, 0.11 mmol) in liquid ammonia (10 mL) was heated in a stainless steel autoclave at 105° C. for 1 d, then cooled and evaporated. The residue was purified by HPLC [C-18 Phenomenex Luna (10μ; 250×21.2 mm) RP-column; solvents: (A) water, (13) acetonitrile; Linear gradient: 2-35% B in 76 min.] to yield the title compound (12 mg) as a white fluffy material after freeze-drying.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5](I)=[CH:4][N:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[CH:4][N:3]=1
Reactant: OCCNc1nc(Cl)ncc1I
Reactant: OB(O)c1cccs1
Product: OCCNc1nc(Cl)ncc1-c1cccs1
Yield: 82 %

Procedure:
In the reaction of 2-(2-chloro-5-iodopyrimidine-4-ylamino)-ethanol (300 mg, 1.0 mmol) with thiophen-2-boronic acid (140 mg, 1.1 mmol) according to procedure 3, the desired product is obtained in 82% yield (210 mg) after chromatographic purification (silica gel, ethyl acetate/hexane (0%-100% ethyl acetate)).
Reaction SMILES: [S:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[CH3:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[S:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:18][C:17]2[CH:19]=[CH:20][C:14]([CH3:13])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: Cc1ccc(N)cc1
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Product: Cc1ccc(N=Cc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-sulfamoylbenzaldehyde and 4-methylaniline as starting materials, the title compound was obtained as a yellow powder (yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](I)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:24]3[CH:23]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:32])([F:33])[F:34])=[O:28])[CH:21]=[CH:20][CH:25]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Reactant: Clc1ccn2c(I)cnc2c1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)ccn23)c1
Temperature: 80 °C

Procedure:
To a solution of 7-chloro-3-iodo-imidazo[1,2-a]pyridine (5.0 g, 17.8 mmol) in DME (350 ml) was added 1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (7.36 g, 21.4 mmol), 2M Na2CO3 (71.6 ml, 35.8 mmol) [reaction degassed by bubbling N2 through] followed by tetrakis(triphenylphosphine)palladium(0) (1.03 g, 0.89 mmol). The mixture was heated at 80° C. overnight, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The crude material was triturated with CH2Cl2 to afford the desired product as a beige solid. MS: [M+H]+ 389
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7](O)[CH3:8])=[CH:3][CH:2]=1.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C.O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([N:14]2[C:10](=[O:20])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:15])[CH3:8])=[CH:3][CH:2]=1
Reactant: CC(O)c1ccncc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(c1ccncc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 29 h
Yield: 48.4 %

Procedure:
A tetrahydrofuran solution (10 mL) of 1-(pyridin-4-yl)ethanol (283 mg, 2.32 mmol), phthalimide (375 mg, 2.55 mmol) and triphenylphosphine (686 mg, 2.55 mmol) was mixed with diisopropyl azodicarboxylate (40% in toluene, 1.34 mL, 2.55 mmol) and stirred at room temperature for 29 hours. After completion of the reaction, the reaction solution was mixed with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate=10/1) to give the desired product (283 mg, 48% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[C:33]([F:32])([F:42])[F:43])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccccc2C(F)(F)F)CCc2ccc(C#N)cc2)cc1

Procedure:
A solution of 438 mg (1.02 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 20 ml of dry acetonitrile is mixed with 382 mg (1.6 mmol) of 2-trifluoromethylbenzyl bromide and 441.3 mg (3.19 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by preparative HPLC. 181 mg (0.32 mmol, 31.3% of theory) of a colorless foam are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][CH3:17])=O.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.O>CCCCCC.C(OCC)(=O)C>[CH3:17][S:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: CSc1ccccc1C(=O)c1ccccc1O
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: CSc1ccccc1Cc1ccccc1O
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a mixture of 0.337 g (2-hydroxyphenyl)(2-(methylthio)phenyl)methanone (H) (1.38 mmol) and 0.5 ml triethylsilane was added 2 ml TFA. After 1 h, water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, and concentrated. Flash silica chromatography (hexane:ethyl acetate 80:20) afforded 0.235 g product (1.02 mmol, 74% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:34])[C:5]([O:26]CC2C=CC=CC=2)=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17]CC3C=CC=CC=3)=[C:13]([F:25])[CH:12]=1)[CH:8]=[CH:7]2>C(OCC)(=O)C.[Pd]>[Br:1][C:2]1[C:10]2[N:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:25])[CH:12]=3)[CH:8]=[CH:7][C:6]=2[C:5]([OH:26])=[C:4]([F:34])[CH:3]=1
Reactant: Fc1cc(-n2ccc3c(OCc4ccccc4)c(F)cc(Br)c32)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1ccc(-n2ccc3c(O)c(F)cc(Br)c32)cc1F

Procedure:
The 7-bromo-5-fluoro-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-4-[(phenylmethyl)oxy]-1H-indole (D6) (442 mg, 0.849 mmol) in ethyl acetate (20 mL) was hydrogenated in the H-cube over 10% Pd—C at a flow rate of 1 mL/min. The product mixture was evaporated and chromatographed (silica gel, ethyl acetate in hexane) to give material that was further purified by MDAP to give the title compound (E4) as an off white solid. (84 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=3)[CH2:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Pb+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1[CH:68]1[CH2:73][NH:72][CH2:71][CH2:70][N:69]1[CH3:74]>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:72]4[CH2:71][CH2:70][N:69]([CH2:68][C:63]5[CH:64]=[CH:65][CH:66]=[CH:67][N:62]=5)[CH2:74][CH2:73]4)=[CH:17][CH:16]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1O[C@H](c2ccc(Cl)cc2)CN1Cc1ccc(I)cc1
Reactant: CN1CCNCC1c1ccccn1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C1O[C@H](c2ccc(Cl)cc2)CN1Cc1ccc(N2CCN(Cc3ccccn3)CC2)cc1
Temperature: 100 °C
Yield: 54 %

Procedure:
To a suspension of 5-(R)-(4-Chloro-phenyl)-3-(4-Iodo-benzyl)-oxazolidin-2-one (50 mg, 0.12 mmol), lead acetate (3 mg, 0.012 mmol), 2-(dicyclohexyl phosphino) biphenyl (5 mg, 0.014 mmol) and cesium carbonate (118 mg, 0.36 mmol) in toluene (2.5 mL), was added 2-pyridyl methyl piperazine and the reaction flask was heated at 100° C. for 3 h. The reaction mixture was diluted with dichloromethane (6 mL), washed with water (3 mL), brine (3 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with dichloromethane containing 0.5-2% ammonia (2 M) in methanol The title compound was isolated as an off white solid (30 mg, 54%). 1H NMR (300 MHz, CDCl3): δ 8.6 (m, 1H), 7.69 (m, 1H), 7.44 (d, 1H), 7.35 (m, 2H), 7.25 (m, 5H), 6.88 (m, 2H), 5.42 (t, 1H), 4.45 (d, 1H), 4.33 (d, 1H), 3.75 (m, 3H), 3.24 (m, 5H), 2.69 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:16])[C:6]=2[CH:17]=1.FC(F)(F)C([NH2:22])=O.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu]I.CO.O>[NH2:22][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:16])[C:6]=2[CH:17]=1
Reactant: NC(=O)C(F)(F)F
Reactant: COC(=O)C1=C(C)c2cc(Br)ccc2CCC1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C1=C(C)c2cc(N)ccc2CCC1
Temperature: 120 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a solution of (E)-methyl 2-bromo-9-methyl-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate from step B2 of preparation B (500 mg, 1.694 mmol) in dioxane (5 mL) was added 2,2,2-trifluoroacetamide (1.92 g, 16.94 mmol), copper(I) iodide (323 mg, 1.69 mmol), N1,N2-dimethylethane-1,2-diamine (448 mg, 5.08 mmol) and potassium carbonate (702 mg, 5.08 mmol). The mixture was heated in a microwave reactor at 120° C. for 2 h and 15 min. Then water (3 mL), MeOH (3 mL), and potassium carbonate (1 g) were added. The mixture was stirred at rt for 16 h. The mixture was concentrated, the residue was diluted with water (50 mL), and the mixture was extracted with EtOAc. The organic layers were combined, and concentrated. The residue was purified by silica gel column chromatography (hexanes-50% EtOAc) to afford methyl 2-amino-9-methyl-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate (260 mg, 1.12 mmol, 66% yield). 1H NMR (400 MHz, chloroform-d) δ 6.96 (d, J=8.0 Hz, 1H), 6.65 (d, J=2.3 Hz, 1H), 6.58 (dd, J=7.8, 2.5 Hz, 1H), 3.80 (s, 3H), 3.62 (br. s., 2H), 2.46 (t, J=6.9 Hz, 2H), 2.37 (s, 3H), 2.17-2.01 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)=[O:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(I)cc1
Reactant: O=Cc1ccc(Cl)cc1
Product: O=C(C=Cc1ccc(Cl)cc1)c1ccc(I)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and 4-iodoacetophenone, 3-(4-chlorophenyl)-1-(4-iodophenyl)prop-2-en-1-one was obtained as beige coloured solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:15]3[CH:16]=[CH:17][CH:18]([CH3:20])[O:19][C:14]=3[C:13]([O:21][CH3:22])=[C:12]([O:23][CH3:24])[CH:11]=2)=[CH:4][N:3]=1.CC(C)([O-])C.[K+]>CS(C)=O.O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:15]3[CH2:16][CH:17]=[C:18]([CH3:20])[O:19][C:14]=3[C:13]([O:21][CH3:22])=[C:12]([O:23][CH3:24])[CH:11]=2)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)c2c(c1OC)OC(C)C=C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(Cc2cnc(N)nc2N)c2c(c1OC)OC(C)=CC2
Yield: 84.9 %

Procedure:
A solution of 2,4-diamino-5-(7,8-dimethoxy-2-methyl-2H-1-benzopyran-5-ylmethyl)pyrimidine (967 mg, 2.94 mmol) and potassium t-butoxide (991 mg, 8.83 mmol) in dimethyl sulfoxide was maintained at 60°-70° for 0.5 hr under nitrogen. The solution was cooled and diluted with water (50 mL). The resulting precipitate (920 mg) was recrystallized from 95% ethanol to give the title compound as white crystals (820 mg, 85%), mp 215°-217° dec., structure confirmed by NMR spectrum. Anal. Calcd for C17H20N4O3 : C, 62.18; H, 6.14; N, 17.06. Found: C, 61.95; H, 6.20; N, 17.00.