Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C2C(=CC=CC=2)C=C1C(NN)=O.[CH3:14][O:15][C:16](=[O:26])[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[O:24][CH3:25].[Br:27]NC(=O)CCC(N)=O>C(O)C>[CH3:14][O:15][C:16](=[O:26])[C:17]1[CH:22]=[C:21]([Br:27])[C:20]([NH2:23])=[CH:19][C:18]=1[O:24][CH3:25]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: NC(=O)CCC(=O)NBr
Agent: NNC(=O)c1cc2ccccc2[nH]1
Solvent: CCO
Product: COC(=O)c1cc(Br)c(N)cc1OC

Procedure:
An indole hydrazide can also be prepared by treating a solution of 2-methoxy-4-amino-benzoic acid methyl ester (xvii) in ethanol with N-bromosuccinamide to form 2-methoxy-4-amino-5-bromo-benzoic acid methyl ester (xviii) (see Scheme VIII). A solution of 2-methoxy-4-amino-5-bromo-benzoic acid methyl ester (xviii) in DMF is then reacted with trimethyl-prop-1-ynyl silane (xix) in the presence of with palladium acetate, Na2CO3, triphenylphosphine and tetrabutylaminium iodide to form 6-methoxy-3-methyl-2-trimethylsilanyl-1H-indole-5-carboxylic acid methyl ester (xx). Compound (xx) is then treated with an aqueous HCl solution to remove the trimethylsilanyl group and form 6-methoxy-3-methyl-1H-indole-5-carboxylic acid methyl ester (xxi). Compound (xxi) is treated with NaOH in a THF/H2O solution to convert the ester to a carboxylic acid. The carboxylic acid is then activated by treating it with oxalyl chloride in dichloromethane and a catalytic amount of DMF, then the activated carboxylic acid is converted to a hydrazide by treating it with hydrazine hydrate in dichloromethane to form 6-methoxy-3-methyl-1H-indole-5-carboxylic acid hydrazide (xxii). Hydrazide (xxii) can be used in the method of Scheme V or VI to form a compound of the invention
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]=2[O:7][CH2:6][CH2:5]1.[C:20]1([C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([CH3:29])[CH2:27][SH:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:30]1([C:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([CH3:29])[CH2:27][S:28][CH2:2][CH2:3][N:4]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]=3[O:7][CH2:6][CH2:5]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)COc1cccc2c1OCCN2CCO
Reactant: CC(CS)(c1ccccc1)c1ccccc1
Product: COC(=O)COc1cccc2c1OCCN2CCSCC(C)(c1ccccc1)c1ccccc1
Yield: 37.5 %

Procedure:
The same process as Example 1 was repeated except that methyl (4-(2-hydroxyethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate (200 mg) and 2,2-diphenylpropanethiol (410 mg) were used to obtain the colorless oily object compound (134 mg, yield 37%).
Reaction SMILES: [CH:1]1[N:9]2[C:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][C:2]=1[C:14]([OH:16])=O.S(Cl)([Cl:19])=O>>[CH:1]1[N:9]2[C:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][C:2]=1[C:14]([Cl:19])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cn2c(n1)COc1ccccc1-2
Product: O=C(Cl)c1cn2c(n1)COc1ccccc1-2
Yield: 83 %

Procedure:
5 g (0.023 mole) of 4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylic acid were suspended in 15 ml of thionyl chloride and the mixture obtained was refluxed for two hours during which time the solid material completely dissolved. Excess thionyl chloride was removed by azeotroping with benzene on a rotary evaporator and the product was triturated with ether, filtered off and dried to obtain 4.5 g (83% yield of 4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carbonyl chloride with a melting point of 240° C. (decomp).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)O.P(Br)(Br)[Br:17].O>C(OCC)C>[Br:17][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: BrP(Br)Br
Reactant: Cc1ccccc1C(O)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: Cc1ccccc1C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 133.9 %

Procedure:
To a solution of 28.1 g (140 mmol) of 5 in 150 mL of dry diethyl ether, 25.6 g (8.89 mL, 94.4 mmol) of PBr3 was added at −10° C. The resulting mixture was stirred for 12 hr at room temperature and then added to 450 mL of cold water. The organic layer was separated, and the aqueous layer was extracted with 2×150 mL of water. The combined organic extracts were washed with aqueous NaHCO3, dried over Na2SO4, and then evaporated to dryness. This procedure gave 33.0 g (89%) of the title product.
Reaction SMILES: [NH:1]([C:22]([O:24]C(C)(C)C)=O)[C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.CCOC(C)=O.C1C=CC2N(O)N=NC=2C=1.[N:46]1([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:54][C@H:52]([OH:53])[CH2:51][C@H:47]1C(O)=O.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[N:46]1([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:54][C@H:52]([OH:53])[CH2:51][C@H:47]1[C:22]([NH:1][C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:24]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)NOCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)NCC(=O)NOCc1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To Boc-Leu-Gly-NHOBzl (3.89 g; 9.89 mmol) obtained in Example 1 (C) was added under ice cooling 4.5N-HCl/AcOEt (30 ml), and the solution was brought back to room temperature. The reaction was carried out for 1 hour. The solvent was distilled off under reduced pressure and the residue was dissolved in THF (100 ml). The solution was cooled with a coolant at -20° C. After TEA (1.40 ml; 10.0 mmol) was added dropwise, HOBt (1.22 g; 9.03 mmol) and Boc-Hyp-OH (1.99 g; 8.60 mmol) were added and DCC (2.31 g; 11.2 mmol) dissolved in THF (10 ml) was added dropwise. The reaction was carried out for 1 hour at -10° C. and overnight in a refrigerator. Insolubles were filtered off and the solvent was then distilled off under reduced pressure. The residue was dissolved in AcOEt and the solution was washed successively with water, 1N-HCl, water, 10% Na2CO3 and water and then dried over anhydrous MgSO4. The solvent was distilled off under reduced pressure and the residue was recrystallized from AcOEt to give Boc-Hyp-Leu-Gly-NHOBzl (2.45 g; 56%) as colorless crystals. m.p. 168°-173° C., specific rotation [α]D28 -50.8 (c= 1.0, EtOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[CH2:7][C:8](=[O:29])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([NH2:27])=[C:22]([Cl:28])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.C=O.[C:36]([BH3-])#N.[Na+]>>[CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[CH2:7][C:8](=[O:29])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:36])[CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([NH2:27])=[C:22]([Cl:28])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: [BH3-]C#N
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCNCCCNc1cc(Cl)c(N)c(Cl)c1)CC2
Agent: C=O
Agent: [Na+]
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCCNc1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-3-(4-amino-3,5-dichlorophenylamino)-propylamine, paraformaldehyde and sodium cyanoborohydride analogously to Example 5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([C:14](O)=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)C>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Cl)cc2)cc1C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccc(Cl)cc2)cc1CO
Reaction time: 18 h
Yield: 57.2 %

Procedure:
To a solution of 5-(4-chlorophenyl)-2-methylfuran-3-carboxylic acid (0.104 g, 0.44 mmol) in THF (2 mL) and MeOH (2 mL) was added TMSCHN2 (2.0 M in Et2O, 0.250 mL). The reaction mixture was stirred for 18 hours at which time it was concentrated in vacuo. The residue was dissolved in 1 ml of THF at 0° C., and a solution of LAH (1.0 M in THF, 0.8 mL) was added. After addition, the reaction was stirred at room temperature for 2 hours, and then water (0.24 mL), 15% aqueous NaOH (0.24 mL), and water (0.72 mL) were added sequentially to the reaction. After 30 minutes, the reaction mixture was filtered through celite, and the filtrate was concentrated to give 53.1 (0.056 g). 1H NMR (400 MHz, CDCl3) δ ppm 7.53-7.63 (m, 2 H), 7.31-7.40 (m, 2 H), 6.64 (s, 1 H), 4.52 (s, 2 H), 2.37 (s, 3 H).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].OO.CC(C)=[O:56]>CO.O>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N+:41]([O-:56])([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: CC(C)=O
Agent: OO
Solvent: CO
Solvent: O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H]([N+](C)(C)[O-])[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
220.2 g(0.3 mol) of erythromycin A was dissolved in a mixture of 1,500 ml of methanol and 1,000 ml of water. 79 ml(0.9 mol) of 35% hydrogen peroxide was added dropwise to the solution at a temperature ranging from 15 to 20° C. and stirred at room temperature for 20 hours in a similar method described in E. H. Flynn et al., J. Am. Chem. Soc., 76, 3121(1954) and P. H. Jones et al., J. Org. Chem., 33, 665(1968). The resulting mixture was concentrated to a half volume under a reduced pressure and extracted successively with 1,000 ml and 500 ml portions of chloroform. The combined chloroform extract was washed with brine, dried over anhydrous magnesium sulfate, and then, concentrated under a reduced pressure to obtain a foamy residue. 1,000 ml of acetone was added to the residue and stirred at room temperature for 3 hours. The crystalline material formed was filtered and dried overnight at 45° C. to obtain 220 g of erythromycin a N-oxide in a yield of 98%.
Reaction SMILES: [OH:1][C@@H:2]([CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O-:12])=O)[CH2:6][CH2:5]1.[Li+].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:26]([NH:33][C:10]([CH:7]1[CH2:6][CH2:5][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[N:20]3)[CH2:9][CH2:8]1)=[O:12])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C([O-])C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Reactant: NCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Reaction time: 18 h

Procedure:
Lithium (R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-4-carboxylate (32) (100 mg; 0.297 mmol) is dissolved in methylene chloride (3 mL) at ambient temperature. Benzylamine (39) (33 mg; 0.312 mmol), N,N-diisopropylethylamine (85 mg; 0.654 mmol) and PyBOP (186 mg; 0.357 mmol) are added sequentially. The reaction is stirred for 18 hr. at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography with gradient elution (90% ethyl acetate in hexanes, then 50%→100% acetone in hexanes) affording the desired product (40) as an oil. CIMS (NH3Cl): 420 (MH+)
Reaction SMILES: [CH2:1]([C:5]1[N:9]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22]Br)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:8]2[CH:24]=[CH:25][CH:26]=[CH:27][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31].O>CS(C)=O>[CH2:1]([C:5]1[N:9]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:32]([CH2:5][CH2:1][CH2:2][CH3:3])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:8]2[CH:24]=[CH:25][CH:26]=[CH:27][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CCCCc1nc2ccccc2n1S(=O)(=O)c1ccc(OCCCBr)cc1
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc2ccccc2n1S(=O)(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Reaction time: 17 h

Procedure:
To a solution of 0.0017 mol of 2-n-butyl-1-(4-bromopropoxy-benzenesulphonyl) benzimidazole in 15 ml of dimethylsulphoxide was added 0.0034 mol of n-butylamine. The reaction medium was allowed to stand for 17 hours at room-temperature and then poured into 50 ml of water. After extraction, the ethereal phase was dried and evaporated to dryness. The residue so obtained was purified by chromatography on a silica column (eluent: dichloromethane/ethyl acetate) to obtain an oil which was the desired product in the form of the free base (yield: 50%). The oxalate of the base so provided was formed by dissolving the base in question into ethyl ether and adding an ethereal solution of oxalic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:54][O:55][CH2:56][CH2:57][NH2:58]>O.CN(C)C=O>[CH3:54][O:55][CH2:56][CH2:57][NH:58][C:18](=[O:20])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)=[CH:4][C:3]=3[O:2][CH3:1])=[N:16][CH2:15]1
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCCNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.3 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg), 1-hydroxybenzotriazole (130 mg), 2-methoxyethylamine (100 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 20 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (200 mg, 59%) as pale yellow prisms. MS 519 (MH+). mp 175-176° C.
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.[F:8][C:9]1([F:24])[CH2:14][CH2:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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.O>[F:8][C:9]1([F:24])[CH2:14][CH2:13][C:12]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=2)=[CH:11][CH2:10]1
Reactant: Cn1nccc1I
Reactant: CC1(C)OB(C2=CCC(F)(F)CC2)OC1(C)C
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1C1=CCC(F)(F)CC1
Yield: 94.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 39a by using 5-iodo-1-methyl-1H-pyrazole (1.90 g, 9.14 mmol), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.00 g, 4.10 mmol), tetrakis(triphenylphosphine)palladium (0) (240 mg, 0.208 mmol), cesium carbonate (2.70 g, 8.29 mmol), 1,4-dioxane (10 mL) and water (5 mL), to yield the title compound (767 mg, 94%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.[Br:16][C:17]1[CH:18]=[C:19]([C@@H:23]2[CH2:29][NH:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>>[Br:16][C:17]1[CH:18]=[C:19]([C@@H:23]2[CH2:29][N:28]([C:2]3[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][N:13]=[CH:12][N:11]=4)[N:3]=3)[CH2:27][CH2:26][CH2:25][O:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: Brc1cccc([C@@H]2CNCCCO2)c1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCCO[C@H](c3cccc(Br)c3)C2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (1.00 g, 4.49 mmol) and (R)-2-(3-bromophenyl)-[1,4]oxazepane (1.58 g, 5.39 mmol) was added triethylamine (1.36 g, 13.5 mmol) at room temperature. The mixture was stirred at room temperature for 9 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: ethyl acetate) to afford (R)-2-[2-(3-bromo-phenyl)-[1,4]oxazepan-4-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (A079) as white solid (1.65 g, 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][O:18][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCc1cccc(OCc2ccccc2)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCc1cccc(OCc2ccccc2)c1
Reaction time: 2 h
Yield: 116.3 %

Procedure:
To a solution of 3-[3-(benzyloxy)phenyl]-1-propanol (1.73 g) in DMF (20 mL) were added imidazole (1.07 g) and tert-butyldimethylchlorosilane (1.83 g) at ambient temperature and the mixture was stirred at the same temperature for 2 hours. Water (20 mL) was added to the mixture at ambient temperature and the mixture was extracted with EtOAc (20 mL) two times. The organic layer was washed successively with 12% NaCl aqueous solution and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo to afford {3-[3-(benzyloxy)phenyl]propoxy}(tert-butyl)dimethylsilane (2.96 g) as a colorless oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:14][C@H:13]([S:15][C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C@H:11]2[CH2:35]O)=[N:8][CH:9]=1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:56]1(=[O:66])[NH:60][C:59](=[O:61])[C:58]2=[CH:62][CH:63]=[CH:64][CH:65]=[C:57]12.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:14][C@H:13]([S:15][C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C@H:11]2[CH2:35][N:60]2[C:56](=[O:66])[C:57]3[C:58](=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:59]2=[O:61])=[N:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1cnc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CO)nc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cnc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN2C(=O)c3ccccc3C2=O)nc1
Temperature: 0 °C
Yield: 96 %

Procedure:
1.0 g (2.0 mmol) (2S,4R)-[1-(5-Propyl-pyrimidin-2-yl)-4-tritylsulfanyl-pyrrolidin-2-yl]-methanol in 15 ml THF were treated with 764 mg (2.82 mmol) triphenyl phosphine and 420 mg (2.82 mmol) phthalimide at RT. The solution was cooled to 0° C. and 615 μl (3.83 mmol) diethylazo dicarboxylate in 3 ml THF were added. The solution was stirred at RT over night, H2O was added and the inorganic layer was extracted with ETOAc. The combined layers were washed with 1M NaOH, sat. NaHCO3 solution and brine, and were dried over Na2SO4. Column chromatography with EtOAc:hexane 1:2 as eluent yielded 1.20 g (95%) (2S,4R)-2-[1-(5-Propyl-pyrimidin-2-yl)-4-tritylsulfanyl-pyrrolidin-2-ylmethyl]-isoindole-1,3-dione as white solid, MS: 625 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)[CH3:2].CN(CCN(CCN(C)C)C)C.[Li]CCCC.B(OC)(OC)[O:28]C>C1COCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([OH:28])[CH:8]=1)[CH3:2]
Reactant: COB(OC)OC
Reactant: CCc1ccc(F)cc1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(F)c(O)c1
Temperature: -60 °C
Reaction time: 0.67 h
Yield: 96 %

Procedure:
To a solution of 1-ethyl-4-fluorobenzene (5.0 g, 40.3 mmol) and PMDTA (8.5 mL, 40.7 mmol) in 20 mL THF at −40° C., was added BuLi (1.4 M in hexanes, 31.6 mL, 44.3 mmol). The tan suspension was stirred at −60° C. for 40 min, was recooled to −78° C., then B(OMe)3 (9.03 mL, 80.6 mmol). The mixture was stirred at −78° C. for 30 min, then was allowed to warm to rt. The reaction was quenched with 8 mL AcOH, then was cooled to 0° C. and treated with 9.8 mL 30% H2O2. The mixture was stirred for 30 min, then was quenched with aq. Na2SO3. The mixture was diluted with hexanes, washed with H2O (3×) and brine, dried (Na2SO4), filtered through 2″ silica gel (eluting with 20% EtOAc/hexanes), then concentrated to afford 5.42 g of Intermediate 188.1 as a pale yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([O:18][CH3:19])=[CH:7][C:8]([N+:15]([O-])=O)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11]>[Pd].CCOC(C)=O.CO>[NH2:15][C:8]1[CH:7]=[C:6]([O:18][CH3:19])[C:5]([O:4][CH2:3][CH2:2][Cl:1])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(OCCCl)c(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OCCCl)c(OC)cc1N
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To methyl 5-(2-chloroethoxy)-4-methoxy-2-nitrobenzoate (4.07 g, 14.1 mmol) under argon was added 10% palladium on carbon and in EtOAc (150 mL) and MeOH (50 mL). The flask was flushed with H2 (g) and stirred under H2 (1 atm) for 30 minutes. The mixture was filtered through Celite and concentrated in vacuo to give methyl 2-amino-5-(2-chloroethoxy)-4-methoxybenzoate (3.61 g, 13.9 mmol, 99%). 1H NMR (300 MHz, DMSO-d6) δ 7.20 (s, 1H), 6.52 (br s, 2H), 6.38 (s, 1H), 4.07 (t, 2H), 3.85 (t, 2H), 3.77 (s, 3H), 3.75 (s, 3H); LC-MS (ESI) m/z 260 (M+H)+.