Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC.[CH3:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O.[C:13]([OH:17])(=[O:16])[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[C:13]([O:17][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH3:4])(=[O:16])[CH:14]=[CH2:15]
Reactant: COCCCCCCO
Reactant: C=CC(=O)O
Agent: COC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCCCCCOC

Procedure:
803.6 grams of the monomethyl ether described in Part (A) above were azeotropically esterified with 629.8 grams acrylic acid in 254.6 grams toluene in the presence of 24 grams p-toluenesulfonic acid and inhibitors until no more water was collected. Conditions were 95°-98° C., nitrogen sparge in vacuo. On completion, the product was washed and neutralized with sodium carbonate. 900 ppm p-methoxyphenol (MEHQ) was added and the solvent removed at 80° C. with maximum vacuum in the presence of an air sparge. Filter aid was added and the product filtered at 60° C. to give a clear, yellow liquid having a viscosity of 6.5 cps and a Gardener color of 3. Equipment used was a 2 liter flask, thermometer, Dean-Stark condenser and sparge tube.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[NH:26][C:27]4[CH:37]=[CH:36][C:35]5[C:30](=[C:31]([OH:42])[CH:32]=[C:33]([S:38](Cl)(=[O:40])=[O:39])[CH:34]=5)[C:28]=4[N:29]=3)[CH:20]=2)[CH:15]=[CH:16][C:17]=1[CH3:18].Cl>C1COCC1.O>[CH3:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[NH:26][C:27]4[CH:37]=[CH:36][C:35]5[C:30](=[C:31]([OH:42])[CH:32]=[C:33]([S:38]([NH:1][C:2]6[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=6)[C:5]([OH:7])=[O:6])(=[O:40])=[O:39])[CH:34]=5)[C:28]=4[N:29]=3)[CH:20]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(S(=O)(=O)Cl)cc(O)c54)[nH]3)c2)cc1C
Reactant: Nc1cccc(C(=O)O)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(S(=O)(=O)Nc6cccc(C(=O)O)c6)cc(O)c54)[nH]3)c2)cc1C
Reaction time: 0.5 h
Yield: 4.9 %

Procedure:
To an agitated suspension of 3-aminobenzoic acid (0.028 g, 0.2 mmol) in THF (1 mL) was added 2-(3′,4′-dimethylbiphenyl-3-yl)-9-hydroxyl-3H-naphtho[1,2-d]imidazole-7-sulfonyl chloride (0.083 g, 0.18 mmol) and sodium hydroxy (0.018 g, 0.4 mmol) in water (0.5 mL). After agitated for 30 minutes, the reaction mixture was added 6N hydrochloride (2 ml) and concentrated under reduced pressure. The residue was subjected to HPLC (ODS-A, gradient 10-90% CH3CN/water 0.1% TFA) to provide the title compound (0.005 g, 4%) MS(ES) m/z 564 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:13](=[O:14])[NH:12][N:11]=[N:10]2)=[CH:4][C:3]=1[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CS(O[CH2:27][CH2:28][CH2:29][F:30])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:27][CH2:28][CH2:29][F:30])[N:11]=[N:10]2)=[CH:4][C:3]=1[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C=Cc1cc(-n2nn[nH]c2=O)c(F)cc1Cl
Reactant: CS(=O)(=O)OCCCF
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cc(-n2nnn(CCCF)c2=O)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
To a stirred mixture of 2.62 g (0.00830 mole) of ethyl 3-[2-chloro-4-fluoro-5-(1,4-dihydro-5-oxo-5H-tetrazol-1-yl)phenyl]propenoate in 20 mL of N,N-dimethylformamide was added 1.46 g (0.00939 mole) of 3-fluoropropyl methanesulfonate and 1.30 g (0.00939 mole) of potassium carbonate. The reaction mixture was heated at 50°-60° C. and was stirred at that temperature for approximately 18 hours. The mixture was cooled and was poured into ice water. This mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure to yield 0.76 g of ethyl 3-[2-chloro-4-fluoro-5-[4-(3-fluoropropyl)-1,4-dihydro-5-oxo-5H-tetrazol-1-yl]phenyl]propenoate as an oil, compound 4 of Table 1.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:15])[NH:9]2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:15])[NH:9]2)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)c2[nH]c(=O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
5-Acetyl-8-hydroxy-1H-quinolin-2-one (430 g, 2.12 mol) was suspended in N,N-dimethylformamide (3.3 L), potassium carbonate (298 g, 2.16 mol) and subsequently benzyl bromide (298 g, 2.11 mol) were added thereto, and the mixture was stirred at room temperature for 2 hours. The insoluble matter was removed by filtration and washed with N,N-dimethylformamide. The filtrate and the washing were mixed and concentrated under reduced pressure. To the residue was added purified water (3.3 L) and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration, washed with purified water, and dried under vacuum to obtain 5-acetyl-8-benzyloxy-1H-quinolin-2-one (541 g).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+].O>C(O)C>[C:1](=[N:14]/[OH:15])(\[C:4]1[N:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)/[CH3:2]
Reactant: NO
Reactant: CCOc1ccnc(C(C)=O)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ccnc(/C(C)=N/O)n1
Yield: 58.6 %

Procedure:
A solution of 2-acetyl-4-ethoxypyrimidine (1.8 g), hydroxylamine hydrochloride (0.83 g) and sodium acetate (2.2 g) in a mixture of ethanol:water (30:10 ml) was heated under reflux for 3 hours. The reaction mixture was then poured into water and extracted with ethyl acetate (×3). the combined extracts were washed with brine, dried and concentrated to give a solid which was washed with hexane to give (E)-2-acetyl-4-ethoxypyrimidine oxime as an off-white solid (1.15 g, 60% yield); 1H NMR (270 MHz): δ1.44(3H,t), 2.38(3H,s), 4.50(2H,q), 6.68(1H,d), 8.48(1H,d), 9.80(1H,brs) ppm.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11](F)[C:8]=1[C:9]#[N:10]>>[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([O:4][CH2:3][C@@H:2]([NH2:1])[CH3:5])[C:8]=1[C:9]#[N:10]
Reactant: N#Cc1c(N)cccc1F
Reactant: C[C@H](N)CO
Product: C[C@H](N)COc1cccc(N)c1C#N

Procedure:
Prepared as in Example 24d from (S)-2-aminopropan-1-ol and 2-amino-6-fluorobenzonitrile as brown solid (73%). 1H NR (400 MHz, DMSO-d6) δ 1.01 (d, J=6.5 Hz, 3H), 3.08 (m, 1H), 3.71 (d, J=6.1 Hz, 2H), 5.95 (s, 2H), 6.15 (d, J=8.3 Hz, 1H), 6.2 (d, J=8.3 Hz, 1H), 7.13 (t, J=8.3 Hz, 1H). MS 192 (MH+).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[CH:9]2.Cl>O>[N:1]([C:7]1[C:6]([OH:5])=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[N:10][CH:11]=[N:12]2)=[O:3]
Reactant: O=N[O-]
Reactant: Oc1ccc2ncncc2c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=Nc1c(O)ccc2ncncc12
Reaction time: 1 h

Procedure:
During one hour and while stirring, a solution of 0.14 mole of sodium nitrite in 30 ml water is added to a cold solution (0°-5° C.) of 0.14 mole of 6-hydroxy quinazolin, 12 ml concentrated hydrochloric acid and 50 ml distilled water. Stirring is continued for one hour. The 5-nitroso 6-hydroxy quinazolin (formula IV) is thus obtained as a yellow precipitate, which is washed with water, then dried.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:2]1.Br[CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]2[NH:23][C:24](=[O:26])[O:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C(C)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:22]4[NH:23][C:24](=[O:26])[O:25][C:21]=4[CH:20]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=c1[nH]c2ccc(CCBr)cc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccc(CCN3CCN(c4nsc5ccccc45)CC3)cc2o1

Procedure:
To a 125 ml round-bottomed flask equipped with condenser were added 4.82 grams (0.022 mol) of N-(3-benzisothiazolyl)piperazine (prepared according to the procedure given in U.S. Pat. No. 4,411,901), 5.32 grams (0.022 mol) of 6-(2-bromoethyl)benzoxazolone, 2.33 grams (0.022 mol) of sodium carbonate, and 50 ml of methyl isobutyl ketone. The mixture was refluxed for 18 hours. The reaction was cooled and partitioned between ethyl acetate and water. The ethyl acetate layer was isolated, washed with water and saturated aqueous sodium chloride solution dried over sodium sulfate, and evaporated to an oil. The oil was chromatographed on silica gel using ethyl acetate as eluent, and the product fractions collected, concentrated to dryness and triturated with methylene chloride/isopropyl ether to give a white solid, 1 m.p. 185°-187° C. NMR (δ, CDCl3): 1.7 (bs, 1H), 2.8 (m, 8H), 3.6 (m, 4H), 6.9-8.0 (m, 7H).
Reaction SMILES: [NH2:1][C:2](=[O:20])[C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH2:1][C:2](=[O:20])[C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:26]2[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(N)=O
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 105.8 %

Procedure:
(S)-tert-Butyl 1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamate (Example 3, step (i), 3.17 g) and 4-cyanophenylboronic acid (1.19 g) in dioxane (5 mL) were treated with 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.08 g) and the mixture was stirred at room temperature for 15 min under nitrogen. An aqueous solution of potassium carbonate (2M, 8.12 mL) was added and the mixture was stirred for 18 h at 75° C. The reaction mixture was extracted with ethyl acetate, dried and evaporated to afford the sub-titled compound (3.13 g).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=3)=[C:10]([CH3:23])[CH:9]=2)=[N:5][N:4]=1)[CH3:2].[CH3:24][N:25]1[CH2:30][CH2:29][C:28]2([C:42]3[C:33](=[CH:34][C:35]4[CH2:36][CH2:37][CH2:38][NH:39][C:40]=4[CH:41]=3)[O:32][CH2:31]2)[CH2:27][CH2:26]1>>[CH3:24][N:25]1[CH2:30][CH2:29][C:28]2([C:42]3[C:33](=[CH:34][C:35]4[CH2:36][CH2:37][CH2:38][N:39]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:11]6[CH:12]=[CH:13][C:8]([C:6]7[O:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=7)=[CH:9][C:10]=6[CH3:23])=[CH:19][CH:18]=5)=[O:21])[C:40]=4[CH:41]=3)[O:32][CH2:31]2)[CH2:27][CH2:26]1
Reactant: CCc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCCC3
Product: CCc1nnc(-c2ccc(-c3ccc(C(=O)N4CCCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)o1

Procedure:
The title compound was prepared from 4'-(5-ethyl-1,3,4-oxadiazol-2-yl)-2'-methylbiphenyl-4-carboxylic acid (D32) and 2,3,5,6,7,8-hexahydro-1'-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine] (D10) using a procedure similar to that of Example 1 (19%). This was converted to its hydrochloride salt, as a white solid. M.p. 241-3° C.
Reaction SMILES: [NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1.[CH:35](=O)[CH3:36].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH2:35][CH3:36])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc(Cl)cc2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(Cl)cc1

Procedure:
4-Amino-5-chloro-N-((1-(5-(4-chlorobenzylamino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide (1.8 g) as starting compound, acetaldehyde (0.26 ml) and sodium cyanoborohydride (0.29 g) were reacted and treated in the same manner as in Example 136 to give 1.05 g of 4-amino-5-chloro-N-((1-(5-(N-(4-chlorobenzyl)-N-ethylamino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:27])=[C:18]([CH2:20][CH2:21]OS(C)(=O)=O)[N:19]=2)=[CH:11][CH:10]=1.ClCCl>O1CCCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]([CH3:27])=[C:18]([CH2:20][CH2:21][N:3]3[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4]3)[N:19]=2)=[CH:13][CH:14]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Reactant: CC1CCCCN1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCCC1
Temperature: 60 °C
Yield: 70.2 %

Procedure:
Add 2-methyl piperidine (0.871 g, 8.77 mmol) to a solution of methanesulfonic acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester (0.316 g, 0.877 mmol) in tetrahydrofuran (5 mL) in a sealed tube, and heat at 60° C. overnight. Cool to room temperature and add dichloromethane. Wash the crude organic material with saturated sodium chloride solution. Dry the organic layer over Na2SO4, filter, and concentrate. Purify on silica gel eluting with 10% ammoniated methanol in dichloromethane to give (+/−)-1-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-piperidine (0.215 g, 67%): MS (m/e): 363 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:17])[CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:17])[CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=O)CC2CCCN2C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc(C(O)CC2CCCN2C)c1

Procedure:
50 g of 1-(3-methoxyphenyl)-2-(1-methyl-2-pyrrolidinyl)ethanone are dissolved in 100 ml of methanol and 20 ml of water; thereafter, 4.05 g of sodium borohydride are added portionwise, with stirring. Stirring is continued for a further hour, methanol is largely distilled off, 100 ml of water are added and extraction is effected with methylene chloride. The organic phase is extracted with 400 ml of 10% strength hydrochloric acid, the hydrochloric acid aqueous phase is rendered alkaline with sodium hydroxide solution and the liberated base is extracted with methylene chloride. The organic phase is concentrated and the resulting oily residue is distilled to obtain 47.4 g (94% of theory) of the title compound as a mixture of diastereoisomers of b.p. 128° at 0.001 mm Hg.
Reaction SMILES: [F:1][C:2]1([F:20])[C:15]([F:17])([F:16])[C:14]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([Br:19])=[CH:6][CH:7]=2.[CH2:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[F:17][C:15]1([F:16])[C:2]([F:20])([F:1])[C:3]2[CH:4]=[C:5]([Br:19])[CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][C:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:11][CH:10]=2
Reactant: CCCCCCCC[Mg]Br
Reactant: FC1(F)c2cc(Br)ccc2-c2ccc(Br)cc2C1(F)F
Product: CCCCCCCCc1ccc2c(c1)C(F)(F)C(F)(F)c1cc(Br)ccc1-2
Yield: 54.1 %

Procedure:
In analogy to Example 1, from 4.1 g of 9,9,10,10-tetrafluoro-2,7-dibromo-phenanthrene and 10 mmol of octylmagnesium bromide. The catalyst used is 0.2 mmol of 1,3-bis(diphenylphosphine)butanenickel(ll) chloride. Chromatography gives 2.4 g of 9,9,10,10-tetrafluoro-2-bromo-7-octyl-9,10-dihydrophenanthrene.
Reaction SMILES: [NH:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([O:11][CH3:12])[N:4]=1)[NH2:2].CC(O)C.[N:17]#[C:18]Br>C(#N)C>[NH2:17][C:18]1[N:4]2[C:5]([O:11][CH3:12])=[N:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]2=[N:1][N:2]=1
Reactant: COc1ncc(OC)c(NN)n1
Reactant: N#CBr
Solvent: CC#N
Solvent: CC(C)O
Product: COc1cnc(OC)n2c(N)nnc12
Temperature: 42 °C
Yield: 87.3 %

Procedure:
4-Hydrazino-2, 5-dimethoxypyrimidine (8.522 g, 0.050 mole) was loaded into a 500 mL three necked flask equipped with an overhead stirrer, condenser, and thermocouple temperature probe. IPA (100 mL) was added and the mixture was stirred to form a slurry. A solution of cyanogen bromide (8.546 g, 0.081 mole) in acetonitrile (15 mL) was added, resulting in a 3° C. endotherm, followed by a 6° C. exotherm. The mixture wash heated to 42° C. for 3.5 h, then cooled to room temperature. A solution of sodium carbonate (5.92 g) in water (100 mL) was added, and the resulting mixture was stirred for 3.3 h. The product precipitated from the solution an d was recovered by filtration through Whatman #54 paper using a Buchner funnel and aspirator vacuum. The solids w ere dried overnight in vacuo at room temperature to give 8.516 g of 3-amino-5,8-dimethoxy[1,2,4]triazolo[4,3-c]pyrimidine (yield=87.1%): mp=232-235° C. 1H NMR (300 MHz, DMSO-d6) 3.83 (s, 3H), 3.97 (s, 3H), 6.45 (br s, 2H), 6.84 (s, 1H); 13C NMR (75.47 MHz, DMSO-d6) 55.4, 56.4, 115.5, 139.7, 142.0, 142.5, 148.3.
Reaction SMILES: [C:1]1(=[O:11])[NH:6][CH2:5][CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH:9]=[C:2]12.[C:12]1([CH3:19])[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.[Cu]I>[C:12]1([CH3:19])[CH:17]=[CH:16][C:15]([N:6]2[CH2:5][CH2:4][N:3]3[C:7](=[O:10])[CH2:8][CH2:9][CH:2]3[C:1]2=[O:11])=[CH:14][CH:13]=1
Reactant: O=C1NCCN2C(=O)CC=C12
Reactant: Cc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN3C(=O)CCC3C2=O)cc1
Yield: 29.5 %

Procedure:
A mixture of tetrahydro-pyrrolo[1,2-a]pyrazine-1,6-dione (compound of Description 15, 150 mg, 0.97 mmol), p-tolyliodide (424 mg, 1.94 mmol), CuI (62 mg, 0.32 mmol) and K2CO3 (134 mg, 0.98 mmol) in dimethylformamide (6 ml) was refluxed for 2 hours. The solvent was removed under vacuum; the residue was triturated with ethyl acetate and after filtering off the insoluble material, the organic layer was washed with brine, dried (Na2SO4) and evaporated under vacuum. The residue was purified by flash chromatography (DCM/MeOH 95/5 respectively) to give the title compound as a light brown powder (70 mg, 30% yield).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][N:17]=[C:16]3[NH:20][N:21]=[CH:22][C:15]=23)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[N+](C1C=CC(N=C=O)=CC=1)([O-])=O.[O:35]([C:42]1[CH:47]=[CH:46][C:45]([N:48]=C=O)=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[O:35]([C:42]1[CH:43]=[CH:44][C:45]([NH:48][C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:19]=[CH:18][N:17]=[C:16]4[NH:20][N:21]=[CH:22][C:15]=34)[CH2:12][CH2:13]2)=[O:7])=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ncc23)CC1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Agent: O=C=Nc1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)N1CCN(c2ncnc3[nH]ncc23)CC1

Procedure:
The target compound was produced in the same manner as in Example 2, except that 4-(6-purinyl)-1-piperazinecarboxylic acid tert-butyl ester was replaced with 4-(4-pyrazolo[3,4-d]pyrimidinyl )-1-piperazinecarboxylic acid tert-butyl ester produced in Reference Example 10, and that 4-nitrophenyl isocyanate was replaced with 4-phenoxyphenyl isocyanate.
Reaction SMILES: CO[C:3]1[C:4]2[CH:18]=[CH:17][CH:16]=[N:15][C:5]=2[N:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:8]=1.[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:30]([NH2:31])=[CH:29][C:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:27][N:26]=2)[CH2:21][CH2:20]1.[H-].[Na+].O>CN(C)C=O>[N:22]1([C:25]2[C:30]([NH:31][C:3]3[C:4]4[CH:18]=[CH:17][CH:16]=[N:15][C:5]=4[N:6]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[N:8]=3)=[CH:29][C:28]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:27][N:26]=2)[CH2:21][CH2:20][O:19][CH2:24][CH2:23]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: COc1nc(-c2ccccn2)nc2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2nc(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c3cccnc3n2)nc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-methoxy-2-(pyridin-2-yl)pyrido[2,3-d]pyrimidine (0.050 g, 0.21 mmol) and 2,5-dimorpholinopyridin-3-amine (0.061 g, 0.23 mmol) in N,N-dimethylformamide (2.0 mL) was added 60% sodium hydride (9.23 mg, 0.23 mmol). The reaction was heated to 60° C. Stirring continued overnight. The reaction was cooled to rt and water was added to quench. The reaction was extracted with EtOAc (3×10 mL). The combined organic layer were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0 to 30% MeOH in DCM) to give N-(2,5-di-4-morpholinyl-3-pyridinyl)-2-(2-pyridinyl)pyrido[2,3-d]pyrimidin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 9.75 (1H, d, J=2.7 Hz), 9.36 (1H, br. s.), 9.23 (1H, dd, J=4.4, 1.7 Hz), 8.87 (1H, d, J=8.0 Hz), 8.70 (1H, m), 8.30 (1H, dd, J=8.2, 1.8 Hz), 7.91 (1H, m), 7.84 (1H, d, J=2.7 Hz), 7.62 (1H, dd, J=8.2, 4.3 Hz), 7.42-7.49 (1H, m), 3.94-4.04 (8H, m), 3.43-3.55 (4H, br m), 3.09 (4H, br. m.). Mass Spectrum (ESI) m/e=471.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]([NH:17][C:18](=[O:49])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[C:28]([CH:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[N:44]=[C:43]([CH:45]([CH3:47])[CH3:46])[O:42][N:41]=4)=[CH:36][CH:35]=3)[CH2:31][CH3:32])[O:27]N=2)=[CH:21][C:20]=1[F:48])(C)[CH3:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:51]1C=C(C2N=C(C(OC3C=CC(C4N=C(C(C)C)ON=4)=CC=3)CC)ON=2)C=CC=1C(N[C@H](C)CO)=O>>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][C@@H:14]([NH:17][C:18](=[O:49])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[C:28]([CH:30]([O:33][C:34]3[CH:35]=[CH:36][C:37]([C:40]4[N:44]=[C:43]([CH:45]([CH3:46])[CH3:47])[O:42][N:41]=4)=[CH:38][CH:39]=3)[CH2:31][CH3:32])[O:27][CH:51]=2)=[CH:21][C:20]=1[F:48])[CH3:15])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(Oc1ccc(-c2noc(C(C)C)n2)cc1)c1nc(-c2ccc(C(=O)NC(C)(C)COC(=O)CNC(=O)OC(C)(C)C)c(F)c2)no1
Reactant: CCC(Oc1ccc(-c2noc(C(C)C)n2)cc1)c1nc(-c2ccc(C(=O)N[C@H](C)CO)c(F)c2)no1
Product: CCC(Oc1ccc(-c2noc(C(C)C)n2)cc1)c1nc(-c2ccc(C(=O)N[C@@H](C)COC(=O)CNC(=O)OC(C)(C)C)c(F)c2)co1

Procedure:
The synthesis was carried out in the same manner as in Reference Example 14, except that the compound obtained in Example 18 that will be described below (20.0 mg, 39.3 μmol) was used in place of 2-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]-4-(5-{1-[4-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1,2,4-oxadiazol-3-yl)benzamide. Thus, the title compound (26 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH2:20]O)[N:17]=[N:16]3)[O:11][C:10]2=[O:22])[CH:5]=[CH:6][C:7]=1[I:8].C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH2:20][Br:24])[N:17]=[N:16]3)[O:11][C:10]2=[O:22])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: BrC(Br)(Br)Br
Reactant: O=C1O[C@@H](Cn2cc(CO)nn2)CN1c1ccc(I)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1O[C@@H](Cn2cc(CBr)nn2)CN1c1ccc(I)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
A stirred mixture of (5R)-3-(3-fluoro-4-iodophenyl)-5-(4-hydroxymethyl-1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (14.7 g, 35.1 mmol) and carbon tetrabromide (12.16 g, 36.7 mmol) in dichloromethane (1 L) was treated at 0° C. with triphenylphosphine (12.34 g, 61.2 mmol). The reaction mixture was stirred for 30 minutes at 0° C. and then at room temperature overnight. The reaction mixture was applied onto a silica-gel column and eluted with hexanes:ethyl acetate (1:1) and then with ethyl acetate:methanol (95:5) to give a product that was further purified by recrystallization from ethyl acetate to give the title compound as a colorless solid (14 g).