Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:9][O:10][CH3:11])[CH:8]=1)[NH2:5].Cl[C:13]1[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=1.CS(O)(=O)=O>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:13]2[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([CH2:9][O:10][CH3:11])[CH:8]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: COCc1cc(N)cc(Br)c1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a solution of the product of Step 2 (258 mg, 1.194 mmol) in dioxane (3.8 mL) were added 2-chloro-4-(trifluoromethyl)pyrimidine (251 mg, 1.373 mmol) and methanesulfonic acid (0.07 mL, 1.015 mmol). The reaction was then stirred overnight at 100° C. The reaction was then cooled, diluted with ethyl acetate and then washed with brine solution. The organic layer was collected, dried over magnesium sulfate and then filtered. Ethyl acetate was then removed in vacuo. Flash chromatography (hexane/ethyl acetate: 70/30) was used for purification to afford N-[3-bromo-5-(methoxymethyl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine as an off-white solid (314 mg, 0.867 mmol, 72.6% yield). MS ESI: [M+H]+ m/z=362.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:6](Cl)=[O:7])#[N:2].O[NH:18][C:19](=[NH:39])[C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][N:24]=[C:25]2[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:7][N:18]=[C:19]([C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][N:24]=[C:25]4[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:39]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)#[N:2]
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Reactant: N#Cc1cc(C(=O)Cl)ccc1OCC1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(OCC5CC5)c(C#N)c4)n3)cccc12
Reaction time: 1.5 h
Yield: 33.1 %

Procedure:
A solution of 3-cyano-4-[(cyclopropylmethyl)oxy]benzoyl chloride (D25; 54.2 mg, 0.23 mmol) in dry DMF (1.5 ml) was added to a stirred solution of 1,1-dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36; 68.9 mg, 0.219 mmol) and triethylamine (0.048 ml, 0.345 mmol) in dry DMF (1.5 ml) at 0° and the mixture was stirred at 0° for 1.5 h. The mixture was then heated at 100° with stirring under nitrogen for 16 h. The cooled mixture was partitioned between saturated aqueous sodium bicarbonate (40 ml) and ethyl acetate (3×25 ml), and the combined organic layers washed with 50:50 brine:water and brine, dried (MgSO4) and evaporated in vacuo to give a brown oil which was purified by flash chromatography on silica gel, eluting with 0-40% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as an off-white solid (36 mg)
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:14][C:15]1[C:16](=[O:34])[N:17]([C:21]2[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:25])[CH:18]=[CH:19][N:20]=1)([CH3:13])[CH3:12].[CH2:35]([NH2:37])[CH3:36]>O>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:37][CH2:35][CH3:36])([CH3:13])[CH3:12])[C:16]3=[O:34])[CH:22]=2)[CH2:29][CH2:28]1
Reactant: CCN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCCl)c1=O
Solvent: O
Product: CCNCCOc1ccccc1C(C)(C)Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O

Procedure:
The title compound was prepared from 3-[3-[[1-[2-(2-chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide (Example 198e) and 70% ethylamine in water using the method of example 167f.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23]O)[CH:16]=2)=[C:7]([NH:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[CH:38]([CH3:40])[CH3:39])=[O:27])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4].C(Br)(Br)(Br)[Br:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(Cl)Cl>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][Br:43])[CH:16]=2)=[C:7]([NH:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[CH:38]([CH3:40])[CH3:39])=[O:27])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCO)c2)c2cccnc21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCBr)c2)c2cccnc21
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a solution of N-[1-butyl-4-{3-(3-hydroxy-1-propynyl)phenyl}-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (90 mg, 0.16 mmol) in methylene chloride (1.5 ml) were added carbon tetrabromide (81 mg, 0.245 mmol) and triphenylphosphine (51 mg, 0.196 mmol) under ice-cooling, and the mixture was stirred for 30 minutes. To the mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane: 1:5) to give the title compound (53 mg, 0.086 mmol).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[B:17](OCCCC)([O:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[B:17]([O:16][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=1[C:12]([CH3:15])([CH3:14])[CH3:13])([O:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CCCCOB(OCCCC)Oc1c(C(C)(C)C)cc(C)cc1C(C)(C)C

Procedure:
Di-n-butyl 2,6-di-t-butyl-4-methylphenyl borate was prepared by reacting boric acid with n-butanol to give tri-n-butyl borate which was isolated by distillation. 2,6-di-t-butyl-4-methylphenol (1 mole) was added to the tri-n-butyl borate (1 mole). The reaction mixture was heated and n-butanol collected as distillate. The di-n-butyl 2,6-di-t-butyl-4-methylphenyl borate was isolated by distillation and its purity was confirmed by infra-red spectrascopy and chemical analysis.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)[C:14]([O-])=[O:15].FC(F)(F)C(O)=O.[O-2].[Mg+2]>[Pd](Cl)Cl.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:14](=[O:15])[O:9][CH2:8][C:4]=2[C:3]=1[O:10][CH3:11]
Reactant: COc1c(Br)cccc1CO
Reactant: O=C([O-])C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1c(Br)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a flask charged with (3-bromo-2-methoxyphenyl)methanol (3.0 g, 14 mmol, 1.0 eq) was added thallic trifluoroacetate (10.0 g, 18.4 mmol, 1.3 eq). To above mixture was added trifluoroacetic acid (25 mL). The reaction was stirred at r.t. for 16 hr, then concentrated. The excess TFA was removed using high vacuum pump. To the residue was added palladium chloride (245 mg, 1.38 mmol, 0.1 eq), magnesium oxide (1.10 g, 27.6 mmol, 2.0 eq) and methanol (35 mL). The reaction was flushed with carbon monoxide three times and stirred under CO at r.t. for 2 hr. To this solution was added ethyl acetate. The mixture was filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated and loaded on silica gel column. The fractions containing 5-bromo-4-methoxy-2-benzofuran-1(3H)-one were concentrated. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.72 (1H, aromatic, d, J=8.0 Hz), 7.49 (1H, aromatic, d, J=8.0 Hz), 5.44 (2H, s, CH2 lactone), 4.00 (3H, s, Me). LC-MS (IE, m/z): 244.88 [M+1]+; tR=2.67 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([O:16][CH3:15])=[CH:18][C:19]=2[N+:24]([O-:26])=[O:25])=[O:13])=[CH:4][N:3]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Product: COc1ccc(NC(=O)c2cnc(Cl)nc2C(F)(F)F)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 2-chloro-4-(trifluoromethyl)pyrimidine-5-carbonyl chloride and 4-methoxy-2-nitroaniline and was obtained as a light yellow solid as described in Example 1. 1H NMR (CDCl3): 10.52 (s, 1H), 9.04 (s, 1H), 8.68 (d, J=9.3, 1H), 7.76 (d, J=3.0, 1H), 7.35-7.31 (m, 1H), 3.91 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])[CH3:30]>>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:35]4[CH2:36][CH2:37][N:32]([C:29](=[O:31])[CH3:30])[CH2:33][CH2:34]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(Cc2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.528 mmol) and 1-acetyl piperazine (75 mg, 0.581 mmol) gave 2-[5-(4-acetyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as an off white solid (96 mg, 37%) [following SiO2 chromatography, eluting with 0-10% (2M NH3 in MeOH)/dichloromethane].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:37]2[CH:38]=[N:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=2)=[N:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:30]3[CH:35]=[N:34][C:33]([NH:36][C:37]4[CH:38]=[N:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=4)=[CH:32][CH:31]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: FC(F)(F)c1ccc(Nc2ccc(Br)cn2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (1.56 g, 4.1 mmol) and (5-Bromo-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine (1.28 g, 4.0 mmol) were dissolved in DME (8 mL) in a pressure vessel, and to the solution was added PdCl2dppf (100 mg, 0.12 mmol) and Na2CO3 (2.0M, 4.0 mL, 8.1 mmol). The mixture was sparged with nitrogen for 10 minutes, then the vessel was sealed and stirred at 80° C. for 18 hours. The mixture was partitioned between EtOAc and saturated aqueous NH4Cl, washed with brine, dried with magnesium sulfate, filtered, and concentrated via rotary evaporation. The crude material was purified via column chromatography on silica gel, eluting with a gradient of EtOAc/hexanes (10-50%) to obtain the target compound as a solid: 1H NMR (400 MHz, DMSO-d6) ppm 1.25 (br. s., 2 H) 1.42 (s, 9 H) 1.52 (qd, J=12.63, 4.55 Hz, 2 H) 1.77 (m, 2 H) 2.66-2.76 (m, 1 H) 4.09 (m, 2 H) 7.03 (d, J=8.59 Hz, 1 H) 7.34 (d, J=8.34 Hz, 2 H) 7.60 (d, J=8.08 Hz, 2 H) 7.79 (d, J=8.84 Hz, 1 H) 7.99 (dd, J=8.72, 2.65 Hz, 1 H) 8.56 (d, J=2.53 Hz, 1 H) 8.91 (d, J=2.53 Hz, 1 H) 9.87 (s, 1 H); MS (M+H)+ 499.3.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[N:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:17]([NH:19][C:20]1([C:27]#[N:28])[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:18]>>[C:27]([C:20]1([NH:19][C:17](=[O:18])[CH:16]([NH:15][C:2]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][C:4](=[O:12])[N:3]=2)[CH2:29][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1)#[N:28]
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: O=c1nc(Cl)c2ccccc2o1
Agent: Cl
Product: CN1CCC(C#N)(NC(=O)C(CC2CCCCC2)Nc2nc(=O)oc3ccccc23)CC1

Procedure:
The title compound was prepared starting from 4-chloro-benzo[e][1,3]oxazin-2-one (prepared from benzo[e][1,3]oxazin-2,4-dione and PCl5 in refluxing toluene) and 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 81. MS, m/z 438=M+1.
Reaction SMILES: Br.Br.[CH2:3]([O:5][C:6]([C:8]1([CH2:20][NH2:21])[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH3:4].Cl[S:23]([C:26]1[CH:35]=[C:34]2[C:29]([CH2:30][CH2:31][N:32]([C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])[CH2:33]2)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH2:3]([O:5][C:6]([C:8]1([CH2:20][NH:21][S:23]([C:26]2[CH:35]=[C:34]3[C:29]([CH2:30][CH2:31][N:32]([C:36](=[O:41])[C:37]([F:40])([F:38])[F:39])[CH2:33]3)=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)C1(CN)CCN(c2ccncc2)CC1
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Agent: Br
Solvent: c1ccncc1
Product: CCOC(=O)C1(CNS(=O)(=O)c2ccc3c(c2)CN(C(=O)C(F)(F)F)CC3)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
To 4-aminomethyl-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrobromide (423 mg) were added pyridine (2 ml) and 7-chlorosulfonyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (273 mg), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated and water was added. The mixture was extracted with chloroform and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=4:1) and dried under reduced pressure to give the title compound (222 mg).
Reaction SMILES: C(O)(=O)C.S(=O)(=O)(O)O.[CH:10]1[C:18]2[C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15](=[O:24])(=[O:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1.[N+:25]([O-])([OH:27])=[O:26]>O>[N+:25]([C:21]1[CH:20]=[CH:19][C:17]2[C:18]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[S:15](=[O:24])(=[O:23])[C:16]=2[CH:22]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])O
Reactant: O=S1(=O)c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)c1ccccc1-2
Temperature: 4 °C

Procedure:
To a mixture of acetic acid (77 ml) and sulphuric acid (77 ml) was added dibenzothiophene-5,5-dioxide (35.0 g), and the mixture cooled to 4° C. Addition of a total of 197 g. (131 ml) fuming nitric acid was begun, but in a short time the resulting paste became too thick to stir efficiently, and a further 77 ml, acetic acid was added. Local heating due to inefficient stirring was observed to occur, but the temperature of the reaction mixture was maintained at 4° C. as far as was possible. When the addition was complete (ca. 20 min.), the mixture was stirred at 4° C. for a further 30 min., and then poured into water. The crude nitrocompound was filtered off and recrystallised from dimethylformamide, m.p. 259° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[CH:10]=[N:9][CH:8]=[N:7]1.[C:11]([NH:14][C:15]1(N)[NH:24][C:23](=O)[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=3)[N:21]=2)[NH:16]1)(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([NH:14][C:15]1[N:24]=[C:23]([C:10]2[N:9]=[CH:8][NH:7][N:6]=2)[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=3)[N:21]=2)[N:16]=1)(=[O:13])[CH3:12]
Reactant: c1nc[nH]n1
Reactant: COc1ccc(-c2cnc3c(n2)C(=O)NC(N)(NC(C)=O)N3)cc1OC
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cnc3nc(NC(C)=O)nc(-c4nc[nH]n4)c3n2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
To a solution of phosphorus oxychloride (1.68 ml, 18 mmoles) and 1,2,4-triazole (4.96 g, 72 mmoles) in dry pyridine (110 ml) was added the compound of example 102 (2.45 g, 7.18 mmoles). The suspension was stirred at room temperature for 4 hours. The precipitate was filtered off, washed with pyridine, toluene and diethyl ether. The resulting solid was dried over P2O5 under vacuum, providing the title compound as a yellow powder (2 g, yield: 80%) which afforded the following mass spectrum: 392 ([M+H]+, 100).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[N:17][CH:16]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]=2[C:15]2[CH:20]=[CH:19][N:18]=[N:17][CH:16]=2)[CH:8]=[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2ccnnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2ccnnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 44.2 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridazin-4-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.065 mmol), β-alanine (576 mg, 6.5 mmol) and NaOMe solution (10 mL, 5.2 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (15-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 15 mg of the title compound. MS: (+) m/z 522.35 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[CH:8]=[C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:10]=[C:11]3[C:17](=[O:18])[NH:16][N:15]=[CH:14][C:13]=1[C:12]=23)=O.C(N(CC)CC)C.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:23]([O:22][C:20](=[O:21])[NH:19][C:9]1[CH:10]=[C:11]2[C:17](=[O:18])[NH:16][N:15]=[CH:14][C:13]3=[C:5]([C:3](=[O:2])[NH:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])[NH:6][C:7]([CH:8]=1)=[C:12]23)([CH3:24])([CH3:25])[CH3:26]
Reactant: COC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Reactant: CN(C)CCN
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Yield: 76.1 %

Procedure:
Thus CO was bubbled through a mixture of Intermediate 147(d) from Example 147 (1.5 g, 3.97 mmol), triethylamine (1.1 mL, 7.92 mmol), N,N-dimethylethylenediamine (0.7 g, 7.94 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (0.65 g, 0.796 mmol) in N,N-dimethylformamide (30.0 mL). Reaction conditions, work up and silica gel chromatography (eluted with 46:4:25 dichloromethane:methanol:ethyl acetate) were also carried out in an analogous manner and afforded the title compound (1.25 g, 3.02 mmol) in 76% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].Cl[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][C:26]3[CH:31]=[N:30][C:29]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: ClCc1ccc(-c2ccccc2)nc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nn(Cc2ccc(OCc3ccc(-c4ccccc4)nc3)cc2)cc1CCC(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (690 mg), 5-chloromethyl-2-phenylpyridine (470 mg), potassium carbonate (450 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). After a mixture of the resulting colorless oily substance, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (5 ml) was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(6-phenyl-3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (900 mg, yield: 91%). This was recrystallized from acetone-hexane. Melting point: 140–141° C.
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][N:8]3[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[O:17])[N:10]=[C:9]3[C:3]([NH2:27])([CH2:4][O:5]2)[CH2:2]1.CCN(CC)CC.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[CH3:36][C:35]([NH:27][C:3]12[CH2:4][O:5][CH:6]([CH2:7][N:8]3[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]([NH:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[O:17])[N:10]=[C:9]31)[CH2:1][CH2:2]2)=[O:37]
Reactant: CC(=O)Cl
Reactant: NC12CCC(Cn3c1nc(C(=O)NCc1ccc(F)cc1)c(O)c3=O)OC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC12CCC(Cn3c1nc(C(=O)NCc1ccc(F)cc1)c(O)c3=O)OC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
To a solution of 10-amino-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-(epoxymethano)pyrimido[1,2-a]azepine-2-carboxamide (30 mg, 0.080 mmol) in CH2Cl2 (2 mL) was added Et3N (0.056 mL, 0.401 mmol) followed by acetyl chloride (0.05 mL, 0.401 mmol) and the resulting mixture stirred at room temperature for 16 h. The reaction mixture was concentrated and the resulting residue dissolved in methanol (2 mL) and treated with 2M dimethylamine in methanol (0.5 mL). The resulting reaction mixture was stirred at 60° C. for 2 h, cooled and purified by preparative HPLC to afford the title compound as a white solid (9 mg, 27% yield). 1H NMR (500 MHz, CDCl3) δ: 11.92 (s, 1H), 7.39 (brs, 1H), 7.29-7.33 (m, 2H), 7.05-7.09 (m, 2H), 6.13 (s, 1H), 4.59-4.65 (m, 2H), 4.48-4.55 (m, 3H), 4.30 (d, 1H, J=11.9 Hz), 4.10 (d, 1H, J=16.17 Hz), 2.52-2.58 (m, 1H), 2.30-2.36 (m, 1H), 1.82 (s, 3H), 1.75-1.82 (m, 1H), 1.50-1.55 (m, 1H). LCMS (M+H)=417.25. HPLC purity>95%.