Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][C:21]=3[C:25]([O:27]CC)=[O:26])=[CH:16][CH:15]=2)[CH2:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[O:24][CH:23]=[N:22][C:21]=3[C:25]([OH:27])=[O:26])=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ncoc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)C(C)(C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ocnc3C(=O)O)cc2)CC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 133.4 %

Procedure:
To a solution of 4-[4-(4-ethoxycarbonyl-oxazol-5-yl)-phenyl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (2.4 g, 5.6 mmol) in 20 mL THF and 20 mL methanol was added 2N aqueous sodium hydroxide solution (11.2 mL, 22.4 mmol). The mixture was stirred at room temperature for 16 hrs and organic solvent was then removed in vacuo. The remaining aqueous mixture was adjusted to pH 4˜5 by the addition of 1N aqueous hydrogen chloride. The mixture was freeze-dried to yield 3 g of 4-[4-(4-carboxy-oxazol-5-yl)-phenyl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as an off-yellow powder, which was used in the next step directly.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[C:5]([Cl:13])=[N:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([C:21]([F:20])([F:30])[F:31])[CH:23]=3)=[CH:9][CH:10]=2)[C:5]([Cl:13])=[N:4][N:3]=1
Reactant: Nc1ccc2c(Cl)nnc(Cl)c2c1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(CNc2ccc3c(Cl)nnc(Cl)c3c2)c1
Temperature: 85 °C
Yield: 26.2 %

Procedure:
A mixture of 1,4-dichloro-6-amino-phthalazine (33 mg, 0.154 mmol), K2CO3 (79 mg, 0.57 mmol), DMF (5 mL) and 3-(trifluoromethyl)benzyl bromide (2.0 mL, 0.17 mmol) were heated to 85° C. for 18 h. The reaction was cooled, poured onto water and extracted with EtOAc. The combined organic layers were washed with H2O, brine, dried (Na2SO4) and concentrated. Column chromatography (Hexanes/EtOAc) afforded the desired product (15 mg, 26.3%) as a yellow solid. m/z 372.08 (M+1).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:10].Cl[C:25]1[N:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[N:26]=1>CN(C=O)C.CCOC(C)=O>[CH3:32][C:27]1[CH:28]=[C:29]([CH3:31])[N:30]=[C:25]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=4[N:19]4[N:20]=[CH:21][CH:22]=[N:23]4)=[O:10])[CH2:3]3)[CH2:6]2)[N:26]=1
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(-n2nccn2)c1
Reactant: Cc1cc(C)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)N2CC3CN(c4nc(C)cc(C)n4)CC3C2)c(-n2nccn2)c1
Temperature: 120 °C
Yield: 104.3 %

Procedure:
To (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (185 mg, 0.4 mmol) in DMF (2.2 mL) was added 2-chloro-4,6-dimethylpyrimidine (61 mg, 0.4 mmol). The flask was heated to 120° C. for 18 h. The flask was allowed to cool to rt, diluted with EtOAc and washed with H2O. The aq was back-extracted with EtOAc (1×). The combined organics were washed with brine and dried (Na2SO4) to give an oil. Purification via silica gel (15-75% EtOAc in hexanes) gave 175 mg (97%) of the title compound. MS (ESI) mass calcd. C22H25N7O2, 419.49; m/z found 420.2 [M+H]+. 1H NMR (CDCl3): 7.73 (s, 2H), 7.49 (d, J=7.8 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 6.95 (dd, J=8.5, 2.5 Hz, 1H), 6.29 (s, 1H), 3.93-3.80 (m, 5H), 3.72-3.63 (m, 2H), 3.58 (dd, J=11.6, 5.2 Hz, 1H), 3.46 (dd, J=11.6, 4.3 Hz, 1H), 3.39-3.28 (m, 1H), 3.05-2.84 (m, 3H), 2.33 (s, 6H).
Reaction SMILES: [2H][C:2]1[C:7]([2H])=[C:6]([NH2:9])[C:5]([NH2:10])=[C:4]([2H])[C:3]=1[2H].[Br:13][CH2:14][C:15](=O)[C:16](O)=[O:17]>O1CCCC1>[Br:13][CH2:14][C:15]1[C:16](=[O:17])[NH:10][C:5]2[C:6]([N:9]=1)=[CH:7][CH:2]=[CH:3][CH:4]=2
Reactant: [2H]c1c([2H])c([2H])c(N)c(N)c1[2H]
Reactant: O=C(O)C(=O)CBr
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2nc1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
O-phenylenediamine (1.0 g., 0.0092 mol.) was dissolved in tetrahydrofuran (50 ml.) and 3-bromopyruvic acid (1.7 g., 0.0102 mol.) added. The reaction mixture was stirred at room temperature for one hour, during which time the product precipitated as a yellow solid. The product was collected by filtration and crystallized from methylene chloride. (0.91 g., m.p. 221°-223° (dec.) 41%)
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl-].[Cl-].[Cl-].[Al+3].[F:23][C:24]1[C:32]([NH:33][S:34]([CH2:37][CH2:38][CH3:39])(=[O:36])=[O:35])=[CH:31][CH:30]=[C:29]([F:40])[C:25]=1[C:26](Cl)=[O:27].C(Cl)(=O)C1C=CC=NC=1>ClCCl.O.O1CCCC1.C(N(CC)CC)C>[F:23][C:24]1[C:32]([NH:33][S:34]([CH2:37][CH2:38][CH3:39])(=[O:35])=[O:36])=[CH:31][CH:30]=[C:29]([F:40])[C:25]=1[C:26]([C:3]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=3)[CH:9]=2)[NH:1][CH:2]=1)=[O:27]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Cl)c1F
Reactant: O=C(Nc1cnc2[nH]ccc2c1)c1cccnc1
Agent: O=C(Cl)c1cccnc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(NC(=O)c4cccnc4)cc23)c1F
Temperature: 25 °C
Reaction time: 36 h

Procedure:
In a reaction vial, N-(1H-pyrrolo[2,3-b]pyridin-5-yl)-nicotinamide (37, 0.050 g, 0.21 mmol) is dissolved in 2 mL of dichloromethane. Aluminum trichloride (0.1 g, 1 mmol) and 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (38, 0.075 g, 0.25 mmol) are added in one portion, and the reaction is stirred at room temperature for 36 hours, then diluted with water and extracted 3× with ethyl acetate. The organic layers are combined and washed 2× with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The amide linked at the 5-position is lost, so half the material is mixed with 3 mL of triethylamine in 2 mL of tetrahydrofuran and nicotinoyl chloride (36, 0.036 g, 0.25 mmol) is added and stirred at room temperature overnight. The reaction is diluted with water and extracted 3× with ethyl acetate. The organic layers are combined and washed 2× with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is further purified by reverse phase chromatography and the resulting material confirmed by LC-MS.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C>>[CH3:29][O:30][CH2:31][CH2:32][NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COCCN
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 19.7 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (22 mg) was prepared by following General Procedure N starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 2-methoxy-ethylamine (18 mg), DPPA (53 uL), and DIEA (43 uL). LC/MS: m/z 466.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.36 (bs, 1H), 8.47 (s, 1H), 8.08 (s, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.71 (d, 1H), 7.47 (d, 1H), 7.34 (d, 1H), 3.62 (bs, 3H), 3.53-3.38 (m, 4H), 3.27 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])=[O:9])=[CH:4][C:3]=1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[H-].[Na+].I[CH3:31].Cl>O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[CH:4][C:3]=1[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH3:31]
Reactant: CI
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(N)c(NC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(C(=O)c2ccccc2C(=O)O)ccc1N
Reaction time: 1.1 h

Procedure:
Methyl 2-{[4-amino-3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)phenyl]carbonyl}benzoate (0.217 g, 0.586 mmol) was dissolved in tetrahydrofuran (3 mL) and cooled in an ice bath. Sodium hydride (60 wt. % dispersion in oil; 0.024 g, 0.600 mmol) was added followed by dropwise addition of iodomethane (0.037 mL, 0.594 mmol). The mixture was stirred for 1.1 h and then iodomethane (0.100 mL, 1.61 mmol) was added dropwise. The mixture was stirred for a further 1 h and then sodium hydride (60 wt. % dispersion in oil; 0.019 g, 0.475 mmol) was added and the mixture was stirred for a further 0.25 h. The mixture was quenched with 1 N hydrochloric acid. The aqueous portion was extracted with ethyl acetate (2×). The combined organic portion was washed with saturated sodium bicarbonate solution. The ethyl acetate portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford a mixture of 4:1 mono-N-methylated: di-N-methylated material (0.115 g). The aqueous portion was acidified with 1 N hydrochloric acid and extracted with ethyl acetate (2×). The organic portion was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-({4-amino-3-[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]phenyl}carbonyl)benzoic acid as an orange oil which was dissolved in methanol (0.5 mL) and toluene (4.5 mL), cooled in an ice-bath and treated with (trimethylsilyl)diazomethane (2.0M solution in hexanes; 0.200 mL, 0.400 mmol). The mixture was stirred for 0.1 h and then was quenched with 0.5 N hydrochloric acid and partitioned with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow foam (0.120 g). This yellow foam was combined with the 4:1 mixture of mono- and di-methylated material isolated above (0.115 g) and was purified by column chromatography (ethyl acetate-hexanes 1:1) to afford methyl 2-({4-amino-3-[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]phenyl}carbonyl)benzoate as a yellow foam (0.167 g, 0.435 mmol, 74% yield). 1H NMR (400 MHz, CDCl3): 8.02 (dd, 1H), 7.65-7.30 (m, 5H), 6.69 (d, 1H), 4.24 (s, 2H), 3.65 (s, 3H), 3.13 (s, 3H), 1.56 (s, 9H); MS (EI) for C21H24N2O5: 407 (MNa+).
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH3:19])=[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]=1[OH:11])([O:3][CH2:4][CH3:5])=[O:2].[CH2:20]([CH:22]1[O:24][CH2:23]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[C:1]([C:6]1[NH:7][C:8]([CH3:19])=[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]=1[O:11][CH2:20][CH:22]1[O:24][CH2:23]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: BrCC1CO1
Reactant: CCOC(=O)c1[nH]c(C)c(Cc2ccccc2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)c1[nH]c(C)c(Cc2ccccc2)c1OCC1CO1
Yield: 61.7 %

Procedure:
Using the method described in Example V, 20 g of 2-carboethoxy-3-hydroxy-4-benzyl-5-methyl-pyrrole, 14 g of epibromohydrin and 20 g of dry potassium carbonate in 150 ml of methyl isobutyl ketone give 15 g of 1-(2-carboethoxy-4-benzyl-5-methyl-pyrrol-3-oxy)-2,3-epoxypropane as a pale yellow, very viscous oil.
Reaction SMILES: Cl.O1[C:6]2([CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[O:5]CC1>C1COCC1>[O:5]=[C:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C2CCC(=O)CC2)cc1
Reaction time: 64 h
Yield: 97.3 %

Procedure:
Aqueous HCl (1.15 mL of a 2M solution) was added to a stirred solution of diethyl [4-(1,4-dioxaspiro[4.5]dec-8-yl)phenyl]malonate (290 mg, 0.77 mmol) in 4 mL THF. The mixture was stirred for 64 h then was partitioned between water and EtOAc. The organic phase was separated and the aqueous further extracted with EtOAc. The organics were combined and dried then concentrated by evaporation to give the title compound (249 mg, 97%) as a gum; 1H NMR δ 1.18 (6H, t), 1.82-1.93 (2H, m), 2.06-2.11 (2H, m), 2.26-2.29 (2H, m), 2.54-2.63 (2H, m), 3.04-3.10 (1H, m), 4.08-4.21 (4H, m), 4.88 (1H, s), 7.31 (4H, s); MS m/e M+Na+ 355.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:17]([CH3:20])=[N:18][N:19]=[C:15]3[C@H:14]([CH2:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[N:13]=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:11]=2[CH:34]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH:43]([C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)=[O:44].C(O)C>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.C1(C)C=CC=CC=1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:12]2[C:11]3[CH:34]=[C:7]([C:49]4[CH:48]=[CH:47][CH:46]=[C:45]([CH:43]=[O:44])[CH:50]=4)[CH:8]=[CH:9][C:10]=3[N:16]3[C:17]([CH3:20])=[N:18][N:19]=[C:15]3[C@H:14]([CH2:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[N:13]=2)=[CH:32][CH:31]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3cccc(C=O)c3)ccc2-n2c(C)nnc21
Temperature: 120 °C

Procedure:
(S)-6-(4-Chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (for a preparation see Intermediate 3) (500 mg) potassium carbonate (638 mg), 3-formylphenylboronic acid (166 mg) and bis(triphenylphosphine)palladium(II) chloride (64.8 mg) were added to a 20 ml microwave vial. Ethanol (9 ml) and toluene (9 ml) were added to the vial and the reaction mixture was heated at 120° C. for 20 min (microwave). The reaction mixture was filtered through Celite™ and the filter bed was washed with ethanol. The solvent was evaporated and the residue was chromatographed (0-10% methanol:DCM) to give (S)-2-(6-(4-chlorophenyl)-8-(3-formylphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide as a light brown solid (287 mg). LCMS (formate): MH+ 498/500, RT 0.99 min
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(O)(=O)C>[C:11]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH3:10])=[N:6][CH:7]=1)(=[O:13])[CH3:12]
Reactant: CCCc1ccc(N)cn1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCc1ccc(NC(C)=O)cn1
Yield: 80.1 %

Procedure:
A mixture of 5-amino-2-n-propylpyridine (example 23, step2) (62.7 g, 0.46 mol) and 45.7 g (0.483 mol) of acetic anhydride in 50 ml of acetic acid was refluxed for 3 hours in a nitrogen atmosphere. The mixture was evaporated and the oily residue was made slightly alkaline (pH=9.2) with a 10% sodium hydroxide solution. The precipitate was filtered off, and triturated with a mixture of water (1000 ml) and heptane (500 ml). The precipitate was filtered off, dried and resuspended in 400 ml of heptane. The resulting precipitate was filtered off and dried to yield 65.7 g (80%) of 5-acetylamino-2-n-propylpyridine. M.p. 122-24° C. 1H-NMR (CDCl3, 200 MHz) δ: 0.95 (t, 3H), 1.72 (sext, 2H), 2.20 (s, 3H), 2.73 (t, 2H), 7.10 (d, 1H), 7.70 (br s, 1H), 8.09 (dd, 1H), 8.43 (d, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2].[C:26](OC(=O)C)(=[O:28])[CH3:27].O1CCCC1>O>[C:26]([O:10][C:9]1[CH:8]=[CH:7][C:6]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][C:4]=1[C:1]([OH:3])=[O:2])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(-n2c(-c3ccccc3)cc3ccccc32)ccc1O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(-n2c(-c3ccccc3)cc3ccccc32)cc1C(=O)O
Reaction time: 48 h

Procedure:
A mixture of 8.25 g. (0.025 mole) of 1-(3-carboxy-4-hydroxyphenyl)-2-phenylindole and 76.5 g. (0.75 mole) of acetic anhydride was heated under reflux for 1 hour, diluted with 75 ml. of tetrahydrofuran and poured into 1 l. of water. An oil separated, and during 2 days solidified. The solid was collected and recrystallized from acetonitrile to provide 4.8 g. (52%) of colorless crystals, m.p. 178°-180°.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][N:31]1[C:35]2[CH:36]=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][C:34]=2[N:33]=[N:32]1.C([O-])([O-])=O.[K+].[K+].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>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:38]3[CH:37]=[CH:36][C:35]4[N:31]([CH3:30])[N:32]=[N:33][C:34]=4[CH:39]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cn1nnc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)nnn4C)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a vial flushed with argon was added (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (100 mg, 0.202 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole (62 mg, 0.24 mmol), Pd(PPh3)4 (23 mg, 20 μmol), and K2CO3 (83 mg, 0.6 mmol). De-gassed dioxane (2 mL) and water (0.5 mL) were then added, and the reaction was heated to 100° C. for 1 h. After cooling to 23° C., the reaction was filtered over a plug of Celite, concentrated, and purified by column chromatography (gradient 0 to 35% EtOAc in hexanes) to give the product. 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.31 (dd, J=8.7, 1.4 Hz, 1H), 7.90 (s, 1H), 7.66-7.44 (m, 5H), 5.17 (s, 1H), 4.33 (s, 3H), 4.26-4.16 (m, 2H), 2.61 (s, 3H), 1.30-1.22 (m, 3H), 0.98 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]#[N:14].C(OCC)(=O)C.Cl.O1CCCC1.CCOP(S)(OCC)=[S:31]>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13](=[S:31])[NH2:14]
Reactant: N#CCN1C(=O)c2ccccc2C1=O
Reactant: CCOP(=S)(S)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=S)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 51 %

Procedure:
To a mixture of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetonitrile (15 g), 4 mol/L hydrogen chloride-ethyl acetate solution (40 mL) and tetrahydrofuran (50 mL) was added O,O-diethyldithiophosphate (15 mL), and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and tetrahydrofuran. The extract was washed twice with water, and then washed with saturated brine and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as white crystals (yield 9.0 g, 51%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.O[CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[CH2:22][NH:21][C:20]1=[O:25].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>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:16][CH2:17][CH2:18][N:19]3[C:23](=[O:24])[CH2:22][NH:21][C:20]3=[O:25])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C1CNC(=O)N1CCCO
Reactant: COc1cc2c(Cl)ncnc2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1C(=O)CNC1=O
Temperature: 0 °C
Yield: 69 %

Procedure:
A mixture of 4-chloro-7-hydroxy-6-methoxyquinazoline (665 mg, 3.16 mmol), (prepared as described for the starting material in Example 4), 3-(3-hydroxypropyl)imidazolidine-2,4-dione (600 mg, 3.79 mmol) and triphenylphosphine in dichloromethane (15 ml) was stirred and cooled to 0° C. Diisopropyl azodicarboxylate (747 μl, 3.79 mmol) in dichloromethane (5 ml) was added and the mixture stirred at ambient temperature for 3 hours. Initially all material went into solution but later a precipitate formed. The mixture was concentrated and the solid residue suspended in methanol, filtered and dried in air to give 4-chloro-7-[3-(2,5-dioxoimidazolidin-1-yl)propoxy]-6-methoxyquinazoline (765 mg, 69%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[CH:26]=[C:27]2[C:36]([CH3:37])=[N:35][N:34]([CH3:38])[C:28]2=[N:29][C:30]=1[C:31](Cl)=O.C(N(CC)CC)C>C(#N)C>[Cl:24][C:25]1[CH:26]=[C:27]2[C:36]([CH3:37])=[N:35][N:34]([CH3:38])[C:28]2=[N:29][C:30]=1[C:31]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: Cc1nn(C)c2nc(C(=O)Cl)c(Cl)cc12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2nc3c(cc2Cl)c(C)nn3C)n1
Temperature: 150 °C
Yield: 77.1 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.05 g, 0.154 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 5-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl chloride (0.095 g, 0.389 mmol) and triethylamine (0.5 mL, 6.81 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.061 g (77% yield) of pure product: MS (ES) m/z 513 (M+).