Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][CH:9]=[C:8]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[C:22]([OH:29])[C:21]=2[CH2:30][CH2:31][CH3:32])[C:7]=1[CH2:33][CH2:34][CH3:35]>CO.[OH-].[Na+]>[C:12]([C:11]1[C:6]([O:5][CH2:4][C:3]([OH:36])=[O:2])=[C:7]([CH2:33][CH2:34][CH3:35])[C:8]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[C:22]([OH:29])[C:21]=2[CH2:30][CH2:31][CH3:32])=[CH:9][CH:10]=1)(=[O:14])[CH3:13]
Reactant: CCCc1c(OCCCOc2ccc(C(C)=O)c(OCC(=O)OC)c2CCC)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(C)=O)c(OCC(=O)O)c2CCC)ccc(C(C)=O)c1O

Procedure:
A solution of 1.41 g of [6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid methyl ester in 50 ml of methanol and 14 ml of 1N sodium hydroxide was stirred at reflux for 22 hours. The methanol was removed in vacuo and the pH of the residue was adjusted to 2.0 with 6N hydrochloric acid. The gummy product was extracted with ether and the crude extract was purified by chromatography on 60 g of silica gel. Elution with a solvent mixture of toluene:ethyl acetate:acetic acid (65:25:10) gave, after recrystallization from methylene chlorideether, 0.51 g (38%), mp 151°-155°, of [6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[I-].[K+].Cl[CH2:39][C:40]1[NH:44][C:43]2[C:45]([F:49])=[CH:46][CH:47]=[CH:48][C:42]=2[N:41]=1>C(#N)C>[F:49][C:45]1[C:43]2[N:44]=[C:40]([CH2:39][N:11]([CH:9]3[C:10]4[N:1]=[CH:2][CH:3]=[CH:4][C:5]=4[CH2:6][CH2:7][CH2:8]3)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[NH:41][C:42]=2[CH:48]=[CH:47][CH:46]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Reactant: Fc1cccc2nc(CCl)[nH]c12
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2c(F)cccc2[nH]1)C1CCCc2cccnc21
Temperature: 60 °C
Yield: 41 %

Procedure:
To a stirred solution of 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione (146 mg, 0.418 mmol), diisopropylethylamine (0.15 mL, 0.861 mmol) and potassium iodide (14 mg, 0.084 mmol) in acetonitrile (2.5 mL) was added 2-chloromethyl-7-fluoro-1H-benzimidazole (prepared according to the procedures described in Bridger et al. U.S. Provisional Application 60/232,891 filed 15 Sep. 2000 and from Application 60/234,510 filed 22 Sep. 2000) (80 mg, 0.433 mmol) and the mixture heated at 60° C. for 18 hours. The mixture was then concentrated and the residue diluted with CH2Cl2 (30 mL). The solution was washed with brine (3×15 mL). The combined aqueous phase was extracted with CH2Cl2 (1×15 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give a crude brown foam. The foam was purified by flash chromatography (1.75 cm ID, 12 g silica, 50:1:1 CH2Cl2: MeOH: NH4OH) to give pure 2-{4-[(4-fluoro-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione (86 mg, 41%). 1H NMR (CDCl3) δ 1.33-1.76 (m, 5H), 1.85-2.10 (m, 3H), 2.14-2.25 (m, 1H), 2.54-2919 (m, 4H), 3.45-3.55 (m, 2H), 3.98-4.24 (m, 3H), 7.29-7.45 (m, 2H), 7.63-7.69 (m, 2H), 7.72-7.77 (m, 2H), 8.56-8.63 (m, 1H).
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][C:7]3[O:13][CH2:12][O:11][C:8]=3[CH:9]=2)[CH2:4][CH2:3]1.C(O)(=O)C.O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:12]1[O:11][C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[CH:3][CH2:2]3)=[CH:6][C:7]=2[O:13]1
Reactant: OC1CCc2cc3c(cc21)OCO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C1=Cc2cc3c(cc2C1)OCO3
Yield: 92.7 %

Procedure:
A solution of 10.8 g of 1-hydroxy-5,6-methylenedioxyindane and 15 ml of acetic acid in 100 ml of toluene was heated under reflux for 4 h. Water and a small amount of potassium carbonate were added to the reaction mixture. After extraction with ethyl acetate, the organic layer was washed with water and an aqueous common salt solution and dried over magnesium sulfate. The solvent was distilled off and the residue was treated according to silica gel column chromatography (chloroform/hexane=1:3) to obtain 9.0 g of the intended compound in the form of colorless crystals.
Reaction SMILES: CC1(C)CO[CH:5]([C:8]2[S:12][CH:11]=[C:10]([CH:13]([N:16]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:14][OH:15])[CH:9]=2)[O:4]C1.O>CC(O)=O.O>[CH:5]([C:8]1[S:12][CH:11]=[C:10]([CH:13]([N:16]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:18])=[O:19])[CH2:14][OH:15])[CH:9]=1)=[O:4]
Reactant: CC(C)CCN(C(CO)c1csc(C2OCC(C)(C)CO2)c1)S(=O)(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CCN(C(CO)c1csc(C=O)c1)S(=O)(=O)c1ccccc1
Reaction time: 5 h

Procedure:
N-{1-[5-(5,5-dimethyl-1,3-dioxan-2-yl)thiophen-3-yl]-2-hydroxyethyl}-N-(3-methylbutyl)benzenesulfonamide was dissolved in 10 mL AcOH/water (4:1) and stirred for 5 hours. 5 mL of water was and the aqueous layer was extracted 2× with EtOAc. The EtOAc layers were combined, washed 3 times with water, once with brine and dried (MgSO4). The residue was purified on silica gel (EtOAc/hexanes).
Reaction SMILES: [OH-].[Na+].[C:3]1([CH2:13][NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1>O.CO.[Zn]>[C:3]1([CH2:13][N:14]2[C:15](=[O:25])[C:16]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:22]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(NCc1cccc2ccccc12)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: O=c1c2ccccc2[nH]n1Cc1cccc2ccccc12
Yield: 44.1 %

Procedure:
A solution of sodium hydroxide (4.13 g) in water (80 ml) was added to a solution of N-(1-naphthylmethyl)-2-nitrobenzamide (7.6 g) in methanol (60 ml). Zinc powder (3.35 g) was then added to the mixture which was heated under reflux for 24 hours. After cooling, the zinc residue was separated by filtration and the methanol was partially evaporated. The residual solution was then adjusted to pH7 with hydrochloric acid. The precipitated solid was collected, dried and purified by column chromatography, eluting with methylene chloride/ether/methanol (50/50/5 v/v) to give 1,2-dihydro-2-(1-naphthylmethyl)-3H-indazol-3-one (3.0 g), as a white solid after washing with acetone, m.p. 198-200° C. (acetone/ether).
Reaction SMILES: C([S:4][CH:5]1[CH2:22][CH2:21][C:8]2([CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]3[CH:20]=[CH:19][O:18][CH:17]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6]1)(=O)C.[H][H].N>CO.O1CCCC1>[SH:4][CH:5]1[CH2:6][CH2:7][C:8]2([CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]3[CH:20]=[CH:19][O:18][CH:17]=3)[CH2:12][CH2:13]2)[CH2:21][CH2:22]1
Reactant: CC(=O)SC1CCC2(CCC(CCc3ccoc3)CC2)CC1
Reactant: [H][H]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: SC1CCC2(CC1)CCC(CCc1ccoc1)CC2
Reaction time: 3 h
Yield: 92.1 %

Procedure:
A solution of 0.100 g of 9-acetylthio-3-(2-(3-furyl)ethyl)-spiro[5.5]undecane in 5 ml of methanol/tetrahydrofuran 3/1, was saturated with hydrogen and successively with gaseous ammonia and kept on standing for 3 hrs at room temperature. The mixture was evaporated to dryness and purified by flash chromatography (SiO2 ; n-hexane/diethylether 80/20) to give 0.080 g of 9-mercapto-3-(2-(3-furyl)ethyl)-spiro[5.5]undecane as a white sticky oil. TLC: Rf=0.38 (SiO2 plates, n-hexane/diethylether 80/20). 1H-NMR (300 MHz, CDCl3, ppm from TMS): 7.36 (1H, m), 7.20 (1H, m), 6.27 (1H, m), 2.90 (1H, m), 2.48 (2H, t), 1.90-0.85 (19H, m).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:13][C:12](=[O:14])[C:9]3([CH2:11][CH2:10]3)[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.IC.[C:23](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:13]([CH3:23])[C:12](=[O:14])[C:9]3([CH2:11][CH2:10]3)[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC12CC2
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of 1.00 g (0.0034 mole) of 2-chloro-9-cyclopentyl-8,9-dihydro-spiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-6(7H)-one (VI-53) in 40 mL of dimethylformamide was added 1.47 g (0.0104 mole) of iodomethane and 1.68 g (0.00575 mole) of cesium carbonate. The mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.957 g of 2-chloro-9-cyclopentyl-8,9-dihydro-5-methylspiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-6(7H)-one (VII-53) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[S:11][C:12]([S:36][CH3:37])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([NH:30][C:31](=[O:34])[CH2:32][Br:33])=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:35])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])(C)(C)C.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40].C(Cl)Cl>>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[Br:33][CH2:32][C:31]([NH:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:35])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8](=[NH:7])[NH2:9])[S:11][C:12]=2[S:36][CH3:37])(=[O:17])=[O:16])[CH:19]=1)=[O:34]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CBr)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CBr)c1
Yield: 68 %

Procedure:
({4-[6′-(2-bromo-acetylamino)-2′-methyl-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester (22 mg, 0.034 mmol, as prepared in Example 246, step a) was stirred in a mixture of TFA/DCM (1:1, 4 mL) for 1 h at rt. The reaction was concentrated in vacuo and the resulting residue was purified using RP-HPLC (10–50% CH3CN in H2O with 0.1% TFA over 30 min) to afford 15 mg (68%) of the title compound as a clear glassy solid (purity>99.9% by analytical RP-HPLC). ESI-MS (m/z): Calcd. for C21H20BrN3O3S3: 538.0 (M+H); found: 538.0 and 540.0
Reaction SMILES: CI.[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C1C[O:13][CH2:12][CH2:11]1.C(C1C=CC=CC=1)C>C1COCC1>[O:13]1[C:12]2[C:6](=[CH:7][CH:8]=[CH:9][CH:11]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: C1CCOC1
Reactant: CCCCCCC
Solvent: CI
Solvent: CCc1ccccc1
Product: c1ccc2c(c1)CCCO2
Reaction time: 0.25 h

Procedure:
To 0.9 g (4 mmole) of sulfone ketone in 40 ml of THF is added 2.5 ml (5 mmole, 1.25 eq.) of 2 M of Lithium diisopropylamine(LDA) in heptane/THF/ethylbenzene at −60° C. The mixture is stirred for about 15 minutes, and then 1.24 ml (20 mmole, 5 eq.) of methyl iodide is added. The reaction mixture is stirred for 1 hour at −60° C., and then the cold bath is removed. After stirring overnight, the reaction mixture is partitioned between EtOAc and water, washed with 0.5N HCl, aqueous sodium bicarbonate solution, and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography to afford 0.68 g of the desired product as an oil, which solidified upon standing. TLC (30% EtOAc/Hexane, Rf=0.39). Mass spec. m/e=239.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].Cl.O.O.[C:13](O)(=[O:17])[C:14](O)=[O:15].[OH-].[Na+]>>[CH3:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:2]=1[NH:1][C:13](=[O:17])[C:14](=[O:15])[NH:8]2
Reactant: O=C(O)C(=O)O
Reactant: Cc1cccc(N)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Yield: 768.5 %

Procedure:
To a stirred solution of 2,3-diaminotoluene (0.498 g, 0.407 mmol, Aldrich) in 2 N HCl (6 mL, 12 mmol), oxalic acid dihydrate (0.520 g, 0.412 mmol, Fisher) was added in one portion. The resulting deep purple solution was refluxed for 13 h, to give a purple suspension. This was cooled to 25° C., filtered, washed with water (5 mL), and dried in vacuo (0.1 mm Hg) to give a purple powder. This was taken up in 2 N NaOH (25 mL, 50 mmol), giving a brown solution, which was filtered. The brown filtrate was acidified to pH 1.0 by addition of 2 N HCl (25 mL, 50 mmol), resulting in a tan suspension. Filtration of the suspension and washing of the filter cake with water (5 mL) gave the title compound as a tan powder (551 mg, 64%); mp 325° C. (the block was preheated to 320° C.); 1H NMR (DMSO-d6) δ 2.26 (s, 3H), 6.86-7.01 (m, 3 H), 11.6 (broad, 2 H).
Reaction SMILES: Br[C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:38])[C@@H:18]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH2:19][N:20]([CH:28]([CH3:30])[CH3:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][C:46]=1[O:47][CH3:48].C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([C@H:18]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:3]3[C:2]([C:44]4[CH:43]=[CH:42][C:41]([O:40][CH3:39])=[C:46]([O:47][CH3:48])[CH:45]=4)=[CH:7][N:6]=[C:5]4[NH:8][CH:9]=[CH:10][C:4]=34)[CH2:16][CH2:15]2)=[O:38])[CH2:19][N:20]([CH:28]([CH3:29])[CH3:30])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:36][CH:35]=1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(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: [K+]
Product: COc1ccc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)[C@H](CN(C(=O)OC(C)(C)C)C(C)C)c3ccc(Cl)cc3)CC2)cc1OC
Temperature: 80 °C
Yield: 18.3 %

Procedure:
(S)-tert-Butyl 3-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate (0.100 g, 0.165 mmol, see Example 4), 3,4-dimethoxyphenylboronic acid (0.0361 g, 0.198 mmol), Pd(PPh3)4 (0.009 g, 0.0083 mmol) and 10% K2CO3 (aq., 0.344 mL, 0.248 mmol) were added to an Ar degassed solution of 2:1 toluene:EtOH (3 mL). The reaction was then heated to 80° C. for 24 hours. The reaction was then cooled to room temperature, diluted with water, and extracted with DCM. The organic fractions were dried, filtered, concentrated, and purified (500:10-500:15) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-(3,4-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.020 g, 18.2% yield).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[NH2:14].[F:15][B-:16]([F:19])([F:18])[F:17].[N:20]#[O+]>C1COCC1>[F:15][B-:16]([F:19])([F:18])[F:17].[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[N+:14]#[N:20]
Reactant: N#[O+]
Reactant: COc1ccc2ncc(N)c(Br)c2n1
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: COc1ccc2ncc([N+]#N)c(Br)c2n1
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A solution of 4-bromo-6-methoxy-[1,5]naphthyridin-3-ylamine (25.2 g, 99.2 mmol) in dry THF (400 mL) was maintained at −5° C. while nitrosonium tetrafluoroborate (12.9 g, 110 mmol) was added portion-wise over 30 min (approximately 2 g portions). The reaction was continued for an additional 1 h at −5° C., at which time TLC* and LC/MS indicated that the reaction was complete. The orange solid was collected by suction filtration, washed with ice-cold THF and dried under vacuum to provide the title compound (31.42 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[CH:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH2:16].[N:18]1[CH:23]=[CH:22]N=N[N:19]=1>ClCCCl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[CH:22]=[CH:23][N:18]=[N:19][CH:11]=2)[C:7]([C:12]([F:13])([F:15])[F:14])=[CH:6][C:5]=1[NH2:16]
Reactant: c1cnnnn1
Reactant: C#Cc1cc(C(=O)OC)c(N)cc1C(F)(F)F
Solvent: ClCCCl
Product: COC(=O)c1cc(-c2ccnnc2)c(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 40.2 %

Procedure:
A solution of 2-amino-5-ethynyl-4-trifluoromethyl-benzoic acid methyl ester (150 mg, 0.62 mmol) and tetrazine (55.7 mg, 0.68 mmol) in 1,2-dichloroethane (3 mL) in a sealed tube was heated in the microwave at 130° C. for 40 min and at 120° C. for 40 min. After cooling to r.t., the solvent was removed in vacuo. The residue was purified by flash chromatography (10 g silica gel, hexanes→EtOAc:hexanes (2:3)) to provide 2-amino-5-pyridazin-4-yl-4-trifluoromethyl-benzoic acid methyl ester (74 mg, 40%) as a solid. API-ES: m/z 298 [M+H]+, rt 3.54 min.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:11][C:12]([F:22])([F:21])[C@H:13]([CH3:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Br[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[CH3:31].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH:14]([C@@H:13]([CH3:20])[C:12]([F:21])([F:22])[F:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:25]([CH3:31])[CH:26]=1
Reactant: Cc1cc(Cl)ccc1Br
Reactant: CCOC(=O)C[C@@H](C)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(c1ccc(Cl)cc1C)[C@@H](C)C(F)(F)F
Reaction time: 0.17 h

Procedure:
22.5 ml (22.5 mmol) of a 1 M solution of lithium hexamethyldisilazide in toluene were cooled to −20° C., and a solution of 2.76 g (50.3 mmol) of ethyl (3R)-4,4,4-trifluoro-3-methylbutanoate in 15 ml of abs. toluene was added dropwise. The mixture was stirred for 10 min. At −20° C., a solution, prepared beforehand, of 4.0 g (19.5 mmol) of 2-bromo-5-chlorotoluene, 101 mg (0.45 mmol) of palladium(II) acetate and 371 mg (0.94 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl in 15 ml of abs. toluene was then added dropwise. After the addition had ended, cooling was removed and the resulting reaction mixture was stirred initially at RT for 1 h and then at 100° C. overnight. After cooling, the mixture was filtered through celite, the residue was washed repeatedly with toluene and the filtrate obtained was concentrated under reduced pressure. This gave 3.10 g of the title compound as a crude product which was directly reacted further.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1.[CH3:13][O-:14].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([O:14][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)nc(C)c1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 65.2 %

Procedure:
2,4-Dichloro-6-methyl-5-nitropyrimidine (3.0 g, 14.4 mmol) was dissolved in methanol (30 mL). The solution was cooled to −10° C. and sodium methoxide (25% in methanol, 3.3 mL, 14.4 mmol) was added drop wise. After 10 minutes, the solution was quenched with acetic acid (5 mL) and concentrated. The residue was suspended in saturated sodium bicarbonate and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Flash chromatography (5% ethyl acetate/hexanes) gave 1.91 g (65% yield) of the title compound as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=2)=[CH:9][CH:8]=1)C.C1COCC1.CO.[OH-].[K+]>O>[CH3:25][O:24][C:19]1[CH:18]=[C:17]([O:26][CH3:27])[CH:16]=[C:15]2[C:20]=1[C:21](=[O:23])[NH:22][C:13]([C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:4]([OH:28])=[O:3])=[CH:12][CH:11]=1)=[N:14]2
Reactant: CCOC(=O)CCc1ccc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(CCC(=O)O)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.8 %

Procedure:
To a round-bottomed flask were added 2-amino-4,6-dimethoxy-benzamide (0.161 g, 0.82 mmol), 3-(4-formyl-phenyl)-propionic acid ethyl ester (0.170 g, 0.82 mmol), sodium bisulfite (0.160 g, 0.902 mmol), p-toluenesulfonic acid (0.016 g, 0.082 mmol) and N,N-dimethylacetamide (10 mL). The reaction mixture was refluxed at 155° C. for 16 h before being cooled to room temperature. Water was added and the precipitated solid was filtered off and washed with water and methanol to obtain 3-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenyl]-propionic acid ethyl ester (0.304 g, 97%). The compound 3-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenyl]-propionic acid ethyl ester (0.304 g, 0.795 mmol) was taken up in a 1:1 mixture of THF and methanol (6 mL). A solution of potassium hydroxide (0.089 g, 1.59 mmol) in water (6 mL) was added to the reaction mixture and stirred at room temperature for 16 h. The solvent was removed and the reaction mixture was acidified with 1 N hydrochloric acid. The precipitated solid was filtered off and washed with water and methanol. The solid was further washed with methanol to obtain 3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)propanoic acid (0.143 g, 51%). Selected data: MS (ES) m/z: 355.0; MP 250.6-251.1° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][NH:25][C:24]3=[O:28])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[CH3:29]I>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][N:25]([CH3:29])[C:24]3=[O:28])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: CI
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCNC4=O)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3)CC2)c(C)c1

Procedure:
Using 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (100 mg) described in Example 401 and methyl iodide (18 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (69 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@H:5]([CH2:7][N:8]2[C:12]([CH3:13])=[C:11](I)[C:10]([CH3:15])=[N:9]2)[CH2:4][O:3]1.C1COCC1.C([Mg]Cl)(C)C.CO[B:29]1[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]1>>[CH3:1][C:2]1([CH3:16])[O:6][C@H:5]([CH2:7][N:8]2[C:12]([CH3:13])=[C:11]([B:29]3[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]3)[C:10]([CH3:15])=[N:9]2)[CH2:4][O:3]1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: Cc1nn(C[C@@H]2COC(C)(C)O2)c(C)c1I
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1nn(C[C@@H]2COC(C)(C)O2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-4-iodo-3,5-dimethyl-1H-pyrazole (180.0 mg, 0.5354 mmol) in THF (5 mL, 60 mmol) was added 2 M isopropylmagnesium chloride in THF (0.5354 mL, 1.071 mmol) at rt, and the mixture was stirred for 10 min. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.2632 mL, 1.606 mmol) was added, and the mixture stirred at rt for 20 min. The reaction was quenched with sat. NH4Cl, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a clear oil. The material was used in the next step without further purification.