Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](Cl)=[O:15])[CH:5]=[CH:4][C:3]1=2.C[Si]([C:22]#[C:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)(C)C.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[O:15]=[C:14]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:17])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)[C:22]#[C:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Cl)ccc21
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(C#CC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.4 g (36 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl chloride, 6.9 g (29.7 mmol) of methyl 4-trimethylsilylethynylbenzoate and 100 ml of dichloromethane are introduced into a round-bottomed flask. 16.8 g (125 mmol) of AlCl3 are added portionwise at 0° C. and the mixture is stirred at room temperature for 8 hours. The reaction medium is poured into ice and extracted with dichloromethane, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and hexane (50/50% by volume). 6.8 g (61%) of the expected product are collected, with a melting point of 113-4° C.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([N:13]([CH:20]([CH3:22])[CH3:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])[C:6]2[CH:23]=[CH:24][CH:25]=[CH:26][C:5]=2[N:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:3]1=[O:33].Cl.[N:35]1[NH:36][N:37]=[N:38][C:39]=1[C:40]1[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=1.[O:47]1CCC[CH2:48]1>>[O:9]=[C:8]1[N:7]([CH2:10][C:11]([N:13]([CH:20]([CH3:22])[CH3:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])[C:6]2[CH:23]=[CH:24][CH:25]=[CH:26][C:5]=2[N:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:3](=[O:33])[CH:2]1[NH:1][C:48]([NH:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:39]2[NH:35][N:36]=[N:37][N:38]=2)[CH:41]=1)=[O:47]
Reactant: C1CCOC1
Reactant: Nc1cccc(-c2nn[nH]n2)c1
Reactant: CC(C)N(C(=O)CN1C(=O)C(N)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Agent: Cl
Product: CC(C)N(C(=O)CN1C(=O)C(NC(=O)Nc2cccc(-c3nnn[nH]3)c2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a vigorously stirring solution of 2-(3-amino-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (0.070 g) in tetrahydrofuran (3 ml) at ambient temperature was added 1,1-carbonyldiimidazole (0.025 g) in one portion. The resulting mixture was stirred for 90 minutes at ambient temperature. 3-(2H-tetrazol-5-yl)-phenylamine hydrochloride (31.3 mg), was added in one portion and the reaction mixture was heated to reflux overnight. The reaction mixture was filtered and the filtrate concentrated to a yellow oil. The oil was purified by preparative RP-HPLC on a C-18 column with a gradient elution of 43-53% acetonitrile in water with 0.1% trifluoroacetic acid buffer over a 30 minute period at a rate of 100 ml/min. Fractions containing the desired material were combined, frozen and lyophilized to provide the title compound as a white powder (50 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[N:27]1([NH:26][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:9][O:10][C:11]=3[CH2:24][OH:25])=[CH:20][N:19]=2)=[O:23])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Reactant: NN1CCOCC1
Product: O=C(NN1CCOCC1)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Yield: 41 %

Procedure:
As described for example 34b, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (100 mg, 0.29 mmol) was converted, using 4-aminomorpholine instead of S-(+)-1-amino-2-propanol, to the title compound (57 mg, 41%), which was obtained as a white solid. MS: m/e=429.2 [M+H]+.
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH2:23][CH2:24][N:25]=3)[C:8]([NH:14][C:15]([C:17]3[CH:18]=N[CH:20]=[N:21][CH:22]=3)=[O:16])=[N:9][C:10]=2[C:11]=1[O:12][CH3:13].[C:26](=O)([O-])[O-].[Cs+].[Cs+].CS([O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])(=O)=O.O>CN(C)C=O>[CH3:13][O:12][C:11]1[C:10]2[N:9]=[C:8]([NH:14][C:15]([C:17]3[CH:22]=[N:21][CH:20]=[CH:26][CH:18]=3)=[O:16])[N:7]3[CH2:23][CH2:24][N:25]=[C:6]3[C:5]=2[CH:4]=[CH:3][C:2]=1[O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:43](=[O:44])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Reactant: O=C([O-])[O-]
Reactant: COc1c(O)ccc2c1N=C(NC(=O)c1cncnc1)N1CCN=C21
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(OCCOCCNC(=O)OC(C)(C)C)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
N-(8-Hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide (Intermediate B, 4.2 g, 7.4 mmol) was diluted in dimethylformamide (75 mL). Cesium carbonate (12.1 g, 37.1 mmol) was added, followed by 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate (Step 2, 5.26 g, 18.6 mmol). The mixture was stirred at 50° C. overnight. After cooling to rt, water was added and the mixture was cooled to 0° C. for 30 min. The product was isolated by vacuum filtration, washing with water, and dried in the vacuum oven. The title compound was obtained as an orange solid (3.55 g, 91%). HPLC MS RT=2.23 min, MH+=525.1. 1H NMR (DMSO-d6+2 drops TFA-d) δ: 1.35 (9H, s), 3.07 (2H, t), 3.46 (2H, t), 3.81 (2H, m), 4.02 (3H, s), 4.25 (2H, m), 4.40 (2H, m), 4.57 (2H, m), 7.49 (1H, d), 7.85 (1H, m), 8.03 (1H, d), 8.82 (1H, m), 8.93 (1H, m), 9.48 (1H, m).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:48][C:49]1[S:50][CH:51]=[CH:52][N:53]=1>C(Cl)Cl>[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([NH:48][C:49]2[S:50][CH:51]=[CH:52][N:53]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
A solution of triphenylphosphine (3.35 g, 12.79 mmol) in methylene chloride (19 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (2.28 g, 12.79 mmol) in small portions. The reaction mixture was stirred at 0° C. for 30 min, and during this time period, the color of the reaction mixture changed from light yellow to a darker yellow then to a purple color. The cooled purple reaction mixture was then treated with the (2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid (2.23 g, 7.52 mmol). The resulting reaction mixture was then allowed to warm to 25° C. over 45 min, at which time, the reaction mixture was then treated with 2-aminothiazole (1.88 g, 18.81 mmol). The resulting reaction mixture was stirred at 25° C. for 12 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining black residue was diluted with ethyl acetate (300 mL) and then washed well with a 10% aqueous hydrochloric acid solution (2×100 mL), a 5% aqueous sodium bicarbonate solution (3×100 mL), and a saturated aqueous sodium chloride solution (1×200 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 9/1, 3/1, and then 11/9 hexanes/ethyl acetate) afforded (2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (2.10 g, 74%) as a white foam: mp 78–80° C. (foam to gel); [α]23589=−70.4° (c=0.027, chloroform); EI-HRMS m/e calcd for C18H22N2O3S2 (M+) 378.1072, found 378.1081.
Reaction SMILES: [C:1]([N:5]([N:9]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:11]([NH2:28])[C:10]1=[O:29])[C:6](=[O:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].[C:30]1([CH3:39])[CH:35]=[CH:34][CH:33]=[C:32]([N:36]=[C:37]=[O:38])[CH:31]=1>C(OCC)(=O)C>[C:1]([N:5]([N:9]1[CH:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:11]([NH:28][C:37]([NH:36][C:32]2[CH:31]=[C:30]([CH3:39])[CH:35]=[CH:34][CH:33]=2)=[O:38])[C:10]1=[O:29])[C:6](=[O:8])[CH3:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)N(N1C(=O)C(N)CC(c2ccccc2)CC1c1ccccc1)C(C)(C)C
Reactant: Cc1cccc(N=C=O)c1
Solvent: CCOC(C)=O
Product: CC(=O)N(N1C(=O)C(NC(=O)Nc2cccc(C)c2)CC(c2ccccc2)CC1c1ccccc1)C(C)(C)C

Procedure:
To a 35 mL round-bottomed flask equipped with N2 inlet and condenser were added 293 mg (0.745 mmol) (-)-1-(N-t-butylacetamido)-3-amino-5,7-diphenylhexahydroazepin-2-one, 10 mL ethyl acetate, and 0.096 mL (0.745 mmol) m-tolylisocyanate. The reaction was refluxed for 2.5 hr, cooled, and evaporated. The residue was chromatographed on silica gel using hexane/ethyl acetate as eluant to afford an oil which was crystallized from methylene chloride/isopropyl ether to a give mp 140°-150° C., 71 mg (18%), αD =-18.6° (c=1, CH2Cl2). The Rf value on TLC and 1H-NMR spectrum match those of the racemate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.[NH:26]([CH2:30][CH2:31][OH:32])[CH2:27][CH2:28][OH:29]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([N:26]([CH2:30][CH2:31][OH:32])[CH2:27][CH2:28][OH:29])=[O:22])[N:9]=1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Reactant: OCCNCCO
Solvent: CCO
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)N(CCO)CCO

Procedure:
2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 6.5 g of diethanolamine are boiled under reflux for 2 h in 5 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is chromatographed on silica gel. After concentration and drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N,N-bis(2-hydroxyethyl)acetamide is obtained as a colorless foam. Rf value: 0.28 (silica gel 60, methylene chloride/methanol=9/1). 1H-NMR (DMSO-d6): 3.2-3.6 (m, 8H) 4.4-5.1 (b, 2H), 5.35 (s, 2H), 7.0 (m, 4H), 7.4 (m, 3H), 7.95 (d, 1H), 10.4 (bs, 1H), 11.05 ppm (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.[CH3:21][C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>O1CCOCC1.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.[Cu](I)I>[CH3:21][C:22]([CH3:26])([CH3:25])[C:23]#[C:24][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:11])=[CH:5][CH:6]=1
Reactant: C#CC(C)(C)C
Reactant: COC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)C#Cc1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
The 4-iodobenzoic acid methyl ester (500 mg; 1.9 mmol) was suspended in 1,4-dioxane (3 ml) in a 5 ml reaction vial. To the vessel was added dichlorobis(triphenylphosphine)palladium(II) (44 mg; 3 mol %), copper iodide (7.5 mg), N,N-diisopropylethylamine (0.39 ml; 3.5 mmol) and 3,3-dimethylbut-1-yne (0.275 ml; 3.5 mmol). The vessel was sealed and the mixture was heated at 80° C. for 24 hrs. The solvents were evaporated to dryness and 20 ml of tetrahydrofuran and 20 ml of 10N NaOH was added. The mixture was stirred at room temperature for 30 minutes and the solvent was evaporated. The basic layer was acidified with concentrated HCl and extracted three times with EtOAc. The organic layers were washed with brine and dried over Na2SO4, filtered and evaporated to give the desired product as a brown powder (210 mg; 28%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([CH2:25][OH:26])=[CH:9]2)=[N:6][CH:7]=1.[CH2:27]([O:29][C:30]1[CH:31]=[CH:32][C:33]([F:39])=[C:34](B(O)O)[CH:35]=1)[CH3:28].[CH3:40]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C[Mg]Br>>[CH2:27]([O:29][C:30]1[CH:31]=[CH:32][C:33]([F:39])=[C:34]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[O:18])[CH:15]=4)[C:10]([CH:25]([OH:26])[CH3:40])=[CH:9]3)=[N:6][CH:7]=2)[CH:35]=1)[CH3:28]
Reactant: O=C(c1ccc2c(CO)cn(-c3ncc(Br)cn3)c2c1)N1CCOCC1
Reactant: CCOc1ccc(F)c(B(O)O)c1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: C[Mg]Br
Product: CCOc1ccc(F)c(-c2cnc(-n3cc(C(C)O)c4ccc(C(=O)N5CCOCC5)cc43)nc2)c1

Procedure:
The target compound was prepared from intermediate 27c in three reaction steps comprising a Suzuki reaction with (5-ethoxy-2-fluorophenyl)boronic acid, an oxidation with Dess-Martin periodinane and a Grignard reaction with methylmagnesium bromide. White solid. Yield: 110 mg
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2].[CH3:19][C:20]([CH3:25])=[CH:21][C:22](Cl)=[O:23]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:22](=[O:23])[CH:21]=[C:20]([CH3:25])[CH3:19])[CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: CCCCCC(C(=O)OCC)c1cccc(N)c1
Reactant: CC(C)=CC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCC(C(=O)OCC)c1cccc(NC(=O)C=C(C)C)c1

Procedure:
A solution of 2-(3-amino-phenyl)-heptanoic acid ethyl ester (3.866 g, 15.5 mmole) in 40 mL of chloroform was treated with 1.73 mL of 3,3-dimethylacryloyl chloride. The mixture was heated at reflux for four hours, quenched by the addition of 100 mL water and extracted with three 50 mL portions of chloroform. The combined organic extracts were washed with 100 mL of saturated aqueous sodium bicarbonate solution, 100 mL of water and 100 mL of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 15% ethyl acetate in hexanes) to yield 3.822 g of 2-[3-(3-methyl-but-2-enoylamino)-phenyl]-heptanoic acid ethyl ester as a pale yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14].[C:15]1([S:21]([O-:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+]>C(#N)C>[OH:13][C:12]1[C:3]([CH2:2][S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:14])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2c1ccc(O)c2CCl
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CC#N
Product: O=C1CCCc2c1ccc(O)c2CS(=O)(=O)c1ccccc1
Yield: 84 %

Procedure:
A mixture of 5-(chloromethyl)-6-hydroxy-3,4-dihydro-1(2H)-naphthalenone (10.0 g, 48 mmol), sodium phenylsulfinate (23.4 g, 142 mmol) and acetonitrile (100 mL) was stirred at reflux under nitrogen overnight. The mixture was poured onto ice. The precipitate was isolated by filtration, air dried, and crystallized from methanol-dichloromethane-ethyl acetate to give 6-hydroxy-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone as a cream solid, 12.16 g, 84% yield. NMR spectrum was consistent with structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:12]2=[N:11][C:10]=1[C:21]([O:23]CC)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:12]2=[N:11][C:10]=1[C:21]([OH:23])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC(=O)N2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1C(=O)Cn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of intermediate 12, ethyl 6-benzyloxy-1-methyl-2,5-dioxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate, (0.084 g, 0.24 mmol) in a mixture of ethanol (5 ml) and tetrahydrofuran (5 ml) was treated with 1.0 ml of a 1 M aqueous sodium hydroxide and the resulting mixture was stirred at 25° C. for 30 min. The reaction mixture was then acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 0.073 g (95% yield) of the title acid as white crystals; mp 194° C. (ethyl acetate). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.07 (3H, s, NCH3), 4.54 (2H, s, CH2), 5.04 (2H, s, CH2), 7.3–7.5 (5H, m, aromatics), 13.8 (1H, s, OH). MS (ESI+) m/z 316 [M+H+].
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:6]=2[N:5]=[C:4]1[CH3:14])[CH3:2].[CH2:15]1[CH2:22][O:21][S:18](=[O:20])(=[O:19])[CH2:17][CH2:16]1>>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:6]=2[N:5]([CH2:22][CH2:15][CH2:16][CH2:17][S:18]([OH:21])(=[O:20])=[O:19])[CH:4]1[CH3:14])[CH3:2]
Reactant: CCn1c(C)nc2cc(C#N)ccc21
Reactant: O=S1(=O)CCCCO1
Product: CCN1c2ccc(C#N)cc2N(CCCCS(=O)(=O)O)C1C
Yield: 72 %

Procedure:
18.6 g (0.1 mole) of compound V and an equimolar amount of 1,4-butanesultone were heated at 140° C for 4 h, then washed with acetone and dried. Melting point: over 260° C. Yield: 72% (23 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=O)[C:13](=[O:19])[C:12]([CH3:21])([CH3:20])[C:11](=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C@:28]1([C:36]3[C:31](=[N:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]1=[O:37])[CH2:27]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:23][C:24]3[CH:25]=[C:26]4[C:39](=[CH:40][CH:41]=3)[CH2:38][C@:28]3([C:36]5[C:31](=[N:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]3=[O:37])[CH2:27]4)=[O:18])[C:13](=[O:19])[C:12]([CH3:20])([CH3:21])[C:11](=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: CC1(C)C(=O)C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1(C)C(=O)C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of [(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2,4-dioxopiperidin-1-yl]acetic acid (156 mg, 0.501 mmol, described in Intermediate 22), (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (145 mg, 0.577 mmol, described in Intermediate 9), HOBT (95 mg, 0.620 mmol), and EDC (123 mg, 0.642 mmol) in DMF (2 mL) was stirred at ambient temperature for 16 h. The reaction mixture was partitioned between H2O (60 mL) and EtOAc (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:CH3OH-100:0 to 90:10, to give the title compound. MS: m/z=545 (M+1). HRMS: m/z=545.2025; calculated m/z=545.1995 for C30H27F2N4O4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[N:3]=1.[NH:19]1[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH:21]=[CH:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[N:3]=[C:2]([N:19]2[C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[CH:21]=[CH:20]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Fc1ccccc1-c1nc(Cl)c2ccccc2n1
Reactant: c1cc2[nH]ccc2cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1ccccc1-c1nc(-n2ccc3cnccc32)c2ccccc2n1
Temperature: 100 °C

Procedure:
4-Chloro-2-(2-fluoro-phenyl)-quinazoline from Step C (0.1 g, 0.38 mmol) was dissolved in N,N-dimethylformamide (1 ml) and to it was added 1H-pyrrolo[3,2-c]pyridine (0.046 g, 0.38 mmol) followed by cesium carbonate (0.134 g, 0.41 mmol). The mixture was magnetically stirred and heated to 100° C. for 0.5 hr. The solvent was removed and title compound was obtained pure after column purification on a HPLC reverse phase column, using a water and acetonitrile gradient containing 0.1% trifluoroacetic acid to yield (0.072 g, 56%). MS (ES) 340.1 (M+H)+
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:16])[CH2:12][C:13]([CH3:15])=[O:14].C[C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[O:27])OC[O:23][C:22]=2[CH:28]=1.C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[OH:23][C:22]1([CH3:1])[CH:28]=[CH:18][CH:19]=[CH:20][CH:21]1[C:26](=[O:27])[CH2:15][C:13](=[O:14])[CH2:12][C:11]([O:10][CH3:9])=[O:16]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)CC(C)=O
Reactant: Cc1ccc2c(c1)OCOC2=O
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)CC(=O)CC(=O)C1C=CC=CC1(C)O
Reaction time: 0.5 h

Procedure:
To a solution of 41.6 mmol of lithium diisopropyl amide in tetrahydrofuran (formed by adding n-butyl lithium in hexanes to diisopropyl amine in THF) is added 2.4 g (20.8 mmole) of methylacetoacetate over 10 minutes at O° C. After stirring for 30 minutes, 2.0 g of 7-methyl-1,3-benzodioxane-4-one is added and the mixture stirred for 30 minutes. 6 ml of acetic acid is added and the mixture diluted with ethyl acetate and filtered The ethyl acetate solution is washed with diluted hydrochloric acid, water and dried over sodium sulfate. The ethyl acetate is removed in vacuo to give methyl 5-(2-hydroxy-2-methylphenyl)-3,5-dioxopentanoate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:34][N:35]([CH3:39])[C:36]([Cl:38])=[O:37]>>[ClH:38].[CH3:34][N:35]([CH3:39])[C:36]([N:31]1[CH2:32][CH2:33][CH:28]([C:25]2[N:24]=[C:23]([NH:22][C:10]3[C:9]([O:8][C:7]4[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=4)=[CH:14][C:13]([S:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:12][N:11]=3)[S:27][N:26]=2)[CH2:29][CH2:30]1)=[O:37]
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CCNCC2)ns1
Reactant: CN(C)C(=O)Cl
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CCN(C(=O)N(C)C)CC2)ns1
Product: Cl
Yield: 79 %

Procedure:
Following the procedure in Example 1, Step G, and using N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(piperidin-4-yl)-1,2,4-thiadiazol-5-amine (150 mg, 0.3141 mmol) and dimethylcarbamic chloride (33.77 mg, 0.3141 mmol) provided N,N-dimethyl-4-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxamide hydrochloride (145.2 mg, 0.2481 mmol, 79.01% yield). Mass spectrum (apci) m/z=549.1 (M+H—HCl).