Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18](=[O:19])[C:17]3[O:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]5[CH:23]=[CH:22][CH:21]=[CH:20][C:14]5=4)[C:9]=3[O:8][C:7]=2[CH:24]=1.N1C(=O)CC[C@H]1C(O)=O.Cl>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18](=[O:19])[C:17]3[O:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]5[CH:23]=[CH:22][CH:21]=[CH:20][C:14]5=4)[C:9]=3[O:8][C:7]=2[CH:24]=1
Reactant: COc1ccc2c(=O)c3oc4c5ccccc5ccc4c3oc2c1
Agent: Cl
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: O
Product: O=c1c2ccc(O)cc2oc2c1oc1c3ccccc3ccc21
Temperature: 220 °C
Yield: 59.2 %

Procedure:
A mixture of 40 (0.300 g, 0.95 mmol) and Pyr-HCl (approximately 5 g) was heated at 220° C. for 1 h. H2O (100 mL) was added to the cooled reaction mixture and then the H2O mixture heated and filtered. The precipitate thus obtained was triturated with MeOH and then CH2Cl2 to yield 41 (0.17 g) as a white solid: Mp>300° C.; 1H NMR (DMSO-d6) δ 10.96 (s, 1H), 8.46 (d, 1H, J=7.8 Hz), 8.20-8.14 (m, 2H), 8.06-7.99 (m, 2H), 7.84-7.73 (m, 2H), 7.12 (d, 1H, J=2.1 Hz), 7.03 (dd, 1H, J=8.8 Hz, 2.2 Hz); MS 301 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10](O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(O)(C1C=CC(C)=CC=1)(=O)=O.O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)CC(O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C=CCC2
Yield: 98.9 %

Procedure:
7-nitro-1,2,3,4-tetrahydo-2-naphthalenol (10.13 g, 0.053 mol) (from Preparation 1) was heated in the presence of TsOH—H2O (1.72 g, 0.009 mol, 0.2 equiv.) in toluene (150 ml) for 2 h at 100° C. The solvent was removed under reduced pressure and the residue was treated with EtOAc (150 ml) and saturated aqueous NaHCO3 (150 ml). The aqueous layer was separated and extracted with additional EtOAc (2×100 ml). The combined organic layers were washed with saturated aqueous NaCl (200 ml), dried (Na2SO4), filtered, and concentrated under reduced pressure to give 7-nitro-3,4-dihydronaphthalene as a brown oil (9.18 g, 100%) which was used in the next step without additional purification. Rf (silica gel): 0.79 (70% hexane: 30% EtOAc); 1H NMR (300 MHZ, CDCl3) 7.95 (dd, J=2.4 and 8.1 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 6.50 (d, J=6.50 Hz, 1H), 6.18 (dt, J=4.5 and 9.6 Hz, 2H), 2.88 (t, J=8.4 Hz, 2H), 2.40-2.34 (m, 2H); 13C NMR (75 MHZ, CDCl3) 147.1, 143.1, 135.3, 131.4, 128.2, 126.5, 121.8, 120.3, 27.4, 22.5.
Reaction SMILES: CC1C=CC(S(N[C@H]([C@@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.[C:27]([C:29]1[CH:38]=[C:37]2[C:32]([C:33](=[O:39])[CH2:34][CH2:35][O:36]2)=[CH:31][CH:30]=1)#[N:28].[Ru:40]>CC(O)C.CC#N.O.CCN(CC)CC.C(O)=O>[Ru:40].[OH:39][C@@H:33]1[C:32]2[C:37](=[CH:38][C:29]([C:27]#[N:28])=[CH:30][CH:31]=2)[O:36][CH2:35][CH2:34]1
Reactant: N#Cc1ccc2c(c1)OCCC2=O
Agent: [Ru]
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: CC#N
Solvent: CC(C)O
Solvent: O
Product: N#Cc1ccc2c(c1)OCC[C@@H]2O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A ruthenium chiral complex was prepared as follows: (1S, 2S)-(+)—N-p-Tosyl-1,2-diphenylethylenediamine (1.10 g, 3.0 mmol, Aldrich) and [RuCl2(η6-para-cymene)]2 (0.92 g, 1.5 mmol, STREM) were dissolved in 35 ml of i-PrOH and stirred at 80° C. for 1 h. The reaction was concentrated under reduced pressure to ˜5 ml. The mixture was cooled to −20° C., and 10 mL of H2O was added with shaking. The solution was scratched with a spatula until it all solidifies. The solid was filtered and washed with H2O to provide the desired chiral complex. The complex was dried in vacuo. A 5/2 mixture of formic acid and Et3N was prepared as follows: A mixture of formic acid (190 ml, 232 g, 5.03 mmol) and Et3N (280 mL, 203 g, 2.01 mmol) were heated to 100° C. under reduced pressure (˜100 mm Hg) to remove volatile chemicals. The residue was used without further purification. 7-Cyanochroman-4-one (10.2 g, 58.9 mmol) and a 5/2 mixture of formic acid and Et3N (50 mL) were dissolved in CH3CN (120 ml). The ruthenium chiral complex (S, S—, 0.380 g, 0.589 mmol) was added. The reaction was stirred at RT for 14 h. After the addition of H2O (100 mL), the mixture was extracted with EtOAc (300 ml, 3×). The organic phases were combined and washed sequentially with a saturated NaHCO3 solution and brine. The organic solution was dried over MgSO4, filtered and concentrated in vacuo to provide a crude brown solid which was purified by flash column chromatography (silica, 50% EtOAc in hexane) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=[O:23])=[C:11]([N+:24]([O-:26])=[O:25])[C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:29]I>CN(C)C=O>[F:1][C:2]1[C:12]([N:13]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=[O:23])=[C:11]([N+:24]([O-:26])=[O:25])[C:5]2[N:6]([CH3:29])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CI
Reactant: O=C1COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)c([N+](=O)[O-])c2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)c([N+](=O)[O-])c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
2-[7-Fluoro-5-nitro-2H-1,4-benzoxazine-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (1.3 g) was dissolved in anhydrous dimethylformamide (15 ml) and was slowly added to a stirred suspension of sodium hydride (0.11 g) in dimethylformamide (15 ml) under ice cooling. Solution was stirred for 0.5 hr followed by the addition of methyl iodide (2.03 g). After stirring for 2 hr at ambient temperature, solution was added to ice-water and product was isolated by partitioning with ethyl acetate. Purification by column chromatography on silica gel in hexane-ethyl acetate (3:1) afforded the title compound (0.58 g).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].Cl.[CH3:24][NH2:25].Cl>>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2=[CH:11][C:10]3[C:14](=[O:15])[N:25]([CH3:24])[C:17](=[O:18])[C:9]=3[CH:8]=[C:7]2[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: CN
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(C)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.3 g, 1.0 mmol) was treated with methylamine hydrochloride(1.35 g, 20.0 mmol). Purification on silica gel, eluting with 2:1 hexane/acetone, afforded an oil that was converted to an HCl salt and recrystallized from EtOAc/2-propanol to give 120 as a white solid (m.p. 245-246° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15](#[N:18])[CH:16]=[CH2:17]>CO>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:17][CH2:16][C:15]#[N:18])[CH2:13][CH2:14]1
Reactant: C=CC#N
Reactant: Cc1cccc(C)c1N1CCNCC1
Solvent: CO
Product: Cc1cccc(C)c1N1CCN(CCC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
4-(2,6-Dimethylphenyl) piperazine (1 g, 5.23 mmol) in MeOH (10 ml) was cooled to 0° and 0.305 g (5.73 mmol) of acrilonitrile was added. The reaction was stirred overnight at room temperature and evaporated under vacuum affording 1 g of crude 3-[4-(2,6-dimethylphenyl)piperazin-1-yl]propionitrile as a waxy solid. This compound was dissolved in MeOH (60 ml), 2 ml 37% HCl and hydrogenated under pressure (40 psi) with 0.2 g of 10% Pd\C. The reaction was filtered and evaporated to dryness obtaining 1 g of the title compound, as a hydrochloride salt, that was used without further purification for the following reaction.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl.[CH:15]([NH:18][C:19]([NH:21][C:22]#[N:23])=[NH:20])([CH3:17])[CH3:16]>C(O)(C)C>[CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:22]([NH:21][C:19]([NH:18][CH:15]([CH3:17])[CH3:16])=[NH:20])=[NH:23])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CC(C)NC(=N)NC#N
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)NC(=N)NC(=N)Nc1ccc(S(=O)(=O)N(C)C)cc1

Procedure:
To 11 g (0.055 mole) of p-N,N-dimethylsulfamylaniline is added 17.68 ml (0.055) of 3.1 N hydrochloric acid. This is heated on a steam bath with 15 ml of isopropanol and 6.94 g (0.055 mole) of 1-i-propyl-3-cyanoguanidine. The reaction mixture is heated for 18 hours. The alcohol is evaporated off and diluted with 250 ml of 7.4% hydrochloric acid. The mixture is filtered, cooled and made alkaline with 10% sodium hydroxide. The precipitate is filtered, triturated with 100 ml of boiling isopropanol and filtered to get 1-(p-N,N-dimethylsulfamylphenyl)-5-i-propylbiguanide.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].S(O)(O)(=O)=O.[NH2:17]O.Cl>O.S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:6][N:17]=1
Reactant: NO
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(N)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 125.1 %

Procedure:
To a suspension of pivaloylacetonitrile (25.03 g) in water (400 ml) is added 96% sodium hydroxide (9.17 g). Hydroxylamine sulfate (18.06 g) is added to the resulting solution at 27° C. The mixture is stirred at room temperature for 30 minutes, adjusted to pH 8 with 10% sulfuric acid (0.97 g), stirred at 60° C. for 22 hours, cooled at 20° C., mixed with conc. hydrochloric acid (7.90 g), and heated at 50° C. for 2 hours. Conc. hydrochloric acid (14.18 g) is added to the mixture, which is heated at 100° C. for 1 hour. After cooling, the reaction mixture is adjusted to pH 11 with 30% sodium hydroxide (49.8 g) and shaken with chloroform. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated to remove chloroform, whereby 3-amino-5-t-butylisoxazole (24.16 g) is obtained. Yield, 86.2%. Purity, 95.4%. m.p. 103.5-109° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[N:17][C:16]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[F:31])=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>CO.O1CCOCC1>[ClH:32].[F:31][C:22]1[CH:23]=[C:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=[CH:26][C:21]=1[O:20][CH2:19][C:16]1[N:17]=[CH:18][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:15]=1.[ClH:32]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(COc3ccc(S(C)(=O)=O)cc3F)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CS(=O)(=O)c1ccc(OCc2ncn(C3CCNCC3)n2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[3-(2-fluoro-4-methanesulfonyl-phenoxymethyl)-[1,2,4]triazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (see Example 1, 0.249 g, 2.74 mmol) in methanol (10 mL) was treated with 10 mL of 4N HCl in dioxane. The resulting solution was stirred at room temperature for 30 minutes and the solvent was removed in vacuo to afford the desired product as an HCl salt which was used without further purification.
Reaction SMILES: [CH3:1][CH2:2][CH2-:3].[Mg+2].[Br-].CON(C)[C:9]([C:11]1[C:12]2[N:13]([C:18]([C:22]3[S:26][C:25]4[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:24]=4[C:23]=3[CH3:32])=[C:19]([CH3:21])[N:20]=2)[N:14]=[C:15]([CH3:17])[CH:16]=1)=[O:10]>C1COCC1>[F:31][C:29]1[CH:28]=[CH:27][C:25]2[S:26][C:22]([C:18]3[N:13]4[N:14]=[C:15]([CH3:17])[CH:16]=[C:11]([C:9](=[O:10])[CH2:1][CH2:2][CH3:3])[C:12]4=[N:20][C:19]=3[CH3:21])=[C:23]([CH3:32])[C:24]=2[CH:30]=1
Reactant: [CH2-]CC
Reactant: CON(C)C(=O)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C)nc12
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCCC(=O)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 463.8 %

Procedure:
N-Propylmagnesium bromide (0.303 g, 2.06 mmol) is added dropwise to a solution of 3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine-8-carboxylic acid methoxy-methyl-amide (0.21 g, 0.52 mmol) in THF (5 mL) at 0° C. The reaction is stirred at room temperature overnight. The mixture is quenched with H2O, extracted with CH2Cl2, dried over sodium sulfate, filtered, and concentrated to dryness. The crude is purified through an ISCO column (5-10% EtOAc/Hexane) to give the title compound (0.92 g, 42%). 1H NMR (CDCl3): δ 7.8 (dd, J=4.8, 8.5 Hz, 1H), 7.5 (dd, J=2.5, 9.7 Hz, 1H), 7.4 (s, 1H), 7.2 (m, 1H), 3.6 (t, J=5.7, 2H), 2.6 (s, 3H), 2.55 (s, 3H), 2.3 (s, 3H), 1.9 (m, 2H), 1.1 (t, J=7.5, 3H) ppm. MS (m/e): 382 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:27][C:28]3[CH:33]=[C:32]([O:34]C)[CH:31]=[C:30]([O:36]C)[CH:29]=3)([CH2:16][C:17]3[CH:22]=[C:21]([O:23]C)[CH:20]=[C:19]([O:25]C)[CH:18]=3)[C:4]=2[CH:3]=1.B(Br)(Br)Br>>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:27][C:28]3[CH:29]=[C:30]([OH:36])[CH:31]=[C:32]([OH:34])[CH:33]=3)([CH2:16][C:17]3[CH:22]=[C:21]([OH:23])[CH:20]=[C:19]([OH:25])[CH:18]=3)[C:4]=2[CH:3]=1
Reactant: COc1cc(CC2(Cc3cc(OC)cc(OC)c3)c3cc(Br)ccc3-c3ccc(Br)cc32)cc(OC)c1
Agent: BrB(Br)Br
Product: Oc1cc(O)cc(CC2(Cc3cc(O)cc(O)c3)c3cc(Br)ccc3-c3ccc(Br)cc32)c1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
2,7-dibromo-9,9-bis(3,5-dimethoxybenzyl)-9H-fluorene (1.3 g, 2.08 mmol) was added to a round bottom flask charged with a stirbar and equipped with a rubber septum. The flask is purged with nitrogen for 10 min. Anhydrous dichloromethane (20 mL) is transferred to the flask via cannula and the mixture is stirred until the solids are completely dissolved. The solution is then cooled with a dry ice/acetone bath for 10 minutes. BBr3 (6.1 mL, 63.3 mmol) is added dropwise via cannula with constant stirring. The bath is allowed to warm to room temperature and the mixture is stirred overnight. The reaction is quenched with the slow addition of 125 mL of water. The solution is then extracted with 3 portions of ethyl acetate (50 mL). The organic layer is dried over MgSO3, filtered, and dried onto silica. Flash chromatography of the crude using ethyl acetate in dichloromethane gives an off-white crystalline solid (800 mg, 68% yield).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[C:11](=[O:25])[CH:10]=2)[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.[ClH:33]>CO>[ClH:33].[CH3:1][C@H:2]1[CH2:7][C@@H:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[C:11](=[O:25])[CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: C[C@H]1C[C@@H](Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: C[C@H]1C[C@@H](Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CCN1
Temperature: 25 °C
Yield: 134.1 %

Procedure:
To a solution of cis-tert-butyl 2-methyl-4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (98.9 mg, 0.214 mmol) in MeOH (1.0 mL) at 0° C. was added hydrochloric acid (2.0 mL, 8.00 mmol, 4.0 M in dioxane, Aldrich). The reaction mixture was warmed up to room temperature and continuously stirred at room temperature. After stirring for 1.5 hrs, the mixture was evaporated under reduced pressure to give the title compound (114.5 mg) as an off-white solid. This material was used in the next step without further purification. MS (ESI) 363 (M+H).
Reaction SMILES: [Cl:1][C:2]([Cl:7])(Cl)[C:3](Cl)=[O:4].[CH2:8]=[C:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>CCOCC.[Zn]>[Cl:1][C:2]1([Cl:7])[C:9]2([CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:8][C:3]1=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=C1CCOCC1
Agent: [Zn]
Solvent: CCOCC
Product: O=C1CC2(CCOCC2)C1(Cl)Cl
Reaction time: 16 h

Procedure:
Zinc was activated according to a published procedure (Synthesis 1971; 415). Hydrated copper sulfate (14 g) was dissolved in water (150 mL) and added to zinc dust (60 g). The mixture was stirred for 2 hours under nitrogen. The activated zinc was isolated by filtration, washed with acetone and dried in a vacuum oven at 100° C. prior to use. The solution of 4-methylenetetrahydro-2H-pyran from Step A was dried with sodium sulfate and magnesium sulfate and filtered through Celite® (washing the cake with ether). This removed some orange solids which had precipitated. A solution of trichloroacetyl chloride (5.00 g; 27.5 mmol) in dry ether (250 mL) was added slowly (over 4 hours) to a stirred refluxing mixture of the 4-methylenetetrahydro-2H-pyran in dry ether (250 mL) and the activated zinc (5.00 g; 76.5 mmol) under nitrogen. The mixture was stirred for 16 hours at reflux. The solution was filtered through Celite® and concentrated under reduced pressure. The material was purified by chromatography on silica gel, eluting with 10:1 hexane/ethyl acetate to give impure product (160 mg) as a colorless oil which was continued directly on to the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17](Br)[CH:16]=2)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([N:33]1[CH:41]=[C:40]2[C:35]([CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=[CH:39]2)=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17]([C:37]3[CH:38]=[CH:39][C:40]4[C:35]([CH:36]=3)=[N:34][N:33]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:41]=4)[CH:16]=2)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(Br)c3c(N)ncnn23)C1
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: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 110 °C
Yield: 66.6 %

Procedure:
To a stirred solution 3-(4-amino-5-bromo-pyrrolo[2,1-f][1,2,4]triazine-7-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.33 g, 3.24 mmol), intermediate C (1.63 g, 4.86 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.32 mmol) in degassed DMF (35 mL) was added aqueous Na2CO3 (2M, 5.34 mL). The resulting mixture was heated at 110° C. for 3 h and then cooled to rt. The reaction mixture was diluted with EtOAc and filtered through a Celite® pad. The organic layer was separated and concentrated in vacuo. The residue was purified by silica-gel column using a gradient of 50 to 100% EtOAc in hexanes to afford 1.16 g (66%) of the desired product. 1H-NMR (CD3OD-d4) 8.39 (s, 1H), 8.05 (s, 1H), 7.87 (dd, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 7.37-7.29, (m, 5 H), 7.24 (dd, 1 H), 5.67 (s, 1 H), 4.47-4.39 (m, 2 H), 3.71-3.59 (m, 2 H), 2.34-2.12 (m, 2 H), 1.45 (s, 1H); LC-MS [M+H]+=537.9, RT=3.36 min.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43][CH:44]([C:48](O)=[O:49])[C:45](O)=[O:46])([CH3:36])[CH3:35]>C(Cl)Cl>[CH2:11]([O:10][C:8](=[O:9])[C:7]1[CH:13]=[CH:14][C:4]([C:1]2[O:3][C:45](=[O:46])[C:44]([S:43][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[CH:34]([CH3:35])[CH3:36])=[C:48]([OH:49])[CH:2]=2)=[CH:5][CH:6]=1)[CH3:12]
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using ethyl 4-acetylbenzoate (2.93 g, 15.1 mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (3.11 g, 10.0 mmol) m.p. 201°-203° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 1.35 (t, 3H), 3.42 (m, 1H), 4.35 (q, 2H), 6.94 (m, 1H), 7.00 (s, 1H), 7.10 (m, 2H), 7.28 (m, 1H), 7.99 (m, 2H), 8.11 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:4].[F:15]C1C=C(O)C=CC=1C(O)=O.COC(Cl)=O>>[F:15][C:13]1[CH:14]=[C:6]([O:5][C:3]([O:2][CH3:1])=[O:4])[CH:7]=[CH:8][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: COC(=O)Oc1ccc(C(=O)O)cc1
Agent: COC(=O)Cl
Product: COC(=O)Oc1ccc(C(=O)O)c(F)c1

Procedure:
This was prepared using a similar method to that described for compound 15. Quantities: 2-fluoro-4-hydroxybenzoic acid (26) (0.97 g, 6.23 mmol), methylchloroformate (1.09 g, 11.48 mmol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C:3]=1[CH3:24].[CH3:25][C:26]1([CH3:41])[C:30]2=[N:31][CH:32]=[C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:34]=[C:29]2[NH:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:25][C:26]1([CH3:41])[C:30]2=[N:31][CH:32]=[C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:34]=[C:29]2[N:28]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[C:3]=2[CH3:24])[CH2:27]1
Reactant: Cc1c(-c2cccc3ccccc23)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc3ccccc23)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
4-Chloro-5,7-difluoro-3-methyl-2-(naphthalen-1-yl)quinoline (43.7 mg, 0.129 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (30 mg, 0.129 mmol), Pd2dba3 (11.8 mg, 0.013 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (12.3 mg, 0.026 mmol), sodium tert-butoxide (37.1 mL, 0.386 mmol), and toluene (1.29 mL) were stirred at 105° C. for 2 h. The reaction mixture was then concentrated and the resulting residue partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and water, then dried (MgSO4) and concentrated. Purification of the crude by reverse-phase chromatography (0-70% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]-pyridin-1-yl)-5,7-difluoro-3-methyl-2-(1-naphthalenyl)quinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 8.12 (1H, dd, J=1.3, 0.7 Hz), 8.01 (1H, d, J=8.6 Hz), 7.90-7.98 (2H, m), 7.69-7.76 (2H, m), 7.58 (3H, dt, J=5.5, 2.2 Hz), 7.01 (1H, s), 5.74-5.82 (1H, m), 3.88 (1H, ddd, J=8.6, 1.1, 0.7 Hz), 3.71-3.83 (5H, m), 2.97-3.08 (4H, m), 2.37 (3H, s), 1.58 (3H, s), 1.51 (3H, s). Mass Spectrum (ESI) m/e=537.2 (M+1).