Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18](=[O:29])[CH2:19][CH2:20][C:21]1([C:26]([OH:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1)([CH3:16])([CH3:15])[CH3:14].[CH3:30][O:31][CH2:32][C:33](OC)=[O:34].Cl>C1COCC1.O.COC(C)(C)C>[C:13]([O:17][C:18]([CH:19]([C:33](=[O:34])[CH2:32][O:31][CH3:30])[CH2:20][C:21]1([C:26]([OH:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:29])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Reactant: COCC(=O)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: COC(C)(C)C
Solvent: O
Product: COCC(=O)C(CC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Temperature: -12.5 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of diisopropylamine (35.0 ml, 250 mmol) in THF (70 ml) was cooled to −15° C. under nitrogen. n-Butyllithium (2.5 M, 100 ml, 250 mmol) was then added dropwise, whilst maintaining the temperature below −10° C. To the resultant solution was added a solution of 1-(3-tert-butoxy-3-oxopropyl)cyclopentane carboxylic acid (see EP274234B1, example 35) (27.52 g, 113.6 mmol) in THF (50 ml) and the reaction was then stirred at −10 to −15° C. for 1 h. To the reaction mixture was then added a solution of methyl methoxyacetate (18.0 ml) in THF (20 ml), and the resultant mixture was then allowed to warm to room temperature and then stirred for 19 hours. To the reaction mixture was added tert-butyl methyl ether (300 ml) and deionised water (300 ml), and the aqueous phase was then acidified with 2M hydrochloric acid to pH 3 with stirring. The phases were separated and the aqueous phase was then extracted with tert-butyl methyl ether (250 ml). The combined organic phases were then washed with water (250 ml) and then brine (250 ml), dried over magnesium sulfate, and the solvent was then removed under reduced pressure. The crude title compound was then purified by flash chromatography on silica gel using ethyl acetate/heptane (1:2 to 1:1) as the eluent to give the title compound (17.35 g, 55.2 mmol, 49% yield);
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.[C:28]([O:32][C:33](=[O:48])[C@@H:34]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35][CH2:36][C:37](O)=[O:38])([CH3:31])([CH3:30])[CH3:29].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C.O>[C:28]([O:32][C:33](=[O:48])[C@@H:34]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35][CH2:36][C:37](=[O:38])[NH:25][C:20]1[C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][C:12]3[CH:26]=[CH:27][C:9]([CH2:8][O:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:10][CH:11]=3)[CH:18]=2)=[CH:24][CH:23]=[CH:22][N:21]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of 3-(3-(4-(pyridin-2-yloxymethyl)-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine (900 mg, 2.5 mmol) described in Reference Example 1 in acetonitrile (15 mL) were added (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-tert-butyl ester (860 mg, 2.8 mmol), triethylamine (0.37 mL, 2.6 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (1.1 g, 2.8 mmol) at 0° C., which was stirred overnight at 60° C. Water and ethyl acetate were added to the reaction solution, and the organic layer was washed with saturated brine. The residue thus obtained was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1), so as to obtain the titled compound (980 mg).
Reaction SMILES: [Na].[O-]CC.[Na+].Cl.[C:7](=[NH:11])([NH2:10])[CH2:8][CH3:9].[C:12]([OH:20])(=[O:19])/[C:13](=[C:15](\[CH:17]=O)/[Br:16])/Br>C(O)C>[Br:16][C:15]1[C:13]([C:12]([OH:20])=[O:19])=[N:11][C:7]([CH2:8][CH3:9])=[N:10][CH:17]=1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: CCC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCc1ncc(Br)c(C(=O)O)n1
Temperature: 55 °C
Yield: 36.9 %

Procedure:
Sodium (356 mg, 15.5 mmol) was carefully added to ethanol (5.9 mL) to prepare sodium ethoxide solution in ethanol. The above freshly prepared ethanol solution (3.5 mL) was added to a stirred suspension of propionimidamide hydrochloride (1.05 g, 9.69 mmol). The mixture was warmed to 55° C., then the heating bath was removed and a solution of mucobromic acid (1 g, 3.87 mmol) in ethanol was added dropwise at a rate which maintained a constant temperature, followed by a further sodium ethoxide solution (2 mL). After cooling, the mixture was filtered and evaporated to a residue which was shaken vigorously with hydrochloric acid (2 M×2.4 mL). The brown precipitate was filtered off and washed with cold water, then freeze-dried to give 5-Bromo-2-ethylpyrimidine-4-carboxylic acid (330 mg, 37%) as a yellow solid. LCMS: 231 [M+1]+, 1H NMR (400 MHz, DMSO-d6): δ 1.25 (t, J=7.6 Hz, 3H), 2.88 (q, J=7.6 Hz, 2H), 9.05 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][N:4]=1.[CH2:13]([S:15][C:16]1[C:17]([C:26]([OH:28])=O)=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH3:14].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH2:13]([S:15][C:16]1[C:17]([C:26]([N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:11])([F:10])[F:12])=[CH:5][N:4]=2)=[O:28])=[N:18][CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1)[CH3:14]
Reactant: CNc1ccc(C(F)(F)F)cn1
Reactant: CCSc1cc(C(F)(F)F)cnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CCSc1cc(C(F)(F)F)cnc1C(=O)N(C)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.1 %

Procedure:
A mixture of 0.35 g of 2-methylamino-5-trifluoromethylpyridine, 0.50 g of 3-ethylsulfanyl-5-trifluoromethylpicolinic acid, 0.46 g of EDCI hydrochloride, 0.02 g of HOBt and 3 mL of pyridine was stirred at room temperature for 3 hours. A saturated aqueous sodium bicarbonate solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.18 g of 3-ethylsulfanyl-N-methyl-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 24).
Reaction SMILES: Cl.[C:2]([O:7][CH2:8][CH2:9][NH2:10])(=[O:6])[C:3]([CH3:5])=[CH2:4].[N:11]1[C:18]([Cl:19])=[N:17][C:15](Cl)=[N:14][C:12]=1[Cl:13].C(=O)(O)[O-].[Na+]>O.CC(C)=O>[C:2]([O:7][CH2:8][CH2:9][NH:10][C:15]1[N:17]=[C:18]([Cl:19])[N:11]=[C:12]([Cl:13])[N:14]=1)(=[O:6])[C:3]([CH3:5])=[CH2:4]
Reactant: C=C(C)C(=O)OCCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)C(=O)OCCNc1nc(Cl)nc(Cl)n1
Temperature: 25 °C

Procedure:
To 194 g of 33% 2-aminoethyl methacrylate hydrochloride solution in water being stirred at 0°-5° C. was added 1 l of additional water followed by dropwise addition of a solution of 74 g (0.4 mole) of cyanuric chloride in 400 ml of acetone. To this mixture was added 67.2 g (0.8 mole) of sodium bicarbonate in portions over a 1 hr. period. The mixture was then stirred for an additional hour at room temperature. The reaction was again cooled to 0°-5° C. and the product was collected by filtration and dried in vacuo at room temperature to give 84.6 g. Recrystallization from a solution of 600 ml of benzene and 850 ml of ligroin with carbon decoloration yielded 56.6 g (mp 138°-140° C.).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12](Cl)(=[O:14])=[O:13])=[CH:7]2.C(Cl)Cl.[F:19][C:20]([F:24])([F:23])[CH2:21][OH:22].C(N(CC)CC)C>CCOC(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:22][CH2:21][C:20]([F:24])([F:23])[F:19])(=[O:13])=[O:14])=[CH:7]2
Reactant: O=S(=O)(Cl)c1ccc2c(Br)cccc2c1
Reactant: OCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(=O)(OCC(F)(F)F)c1ccc2c(Br)cccc2c1
Temperature: 25 °C
Yield: 41.3 %

Procedure:
A round bottom flask was charged with 5-bromonaphthalene-2-sulfonyl chloride (5.00 g, 16.36 mmol) and CH2Cl2 (16.36 mL) was added. To this solution was added 2,2,2-trifluoroethanol (1.542 mL, 21.27 mmol) followed by triethylamine (3.42 mL, 24.54 mmol). The resulting solution was maintained at rt for 1 h and then concentrated. The residue was purified by MPLC using a silica gel column (80 g) using a 98:2 Heptane:EtOAc to 100% EtOAc gradient to afford 2,2,2-trifluoroethyl 5-bromonaphthalene-2-sulfonate (2.49 g, 6.75 mmol) as a white amorphous solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:19]([OH:21])=O)[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.C(Cl)(=O)C([Cl:25])=O>ClCCl.CN(C)C=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:19]([Cl:25])=[O:21])[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1(CCCCBr)c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
23 g (0.067 mol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid are dissolved in 40 ml of dichloromethane, and combined with three drops of dimethylformamide and 6.96 ml (0.081 mol) of oxalyl chloride, dissolved in 10 ml of dichloromethane, under nitrogen at 0° C. The mixture is stirred for 3 hours at ambient temperature. Then the solvent is eliminated and the crude product is reacted further without additional purification.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[C:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=O)[CH:14]([CH3:16])[CH3:15].[NH3:24]>C1(C)C=CC=CC=1>[NH2:24][C:13]([CH:14]([CH3:16])[CH3:15])=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C=C(N)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.8 g of p-toluenesulphonic acid×4 H2O are added to 500 g (3.16 mol) of ethyl isobutyrylacetate in 1,500 ml of toluene p.a., the mixture is saturated with ammonia gas while stirring at room temperature and allowed to stand overnight. It is then heated under reflux in a water separator and ammonia gas is continuously introduced until the calculated amount of water has separated (47 ml of water after reflux for 8 hours). The mixture is allowed to cool overnight, and the precipitate which has deposited is filtered off with suction and washed with toluene. The combined toluene phases are washed several times with water, dried using sodium sulphate, concentrated in vacuo and distilled in a high vacuum.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[CH2:19][NH:18][N:17]([S:22]([CH:25]4[CH2:27][CH2:26]4)(=[O:24])=[O:23])[C:16]=3[CH2:15]2)[CH2:11][O:10][C@@H:9]1[C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[F:35])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[F:35][C:29]1[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=1[C@@H:9]1[C@@H:8]([NH2:7])[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[CH2:19][NH:18][N:17]([S:22]([CH:25]4[CH2:27][CH2:26]4)(=[O:23])=[O:24])[C:16]=3[CH2:15]2)[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2CC3=C(C2)N(S(=O)(=O)C2CC2)NC3)CO[C@@H]1c1cc(F)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](N2CC3=C(C2)N(S(=O)(=O)C2CC2)NC3)CO[C@@H]1c1cc(F)ccc1F
Reaction time: 1.5 h

Procedure:
A solution of the intermediate obtained in Step A above (52 mg, 0.099 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (1 mL) at room temperature. After 1.5 h, the reaction mixture was concentrated and purified on reverse phase HPLC using H2O/acetonitrile containing 0.05 TFAv/v, to give the title compound. 1H NMR (500 MHz, CD3OD): δ 1.21-1.27 (m, 2H); 1.38-1.43 (m, 2H); 2.06 (q, 1H, J=14 Hz); 2.73-2.79 (m, 1H); 2.29-3.06 (m, 1H); 3.57-3.64 (m, 1H); 3.74 (t, 1H, J=12 Hz); 3.81-3.90 (m, 1H); 4.44-4.54 (m, 3H); 4.69 (d, 1H, J=12 Hz); 4.71-4.81 (m, 2H); 7.18-7.26 (m, 2H); 7.27-7.32 (m, 1H); 7.74 (s, 1H). LC-MS: 425.21 (M+1).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[OH:17][C:18]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]2[C:19]=1[C:20](=[O:38])[N:21]([CH2:30][O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:22]=[N:23]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:59]1[CH2:64][CH2:63][N:62]([CH3:65])[CH2:61][CH2:60]1>C(Cl)Cl>[CH3:29][O:28][C:26]1[CH:25]=[C:24]2[C:19]([C:20](=[O:38])[N:21]([CH2:30][O:31][C:32](=[O:37])[C:33]([CH3:35])([CH3:34])[CH3:36])[CH:22]=[N:23]2)=[C:18]([O:17][CH:59]2[CH2:64][CH2:63][N:62]([CH3:65])[CH2:61][CH2:60]2)[CH:27]=1
Reactant: COc1cc(O)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(OC2CCN(C)CC2)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A solution of di-tert-butyl azodicarboxylate (1.7 g) in methylene chloride (5 ml) was added to a stirred mixture of 5-hydroxy-7-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (1.5 g), triphenylphosphine (1.9 g), 4-hydroxy-1-methylpiperidine (0.675 g) and methylene chloride (20 ml) which had been cooled to 5° C. The mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was purified by column chromatography on silica using a 9:10:1 mixture of methylene chloride, ethyl acetate and a saturated methanolic ammonia solution as eluent. The material so obtained was triturated under diethyl ether. The resultant solid was washed with diethyl ether and dried under vacuum to give 7-methoxy-5-(N-methylpiperidin-4-yloxy)-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (1.75 g); NMR Spectrum: (CDCl3): 1.2 (s, 9H), 2.05 (br s, 4H), 2.3 (s, 3H), 2.3–2.42 (m, 2H), 2.7–2.8 (m, 2H), 3.9 (s, 3H), 4.48 (m, 1H), 5.9 (s, 2H), 6.5 (d, 1H), 6.71 (d, 1H), 8.18 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6](C)=[CH:5][C:3]=1[NH2:4].O.O=[As](O[As](=O)=O)=O.S(=O)(=O)(O)O.[OH-].[NH4+].[C:25](O)(=O)[CH3:26]>OCC(CO)O>[N:4]1[C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]=[CH:26][CH:25]=1
Reactant: Cc1ccc(C)c(N)c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: O=[As](=O)O[As](=O)=O
Agent: [NH4+]
Solvent: O
Solvent: OCC(O)CO
Product: c1ccc2ncccc2c1

Procedure:
To a mixture of 2,5-dimethylaniline (20.73 g), glycerin (54.81 g) and arsenic pentoxide hydrate (As2O5.xH2O) (Aldrich, 54% As, 35.06 g) under argon and in a 1 L 3-neck round bottom flask equipped with a mechanical stirrer is carefully added sulfuric acid (51.6 g). The resulting hot solution is then heated at 140°-150° C. for 4 hours. The reaction mixture is then cooled to room temperature and slowly basified to pH=10 by the addition of ammonium hydroxide solution (28-30%). After a period of about 10 minutes the basic solution is acidified to pH=5 by the addition of glacial acetic acid and extracted with methylene chloride (CH2Cl2) (3×500 mL). The organic layer is then washed with water (2×500 mL) and brine (2×500 mL), dried over magnesium sulfate (MgSO4), filtered, and rotary evaporated to yield crude quinoline (31 g) which is flash chromatographed on silica gel eluting with 10% ethyl acetate/hexane. Compound-containing fractions are combined and rotary evaporated to yield 5,8-dimethylquinoline.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([F:23])[C:5]2[NH:6][C:7]([CH2:9][C:10]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[C:15]4[C:11]=3[CH:12]=[CH:13][NH:14]4)=[N:8][C:4]=2[CH:3]=1.[CH3:24][N:25](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].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]>[CH3:19][C:18]1[C:10]([CH2:9][C:7]2[NH:6][C:5]3[C:21]([F:23])=[CH:22][C:2]([C:24]#[N:25])=[CH:3][C:4]=3[N:8]=2)=[C:11]2[C:15](=[C:16]([CH3:20])[CH:17]=1)[NH:14][CH:13]=[CH:12]2
Reactant: Cc1cc(C)c2[nH]ccc2c1Cc1nc2cc(Br)cc(F)c2[nH]1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c2[nH]ccc2c1Cc1nc2cc(C#N)cc(F)c2[nH]1
Temperature: 120 °C

Procedure:
Zinc cyanide (44 mg, 0.375 mmol) was weighed into a 50 mL flask, a degassed solution of 5-bromo-2-((5,7-dimethyl-1H-indol-4-yl)methyl)-7-fluoro-1H-benzo[d]imidazole (45 mg, 0.121 mmol) in DMF (4 mL) was added followed by Pd(Ph3P)4 (14 mg, 0.012 mmol). The reaction mixture was heated at 120° C. for 2 hours. Additional portions of zinc dust, dppf, and Pd2(dba)3 were added followed by heating to 130° C. until no starting material remained by LC-MS. The reaction was diluted with EtOAc and a saturated solution of NaHCO3, then filtered through a Celite® pad. The filtrate was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by reverse phase HPLC (HC-B) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.98 (br. s., 1H) 7.78 (s, 1H) 7.52-7.67 (m, 1H) 7.48 (d, J=10.61 Hz, 1H) 7.24 (t, J=2.78 Hz, 1H) 6.76 (s, 1H) 6.46 (dd, J=3.03, 2.02 Hz, 1H) 4.44 (s, 2H) 2.41 (s, 3H) 2.36 (s, 3H). HRMS calculated for C19H15FN4(M+H)+ 319.1354. found 319.1361.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][S:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[S:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CS5)CC3)c2c1
Yield: 57.7 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxyquinoxalin-2(1H)-one (Intermediate 146, 250 mg crude, 0.83 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (WO 2004/058144) (160 mg, 0.83 mmol), and sodium triacetoxy borohydride (530 mg, 2.50 mmol) were reacted as described according to Example 69. Chromatography on silica gel with 10% methanol in dichloromethane containing 0.25% ammonium hydroxide afforded the free base of the product. This was triturated with dichloromethane and the precipitate was collected by filtration giving 230 mg (58%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][CH:14]1[CH2:16][CH2:15]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH:13][CH2:14][CH2:15][CH3:16]
Reactant: Cn1c(C(=O)NC2CC2)cc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCNCc1cc2ccccc2n1C
Yield: 32.8 %

Procedure:
To a solution of 1-methyl-N-cyclopropylindole-2-carboxamide (2.1 g. 9.8 mmole) in dry THF (40 mL) was added dropwise a solution of 1.0 M LiAlH4 in THF (2.2 mL, 22 mmole). The reaction mixture was heated at reflux overnight, then was cooled and uenched with 10% NaOH. The mixture was filtered and the filtrate was concentrated in vacuo. Flash chromatography on silica gel (5% MeOlUCH2Cl2) gave the title compound (0.65 g, 33%) as a viscous oil: MS (ES) m/e 203 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8](=[N:10][OH:11])[CH3:9].F[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[C:21]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:33][CH3:34])[CH:29]=2)[CH:24]=1)=[O:22].[Cl-].[NH4+]>C1COCC1>[CH3:20][O:19][C:17]1[CH:16]=[CH:15][C:14]([C:21]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([O:33][CH3:34])[CH:29]=3)[CH:24]=2)=[O:22])=[C:13]([O:11][N:10]=[C:8]([CH3:9])[CH3:7])[CH:18]=1
Reactant: CC(C)=NO
Reactant: COc1ccc(C(=O)c2ccc3cc(OC)ccc3c2)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccc3cc(OC)ccc3c2)c(ON=C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Potassium tert-butoxide (1.2 g, 10.6 mmol) was added into a solution of acetone oxime (0.78 g, 10.6 mmol) and THF (15 mL). After stirring for 1 h, (2-fluoro-4-methoxyphenyl)(6-methoxy-2-naphthyl)methanone (3.0 g, 9.7 mmol) in THF (3 mL) was added. The reaction mixture was refluxed for 3 h, then cooled to room temperature, poured into aqueous ammonium chloride, and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/EtOAc 3/1) gave a brown solid (3.35 g, 95% yield, m.p. 117-118° C.); MS m/e 364 (M+).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=[C:4]([F:12])[C:3]=1[OH:13].[CH2:14]([O:16][C:17](=[O:21])[C:18]#[C:19][CH3:20])[CH3:15].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:14]([O:16][C:17](=[O:21])/[CH:18]=[C:19](/[O:13][C:3]1[C:4]([F:12])=[CH:5][CH:6]=[C:7]([O:8][CH:9]([CH3:11])[CH3:10])[C:2]=1[F:1])\[CH3:20])[CH3:15]
Reactant: CC(C)Oc1ccc(F)c(O)c1F
Reactant: CC#CC(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1c(F)ccc(OC(C)C)c1F
Yield: 73.6 %

Procedure:
To a stirred mixture of 2,6-difluoro-3-isopropoxy-phenol (5.74 g, 0.031 mol) and ethyl-2-butynoate (6.85 g, 0.061 mol) in tetrahydrofuran (50 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.64 g, 0.030 mol) slowly. After addition was complete the mixture was stirred at reflux for 6 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated which afforded (E)-3-(2,6-difluoro-3-isopropoxy-phenoxy)-but-2-enoic acid ethyl ester as a brown oil (6.85 g, 75%) and used without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([Br:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]1(B(O)O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].O.COCCOC>[Br:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:21]1[C:22]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][CH:20]=1)[CH:11]=[CH:10]2
Reactant: OB(O)c1cccc2ccccc12
Reactant: Brc1ccc2cccc(Br)c2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Solvent: O
Product: Brc1cccc2ccc(-c3cccc4ccccc34)nc12

Procedure:
A mixture of 2,8-dibromoquinoline (6.0 g, 21 mmol, prepared by the method of L. Mao et al., Tetrahedron Lett. 46 (2005) 8419), 1-naphthylboronic acid (4.1 g, 24 mmol), K2CO3 (6.6 g, 48 mmol), Pd(OAc)2 (0.1 g, 0.4 mmol), P(o-Tol)3 (0.25 g, 0.8 mmol), DME (50 mL) and water (10 mL) is refluxed for 6 h under stirring in an argon atmosphere. The mixture is then poured into water and extracted with CHCl3 (3×50 mL). The combined organic phase is washed with water and brine, and then concentrated. The residue is purified by column chromatography (silica gel 40, hexane/benzene 1:1). Yield of red purple oil: 4.1 g (57%).