Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Br[CH2:39][C:40]([N:42]1[C:47]([CH3:49])([CH3:48])[CH2:46][CH2:45][CH2:44][C:43]1([CH3:51])[CH3:50])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH2:39][CH2:40][N:42]1[C:47]([CH3:49])([CH3:48])[CH2:46][CH2:45][CH2:44][C:43]1([CH3:51])[CH3:50])[CH2:5][CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Reactant: CC1(C)CCCC(C)(C)N1C(=O)CBr
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3C(C)(C)CCCC3(C)C)c(F)c2)c1
Yield: 33.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-bromo-1-(2,2,6,6-tetramethylpiperidin-1-yl)ethanone (21 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.7 mg) was obtained.
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:14][CH2:15][O:16][CH3:17])=[C:11]([OH:13])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH:24]1(Br)[CH2:27][CH2:26][CH2:25]1>O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:14][CH2:15][O:16][CH3:17])=[C:11]([O:13][CH:24]2[CH2:27][CH2:26][CH2:25]2)[CH:12]=1
Reactant: BrC1CCC1
Reactant: COCOc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)cc1OC1CCC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 65.9 %

Procedure:
To 10 ml of N,N-dimethylformamide solution containing 1.73 g (7.4 mmol) of 5-bromo-2-methoxymethoxyphenol obtained in Reference Example 5-(b) were added 1.0 g (7.2 mmol) of potassium carbonate and 1.0 g (7.4 mmol) of cyclobutyl bromide, and the mixture was stirred at 100° C. for 5 hours. After completion of the reaction, 10 ml of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 1.4 g of the title compound as a colorless oil. (Yield: 66%)
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][O:5][CH2:6][CH2:7]OCCOC1CCCCO1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C[O:42][CH2:41]C1>>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:41][O:42][CH:27]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1
Reactant: C1=COCCC1
Reactant: C1CCOC1
Reactant: Brc1ccccc1COCCOCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Brc1ccccc1COCCCOC1CCCCO1

Procedure:
The reaction and work up was conducted as described in the preparation of compound 420. Starting compounds were compound 424 (2.41 g, 9.8 mmol) in 7 mL dry THF, 3,4-dihydro-2H-pyran (0.99 mL, 10.8 mmol) and p-toluenesulfonic acid (37 mg, 0.19 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether 1:4 as the eluent to afford the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5](=[CH:8][C:9]=1Cl)[C:6]#[N:7].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20](=[O:23])([O-])[O-].[K+].[K+]>CS(C)=O>[O:19]([C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5](=[CH:8][C:9]=1[O:23][C:20]1[CH:4]=[CH:3][CH:2]=[CH:9][CH:8]=1)[C:6]#[N:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cc(Cl)c(Cl)cc1C#N
Reactant: Oc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(Oc2ccccc2)c(Oc2ccccc2)cc1C#N
Temperature: 90 °C
Yield: 90.8 %

Procedure:
5.0 g of 4,5-dichlorophthalonitrile was dissolved in 50 ml of DMSO. 14.3 g of phenol was added and the solution was heated to 90° C. Portions of 6.9 g of potassium carbonate was added every five minutes until a total of 55.2 g had been added. The mixture was stirred at 90° C. for thirty minutes then cooled and poured into 500 ml of ice-water. The resulting solid precipitate was collected and crystallized from methanol to produce 3.6 g of product; 1H NMR (200 Mz, CDCl3) δ=7.49-7.38 (m, 4H), 7.32-7.25 (m, 2H), 7.15 (s, 2H), 7.10-7.02 (m, 4H)
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](=[C:15]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:28])[CH2:4][CH2:3]1.[O:29]1[C:38]2[CH:37]=[C:36]([CH:39]=O)[N:35]=[CH:34][C:33]=2[O:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:29]1[C:38]2[CH:37]=[C:36]([CH2:39][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[C:15]([C:22]6[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=6)[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:28])[CH2:6][CH2:7]3)[N:35]=[CH:34][C:33]=2[O:32][CH2:31][CH2:30]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COc1cc(-c2ccncc2)c2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2ccncc2)c2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
To 3 mL of a chloroform solution containing 160 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-5-(pyridin-4-yl)quinoxalin-2(1H)-one and 63 mg of 2,3-dihydro-1,4-dioxino[2,3-c]pyridine-7-carbaldehyde, 0.04 mL of acetic acid was added, and stirred at room temperature for 4 hours. To the reaction mixture, 140 mg of sodium triacetoxyborohydride was added, and stirred for 13 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=4:1] to give 139 mg of 1-(2-(4-((2,3-dihydro-1,4-dioxino[2,3-c]pyridin-7-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxy-5-(pyridin-4-yl)quinoxalin-2(1H)-one as a white foam.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([CH:16]=[CH2:17])=[O:15].[C:18]1([Mg]Cl)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>C1CCN2C(=NCCC2)CC1.CCOC(C)=O.C1COCC1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:17][CH2:16][CH:14]([OH:15])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC=O
Reactant: Cl[Mg]c1ccccc1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(CCN1CCC(Cc2ccccc2)CC1)c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
To a flame-dried 3-neck flask under a N2 atmosphere with a magnetic stirring bar, 4-benzylpiperidine (5.00 mL, 28 mmol, 1 eq), DBU (42 μL, 0.28 mmol, 0.01 eq), and THF (100 mL) were added, mixed, and cooled to −15° C. using a CCl4/CO2(s) bath. Acrolein (1.87 mL, 28 mmol, 1 eq) was then syringed in slowly during 10 minutes maintaining the temp. at −15° C. After 0.5 hours at −15° C., phenylmagnesium chloride (2.0 M, 14.0 mL, 28 mmol, 1 eq) was syringed in slowly and the contents allowed to slowly warm to room temperature and then stirred for 48 h. The reaction was worked up by adding 0.1 N NaOH and EtOAc (200 mL each). The viscous magnesium salts were suction filtered through fiberglass filter paper. The layers were separated and the aqueous layer was extracted again with ethyl acetate (2×200 mL). The organic layers were combined, washed with brine (1×200 mL), dried (MgSO4) and the solvent removed in vacuo to yield 7.39 g of an amber oil. Flash chromatography in 100% ethyl actetate yielded 2.48 g of an orange oil. NMR (CDCl3) δ 7.40-7.10 (m, 10H); 4.93 (d of d, 1H, J=3,7 Hz); 3.12-2.96 (m, 2H); 2.68-2.46 (m, 4H); 2.01 (t of d, 1H, J=2, 10 Hz); 1.86-1.26 (m, 8H). ESI MS detects (M+H)+=310.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15](Cl)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(O)(C)C>[C:1]1([C:7]2[N:16]=[C:15]([N:27]3[CH2:28][CH2:29][N:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)[CH2:25][CH2:26]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Solvent: CC(C)O
Product: c1ccc(-c2nc(N3CCN(c4ccccn4)CC3)c3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
A mixture containing 9.6 g (0.04 mole) of 2-phenyl-4-chloroquinazoline, 6.4 g. (0.04 mole) of 1-(2-pyridyl) piperazine and 250 ml of isopropanol was refluxed for 4 hrs. The resulting reaction mixture was filtered after cooling to room temperature. The crystalline solid was dissolved in 400 ml of 3N hydrochloric acid and the aqueous acidic liquid was washed with ether. The aqueous layer was adjusted to pH=7.5 which precipitated crystalline solid. This acidification and basification were repeated once. Yield of product was 6.9 g, m.p. 164°-166° C. (air dried).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:19][N:20]([CH3:22])[CH3:21])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(CC(=O)OC)CC1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=CN(C)C)C(=O)OC)CC1
Reaction time: 48 h

Procedure:
To a solution of the product of step (i) (10 g) in dry DMF (80 ml) was added dimethylformamide dimethyl acetal (DMFDMA) (30 ml) and the reaction mixture was heated to reflux. After 2 days a further quantity of DMFDMA (30 ml) was added and refluxing was continued for a further 2 days. The reaction mixture was evaporated and the residue partitioned between aqueous ammonium chloride solution and ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica by elution with ethyl acetate to yield 1-ethoxycarbonyl-4-(1-dimethylamino-2-methoxycarbonylethen-2-yl)piperazine (7 g) as an orange oil: NMR (CDCl3) δ1.28 (3H, t), 2.90 (4H, m), 3.14 (6H, s), 3.50 (4H, m), 3.64 (3H, s), 4.12 (2H, q), 7.01 (1H, s); m/Z 286 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]([OH:14])[CH2:11][CH:12]=[CH2:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C12BC(CCC1)CCC2.[OH-:32].[Na+].O.OO>C1COCC1.C(O)C>[C:1]([O:5][C:6](=[O:22])[N:7]([C@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]([OH:14])[CH2:11][CH2:12][CH2:13][OH:32])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCC(O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(O)CCCO
Temperature: 25 °C

Procedure:
N-((1R)-1-Benzyl-2-hydroxypent-4-enyl)-N-methylcarbamic acid tert-butylester (3.95 g, 11.60 mmol) was dissolvend in THF (90 mL) and added to a solution of 9-borabicyclo[3.3.1]nonane (46.64 mL of a 0.5M solution in THF, 23.32 mmol) in THF (90 mL). The solution was heated to reflux for 16 h. The mixture was cooled to room temp. Ethanol (22 mL) was added dropwise. 6N Sodium hydroxide solution in water (6.6 mL, 39,44 mmol) and subsequently hydrogen peroxide (35% solution in water) were added slowly. The reaction mixture was heated to reflux for 1 h and cooled to room temp. It was given onto 1N sodium hydroxide solution (200 mL). The phases were separated. The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a 37% solution of sodium hydrogensulfite (150 mL). The solution was dried over magnesium sulfate. It was washed with a 37% solution of sodium hydrogensulfite (200 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with 37% solution of sodium hydrogensulfite (200 mL) and dried over magnesium sulfate. The crude product was chromatographed on silica (180 g) with ethyl acetate and subsequently on silica (100 g) with dichloromethane/methanol/25% aqueous ammonia 100:10:1 to give 586 mg of ((1R)-1-benzyl-2,5-dihydroxypentyl)methylcarbamic acid tert-butylester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1.Cl[C:14]1[N:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].C(O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:14]2[N:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1
Reactant: COC(=O)c1cccnc1Cl
Reactant: O=Cc1cc(Br)cc(B(O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1cccnc1-c1cc(Br)cc(C=O)c1

Procedure:
A mixture of 1.14 g (5 mmoles) of 3-bromo-5-formyl-phenylboronic acid, 1.715 g (10 mmoles) of methyl 2-chloro-nicotinate, 100 mg of tetrakis-(triphenyl phosphine)palladium, 2.5 mL of ethanol, 10 mL of 2M sodium bicarbonate solution, and 10 mL of toluene was heated 20 hrs at 80° under nitrogen. After diluting with ethyl acetate, the reaction mixture was washed with saturated NaCl solution. The organic phase was dried over anhydrous MgSO4. Solvent removal gave a crude product which was purified on silica using ethyl acetate:hexane mixture as solvent to give the desired product as a solid.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[C:7]([Br:16])[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][C@@H:4]([CH:17]2[CH2:19][CH2:18]2)[CH2:3]1.C(O)(=O)C.[F:24][C:25]([F:39])([F:38])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH:29]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:24][C:25]([F:38])([F:39])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=1)[CH2:29][NH:1][C@H:2]1[C:11]2[C:6](=[C:7]([Br:16])[CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][C@@H:4]([CH:17]2[CH2:18][CH2:19]2)[CH2:3]1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N[C@@H]1C[C@H](C2CC2)Nc2c(Br)cc(C(F)(F)F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: FC(F)(F)c1cc(CN[C@@H]2C[C@H](C3CC3)Nc3c(Br)cc(C(F)(F)F)cc32)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.8 %

Procedure:
To a solution of cis-4-amino-8-bromo-2-cyclopropyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (Example 100A) (250 mg, 0.75 mmol) in anhydrous dichloromethane (10 mL) was added acetic acid (112 mg, 1.90 mmol), followed by 3,5-bis(trifluoromethyl)benzaldehyde (180 mg, 0.75 mmol) and sodium triacetoxyborohydride (791 mg, 3.73 mmol). The reaction was stirred at room temperature for 5 h. The reaction mixture was then diluted with dichloromethane and washed with 1N NaOH. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title crude product (420 mg) which was used without further purification. 1H NMR (CDCl3) δ 0.3 (m, 2H), 0.6 (m, 2H), 1.0 (m, 1H), 7.5 (s, 1H), 7.8 (s, 2H), 7.9 (s, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].FC(F)(F)S(O[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]2[O:16][CH:2]3[CH:3]=[CH:4][C:5]4[C:10]([N:1]3[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]2=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: c1ccc2ncccc2c1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Brc1cccc(C2OC3C=Cc4ccccc4N3c3ccccc32)c1
Yield: 65 %

Procedure:
Following the general procedure, treatment of quinoline (0.064 g, 59 μL, 0.50 mmol) and 3-bromobenzaldehyde (0.139 g, 88 μL, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=75/25) of the crude reaction mixture afforded 5-(3-bromophenyl)-5H,6aH-benzo[4,5][1,3]oxazino[3,2-a]quinoline as a yellow solid (0.127 g, 65% yield, dr determined by 1H NMR analysis of crude reaction mixture is >20:1).
Reaction SMILES: [CH3:1][C:2]([CH3:59])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:56])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:55])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C:45]4([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=5[Cl:54])[CH2:47][CH2:46]4)=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:58])[CH3:57])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61].CC#N>ClCCl>[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61].[OH2:4].[Cl:54][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[C:45]1([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]23[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]2[C@@H:25]2[C@@:20]([CH3:55])([CH2:21][CH2:22]3)[C@@:19]3([CH3:56])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:58])([CH3:57])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:59])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)[CH2:47][CH2:46]1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3ccccc3Cl)CC2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3ccccc3Cl)CC2)CC1=O
Product: O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((1-(2-chlorophenyl)cyclopropyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (300 mg, 0.361 mmol) in dichloromethane (6 mL) was added TFA (3 mL, 0.361 mmol). The reaction mixture was stirred at rt for 2 hr and evaporated in vacuo to afford crude product which was purified by preparative-HPLC (Mobile Phase: A=0.05% TFA/H2O, B=MeCN) to give the title compound (110 mg, 0.142 mmol, 39.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=12.23 (br. s., 1H), 8.67 (d, J=7.3 Hz, 1H), 7.67 (br. s., 1H), 7.52-7.13 (m, 3H), 6.69-6.41 (m, 1H), 6.00-5.76 (m, 1H), 4.49-4.20 (m, 1H), 3.29-3.02 (m, 1H), 2.78-2.60 (m, 1H), 2.30-0.57 (m, 53H); LC/MS: m/z calculated 773.4. Found 774.4 (M+1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Cl.Cl.[NH2:17][CH:18]1[NH:23][CH2:22][CH:21]=[CH:20][NH:19]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:17]=[C:18]3[NH:23][CH2:22][CH2:21][CH2:20][N:19]3[C:9](=[O:11])[CH:8]=2)=[CH:5][CH:6]=1
Reactant: NC1NC=CCN1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncc2)nc2n1CCCN2

Procedure:
A mixture of 8.98 g (46.5 mmol) of ethyl 3-(4-pyridyl)-3-oxopropionate and 8.0 g (46.5 mmol) of 2-amino tetrahydropyrimidine dihydrochloride (prepared according to J. Org. Chem. 1955, 20, 829.) and 19.3 g (139.5 mmol) of potassium carbonate in 60 ml of ethanol was heated at reflux temperature during 18 h.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([NH:41][CH2:42][C:43](O)=[O:44])(OC(C)(C)C)=O>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:31])[F:32])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:43](=[O:44])[CH2:42][NH2:41])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)Oc1cccc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Product: NCC(=O)N1CC[C@H](OCc2cccc(OC(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (27.7 mg) obtained in Example 27 and Boc-glycine (21.0 mg) were reacted and treated in the same manner as in the method described in Example 29 to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:8]([CH:11]=1)[C:9]#[N:10])([O-])=O.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1-c1ccccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#Cc1cc(N)ccc1-c1ccccn1

Procedure:
A mixture of 5-nitro-2-pyridin-2-ylbenzonitrile (370 mg, 1.69 mmol), iron powder (473 mg, 8.45 mmol), ammonium chloride (99 mg, 1.86 mmol), ethanol (20 mL) and water (10 mL) was heated at reflux for 1 h. Upon cooling, the reaction mixture was filtered through Celite, rinsed with ethyl acetate, and the filtrate was concentrated. The resulting residue was purified by flash column chromatography on silica gel eluting with 0-50% ethyl acetate hexanes to provide 5-amino-2-pyridin-2-ylbenzonitrile.
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[C:15]1(/[CH:21]=[CH:22]/B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>>[F:14][C:3]1[C:2](/[CH:22]=[CH:21]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([O:12][CH3:13])=[N:10]2)=[N:5][CH:4]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc2ncc(F)c(/C=C/c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.4 %

Procedure:
8-bromo-7-fluoro-2-methoxy-[1,5]naphthyridine (prepared as in WO 2004/058144; 7 g, 27.2 mmol), trans-phenylvinyl boronic acid (4.23 g, 1.05 eq) and K2CO3 (4.9 g) were introduced in a two-necked flask. The atmosphere was flushed with nitrogen and dioxane (40 ml) and water (10 ml) were added. The mixture was stirred at rt for 5 min and Pd(PPh3)4 (1.56 g, 5 mol %) was added. The mixture was heated at reflux overnight. After cooling, the solvent was evaporated in vacuo and the residue was extracted with EA (2×150 ml). The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed (Hept-EA 2-1) to afford the title compound (7.2 g, 94% yield) as a white solid.