Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]1[O:10][CH:9]1[CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:10]1[CH2:8][CH:9]1[CH2:11][O:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Oc1ccncc1
Reactant: OCC1CO1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCC2CO2)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.1 %

Procedure:
To a round bottom flask was added 4-hydroxypyridine (250 mg, 2.63 mmol), glycidol (194.74 mg, 2.63 mmol) and triphenylphosphine (758.45 mg, 2.89 mmol) in 20 mL of dry THF, followed by the addition of diethyl azodicarboxylate (503.6 mg, 2.89 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo. The residue was diluted with CH2Cl2. The organic phase was washed with saturated NaHCO3 and brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was loaded to a flash chromatography column. The column was eluted with 0–5% MeOH/CH2Cl2. The product fractions were collected and concentrated to afford 80 mg (20.1%) of 4-oxiranylmethoxy-pyridine. (TLC: Rf=0.4, 5% MeOH/CH2Cl2, UV). MH+=152.31.
Reaction SMILES: [P:1]([O-:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[Al](C)C.[CH2:23]=[C:24]([CH2:35][CH2:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[CH2:3]([O:2][P:1]([CH2:23][CH:24]([CH2:35][CH2:36][C:37]([O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:38])[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(CCC(CP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
Dibenzyl phosphite (9.5 g, 36 mmol) in 350 ml of dichloromethane was cooled to 0° C. To this stirring solution was added trimethyl aluminum (18.2 ml, 2.0M solution in hexane, 36.4 mmol). After 30 minutes 1 (6.0 g, 37 mmol) in 90 ml of dichloromethane was added dropwise over 10 minutes. The clear and colorless solution was then warmed to room temperature and left to stir overnight. The mixture was then quenched by the slow addition of 5% HCl. After stirring an additional 1.5 hours the lower organic layer was removed and the aqueous layer extracted once with 100 ml of dichloromethane. The organics were combined, dried (MgSO4), and evaporated to give a clear light golden liquid. The liquid was chromatographed on silica gel (4 cm*30 cm) and eluted with a gradient (4:1-1:1) solvent system (Hexane/EtOAc). The fractions containing the desired product were combined and evaporated to yield 2 (7.1 g, 42%) as a clear and colorless liquid. The liquid was then distilled on a Kughleror apparatus at 0.5 mm Hg and 195-200° C. The distillate was discarded and the remaining light golden oil was chromatographed on silica gel (1:1, Hex./EtOAc) to give 2.9 g of 2 as a clear and colorless oil. TLC Rf 0.5 (1:1, Hex./EtOAc).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[CH:8]1[C:13]([Cl:14])=[C:12]([CH2:15][CH3:16])[C:11](Br)=[C:10]([Cl:18])[C:9]1([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH3:20]>C(NC(C)C)(C)C.C1(C)C=CC=CC=1.O.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>[Cl:18][CH:10]1[C:11]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[C:12]([CH2:15][CH3:16])[C:13]([Cl:14])=[C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[C:9]1([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH3:20]
Reactant: CCCCCCOC1(CC)C(Cl)=C(Br)C(CC)=C(Cl)C1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCOC1(CC)C(C#C[Si](C)(C)C)=C(Cl)C(CC)=C(C#C[Si](C)(C)C)C1Cl
Yield: 53.5 %

Procedure:
Trimethylsilylacetylene (3.1 mL, 21.43 mmol), PdCl2(PPh3)2 (400 mg, 0.6 mmol), and CuI (235 mg, 0.79 mmol) were added successively to a deaerated solution of 2,5-dibromo-3,6-dichloro-1,4-diethylhexyloxybenzene (10) (4.00 g, 7.14 mmol) in diisopropylamine (25 mL) and toluene (55 mL). The resulting mixture was refluxed for 48 hours, then diluted with water (150 mL), and extracted with hexane (2×80 mL). The extract was washed with water (2×80 mL) and dried (MgSO4). Evaporation of the solvent gave an oily residue, which was purified by column chromatography (hexane:CH2Cl2, 98:2) to give an orange-red solid (1.90 gm, 45%). 1H-NMR(CDCl3): δ 3.87 (m, 4H), 1.81 (m, 2H), 1.31-1.64 (m, 12H), 0.97 (t, J=7.5 Hz, 6H), 0.92 (t, J=7.5 Hz, 6H). MS (EI): Calculated. 595.8. found [M+I]+, 596.8.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>N1C=CC=CC=1>[C:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)c1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.25 g of ethyl 2-(4-hydroxyphenyl)-2-oxoacetate was dissolved in 15 ml of pyridine, followed by adding 4 ml of acetic anhydride and then stirring at room temperature for 1 hour. The resulting reaction solution was poured into water, and extracted with diethyl ether. The resulting organic layer was washed with water, and then concentrated to dryness. Thereafter, the residue was dissolved in benzene, and then concentrated to obtain 8.3 g of the title compound in an oily form.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([C:11]3[C:12](=[O:28])[NH:13][CH:14]=[CH:15][C:16]=3[NH:17][CH2:18][C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[OH:20])[NH:7][C:6]=2[CH:5]=[C:4]([CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)[CH:3]=1.[CH3:37][Sn](C)(C)C.[F-].[K+]>CN(C=O)C>[Cl:27][C:23]1[CH:22]=[C:21]([C@H:19]([OH:20])[CH2:18][NH:17][C:16]2[CH:15]=[CH:14][NH:13][C:12](=[O:28])[C:11]=2[C:8]2[NH:7][C:6]3[CH:5]=[C:4]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:3]=[C:2]([CH3:37])[C:10]=3[N:9]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CN1CCN(Cc2cc(Br)c3nc(-c4c(NC[C@@H](O)c5cccc(Cl)c5)cc[nH]c4=O)[nH]c3c2)CC1
Reactant: C[Sn](C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CN2CCN(C)CC2)cc2[nH]c(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: 100 °C
Yield: 48 %

Procedure:
Through a mixture of (S)-3-[4-Bromo-6-(4-methyl-piperazin-1-ylmethyl)-1H-benzimidazol-2-yl]-4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-1H-pyridin-2-one (80 mg, 0.14 mmol), tetramethyl tin (2.5 mL, excess), PdCl2 (PPh3)4 (10 mg, 0.014 mmol), and KF (40 mg, 0.7 mmol) in DMF (2 mL) in a vial was bubbled nitrogen, sealed, and heated to 100° C. for two days. The reaction mixture was passed through a small pad of celite. After concentration, the residue was purified by prep. HPLC to give the titled compound (34 mg, 48%). 1H NMR (400 MHz, CD3OD) δ 7.53 (1H, s), 7.45 (1H, s), 7.24–7.40 (4H, m), 7.09 (1H, s), 6.22 (1H, d, J=7.6 Hz), 4.99 (1H, t, J=6.4 Hz), 4.04 (2H, br s), 3.61–3.74 (2H, m), 2.98–3.34 (8H, m), 2.80 (3H, s), 2.58 (3H, s). LCMS (M+H)+ m/z 507 (t=1.29 min.).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:18][C:17]2[CH:16]=[N:15][C:14]3[N:19](CC4C=CC(OC)=CC=4)[N:20]=[CH:21][C:13]=3[C:12]=2[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][CH:9]1[CH2:18][C:17]2[CH:16]=[N:15][C:14]3[NH:19][N:20]=[CH:21][C:13]=3[C:12]=2[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([OH:35])([C:32]([F:37])([F:36])[F:31])=[O:34]
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(NCc2ccccc2)CC4)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: c1ccc(CNC2CCc3c(cnc4[nH]ncc34)C2)cc1
Temperature: 65 °C

Procedure:
To N-benzyl-3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-amine (0.030 g, 0.075 mmol) was added trifluoroacetic acid (3 mL). The reaction mixture was heated at 65° C. for 2 hours. On completion of the reaction, toluene (2 mL) was added and the solvent removed under reduced pressure. The crude product was purified using reverse phase HPLC to give the desired product, N-benzyl-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-amine as a TFA salt and a white solid (0.015 g, 71%). M.p.>232° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.39 (s, 1H), 9.06 (brs, 2H), 8.05 (d, J=1.6 Hz, 1H), 7.99 (s, 1H), 7.56 (m, 2H), 7.46 (m, 3H), 4.31 (s, 2H), 3.61 (m, 1H), 3.43 (m, 1H), 3.08 (m, 3H), 2.43 (m, 1H), 1.97 (m, 1H); LCMS [M+H]: 279.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)/[CH:10]=[C:11](\O)/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1)#[N:2].[CH3:19][NH:20][NH2:21]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:20]([CH3:19])[N:21]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CNN
Reactant: CCOC(=O)/C(O)=C/C(=O)c1ccc(C#N)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(C#N)cc2)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
Under argon atmosphere (Z)-ethyl 4-(4-cyanophenyl)-2-hydroxy-4-oxobut-2-enoate (500 mg, 2.04 mmol, Eq: 1.00) was dissolved in Ethanol (10 ml) at rt. Methylhydrazine (95.9 mg, 110 μl, 2.04 mmol, Eq: 1.00) was added dropwise (The solution became yellow). The solution was stirred overnight at rt followed by 6 h heating at 50° C., cooled down to rt and concentrated. in vacuo. The residue was directly purified by column chromatography (20 g) Heptane/EtOAC:9/1 to give the expected pyrazole (173 mg, 33.2%) as a white solid. MS (ISP): 256.3 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][OH:12])[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1>CS(C)=O>[Br:1][C:2]1[N:7]2[CH:8]=[C:9]([CH:11]=[O:12])[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1
Reactant: OCc1cn2c(Br)cnc(N3CCOCC3)c2n1
Solvent: CS(C)=O
Product: O=Cc1cn2c(Br)cnc(N3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
To a solution of compound 1e (10.0 g, 32.1 mmol, as prepared in Example 1, Step E) in DMSO (50 mL) was added IBX (5.54 g, 19.7 mmol) in portions. The reaction mixture was stirred at rt for 3 h, and was quenched with 2N NaOH solution (50 mL). The resulting mixture was extracted with DCM (3×25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with EtOAc/petroleum ether (1:2 v/v) to obtain compound 2a as a yellow solid (6.00 g, 54% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C11H11BrN4O2: 311.0 (M+H). found 311.2.
Reaction SMILES: [CH2:1]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-])=O)[CH:7]=1)[C:2]([CH3:5])([CH3:4])[CH3:3]>CO.[Pd]>[CH2:1]([C:6]1[CH:7]=[C:8]([NH2:13])[C:9]([NH2:10])=[CH:11][CH:12]=1)[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)Cc1ccc(N)c(N)c1
Reaction time: 3.5 h
Yield: 65.9 %

Procedure:
To a solution of 4-neopentyl-2-nitroaniline (Preparation 88, 5.23 g, 25.1 mmol) in methanol (50 mL) was added 10% palladium on carbon (800 mg, 8 mmol) and hydrogenated at 40 psi for 3.5 hours. The mixture was filtered through celite and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with a 0-10% methanol/methylene chloride gradient to provide the title compound (2.95 g, 66%) as a purple solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=4[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>>[N:11]1([C:14]2[N:19]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=4[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3ccnc(N4CCNCC4)n3)ccc21

Procedure:
The above compound is prepared analogously to FS201 starting from 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester. Product is the hydrochloride.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:21](=O)[C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]([O:19][CH3:20])=[O:18]>CC(O)C>[C:22]([C:21]1[N:13]=[C:12]([C:11]2[C:3]([CH3:2])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[S:14][C:16]=1[C:17]([O:19][CH3:20])=[O:18])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1nn2ccccc2c1C(N)=S
Reactant: COC(=O)C(Cl)C(=O)C(C)(C)C
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1C(C)(C)C
Yield: 77.1 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (300 mg, 1.3 mmol) produced in Example 11-B(v), methyl 2-chloro-4,4-dimethyl-3-oxopentanoate (950 mg, 4.9 mmol) produced in the above and 2-propanol (25 mL) as starting materials and in the same manner as in Example 11(vi), the title compound (330 mg, 76%) was obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[F:9][C:10]([C:13]1[CH:18]=[CH:17][N:16]2[C:19]([Sn](CCCC)(CCCC)CCCC)=[CH:20][N:21]=[C:15]2[N:14]=1)([CH3:12])[CH3:11]>>[Br:8][C:4]1[N:3]=[C:2]([C:19]2[N:16]3[CH:17]=[CH:18][C:13]([C:10]([F:9])([CH3:11])[CH3:12])=[N:14][C:15]3=[N:21][CH:20]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(C)(C)F)ccn12
Reactant: Brc1cccc(Br)n1
Product: CC(C)(F)c1ccn2c(-c3cccc(Br)n3)cnc2n1
Yield: 68 %

Procedure:
2,6-Dibromopyridine was coupled with 7-(1-fluoro-1-methylethyl)-3-tributylstannylimidazo[1,2-α]pyrimidine by the method of Example 1 to afford 3-(6-bromopyridin-2-yl)-7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine (1.0 g, 68%) as a pale yellow solid: δH (360 MHz, CDCl3) 1.81 (6H, d, J 22), 7.37 (1H, d, J 8), 7.42 (1H, dd, J 7 and 2), 7.61 (1H, dd, J 8 and 8), 7.71 (1H, dd, J 8 and 1), 8.33 (1H, s), 10.09 (1H, d, J 7).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:9]([OH:11])=[O:10].[C:18]1(C)C=CC=C[CH:19]=1>>[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:9]([O:11][CH2:18][CH3:19])=[O:10]
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Thionyl chloride (15.7 g, 120 mmol) was added to a solution of 3-bromo-5-nitrobenzoic acid in toluene (100 ml). The mixture was refluxed for 6 hours. The solvent was evaporated and the residue dissolved in dry tetrahydrofuran (50 ml), ethanol (10 ml) was added and the mixture stirred at room temperature for 30 mins. The solvent was evaporated and the residue chromatographed in dichloromethane to give the title compound as an off-white solid (13 g, 79%)
Reaction SMILES: [C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=1>>[Cl:18][C:19]1[N:20]=[CH:21][C:22]([N:6]2[CH2:7][C@@H:1]3[C@H:5]2[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]3)=[CH:23][CH:24]=1
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN[C@@H]2C1
Reactant: Clc1ccc(Br)cn1
Product: O=C(OCc1ccccc1)N1C[C@@H]2CN(c3ccc(Cl)nc3)[C@@H]2C1
Yield: 37.8 %

Procedure:
The product of Example 52D (0.23 g, 1.0 mmol) and 2-chloro-5-bromopyridine (0.29 g, 1.5 mmol) were processed according to the procedure described in Example 1E. The crude product was purified by chromatography (SiO2, hexane:ethyl acetate, 60:40, Rf 0.3) to provide the title compound (0.13 g, 38% yield). 1H NMR (MeOH-d4, 300 MHz) δ3.24 (dd, J=12.9, 4.1 Hz, 1H), 3.30 (m, 1H), 3.40 (m, 1H), 3.65 (dd, J=7.8, 3.4 Hz, 1H), 4.08-3.92 (m, 3H), 4.70 (dd, J=5.7, 3.7 Hz, 1H), 5.10 (m, 2H), 6.90 (dd, J=8.5, 3.1 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.25 (m, 3H), 7.35 (m, 2H), 7.54 (d, J=3.0 Hz, 1H); MS (DCI/NH3) m/z 346 (M+2+H)+, 344 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[N+:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([O-:28])=[O:27]>ClCCl>[CH2:1]([N:8]([CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])[C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([N+:26]([O-:28])=[O:27])=[CH:37][CH:36]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(NCc1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(c1ccccc1)N(Cc1ccccc1)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
to a solution of methyl 2-(benzylamino)-2-phenylacetate (4.818 g, 18.9 mmol) and pyridine (15.3 ml, 189 mmol) in 75 mL dichloromethane cooled by an ice bath was added 4-nitrobenzoyl chloride (3.50 g, 18.9 mmol) all at once. The cold bath was removed and the reaction stirred to room temperature. The reaction was stirred at room temperature for four hours then concentrated under reduced pressure, taken up in 100 mL heptane and concentrated under reduced pressure. The concentrate was partitioned between 100 mL dichloromethane and 100 mL water. The organic separation was washed with 50 mL brine then stirred over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless oil. The product was purified by chromatography on silica, eluting with 10-30% ethyl acetate in hexane to afford a colorless foamy solid (7.37 g, 96%). ESI+ m/z=405.1 [MH]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=2)[N:3]=1>[Zn].O1CCOCC1>[C:8]([C:7]1[CH:6]=[N:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=2)=[N:3][CH:2]=1)#[N:9]
Reactant: CCCCCCOc1ccc(-c2ncc(C#N)c(Cl)n2)cc1
Agent: [Zn]
Solvent: C1COCCO1
Product: CCCCCCOc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
3.0 G. of 4-chloro-5-cyano-2-(4-n-hexyloxyphenyl)-pyrimidine are reacted in 125 ml. of 50% dioxane with 11.0 g. of pre-treated zinc dust and worked up after the reaction in manner analogous to that described in Example 13. There is obtained 5-cyano-2-(4-n-hexyloxyphenyl)-pyrimidine as colorless crystals having a melting point of 93.5°-93.8° C. (smectic); nematic at 121.2° C; clearing point 134.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[NH:5][CH:6]([CH3:11])[CH2:7][C:8]([OH:10])=O.[OH-].[Na+]>O>[Cl:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[C:4]2[C:3]=1[C:8](=[O:10])[CH2:7][CH:6]([CH3:11])[NH:5]2
Reactant: CC(CC(=O)O)Nc1ccc(F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1CC(=O)c2c(ccc(F)c2Cl)N1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 8.7 %

Procedure:
400 g of polyphosphoric acid was added to 92.66 g (0.40 mole) of the 3-(3-chloro-4-fluoroanilino) butyric acid and this mixture was stirred at 110° C. for 1.5 hours. After being allowed to cool to room temperature, the resulting reaction solution was diluted with 3 liters of water and then adjusted to pH 4-5 with an aqueous sodium hydroxide solution. Then, the solid matter which separated out was extracted with chloroform and this extract was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (using chloroform as the developing solvent). The fraction containing the desired product was evaporated to dryness under reduced pressure and the resulting residue was recrystallized from benzene to obtain 7.43 g (8.7% yield) of 5-chloro-6-fluoro-2-methyl-4-oxo-1,2,3, 4-tetrahydroquinoline in the form of yellow crystals. On the other hand, another fraction was worked up in the same manner as above to obtain 8.55 g (10.0% yield) of a structural isomer thereof, or 7-chloro-6-fluoro-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline, in the form of yellow crystals.
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][CH:9]([NH2:11])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)[O:19][CH2:18][CH2:17][CH:16]2[C:33]([O:35][CH2:36][CH3:37])=[O:34].Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.CCOC(C)=O>[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](=[O:29])[NH:11][CH:9]3[CH2:8][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:10]3)=[CH:26][CH:25]=1)[O:19][CH2:18][CH2:17][CH:16]2[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: NC1CC(c2ccccc2)C1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CC(c5ccccc5)C4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.6 %

Procedure:
To a solution of 3-phenylcyclobutanamine (0.101 g, 0.686 mmol) in DMF (2 ml) was added 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.129 g, 0.343 mmol), N,N-dimethylpyridin-4-amine (0.00838 g, 0.0686 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.0789 g, 0.412 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was on a Biotage SP1 system eluting with a 5-70% EtOAc in hexanes linear gradient to yield 86 mg of the title compound (49.5% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[C:8]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]=2[NH:10][N:11]=1)=[O:5])[CH3:2].N1C=CC=CC=1.C1(C)C=CC(S([Cl:33])(=O)=O)=CC=1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[N:10][C:9]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:8]=2[C:7]=1[Cl:33])=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1n[nH]c2c(c1=O)CCCCC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc2c(c1Cl)CCCCC2
Yield: 22.3 %

Procedure:
To a solution of 4-oxo-4,5,6,7,8,9-hexahydro-1H-cyclohepta[c]pyridazine-3-carboxylic acid ethyl ester (2.7 g) and pyridine (0.93 ml) in dichloromethane (150 ml) was added p-toluenesulphonyl chloride (2.2 g). The reaction mixture was heated at reflux for 20 h. The reaction mixture was washed with 1M potassium carbonate solution, brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil. The oil was purified by flash chromatography using a gradient elution: CH2Cl2 (500 ml), CH2Cl2/MeOH 99:1 (500 ml), CH2Cl2/MeOH 98:2 (500 ml), CH2Cl2/MeOH 97:3 (500 ml), CH2Cl2/MeOH 96:4 (500 ml). The appropriate fractions were combined and evaporated under reduced pressure to give a solid (0.65 g, 22%). C12H15ClN2O2 requires C, 56.58; H, 5.93; N, 11.00. Found C, 56.52; H, 6.06; N, 11.01%. δH (360 MHz; CDCl3) 1.44 (3H, t, J=7 Hz, CH3), 1.70 (2H, m, CH2), 1.77 (2H, m, CH2), 1.92 (2H, m, CH2), 3.06 (2H, m, CH2), 3.32 (2H, m, CH2), 4.51 (2H, t, J=7 Hz, CH2), m/z (ESP+) 255/257 (MH+).