Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]2=[N:8][N:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:10]=[C:6]2[C:5]([C:17]2[CH:29]=[CH:28][C:27]3[C:26]4[C:21](=[CH:22][C:23]([C:30]5[C:38]6[C:34](=[N:35][N:36]([C:39]7[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=7)[N:37]=6)[C:33](Br)=[CH:32][CH:31]=5)=[CH:24][CH:25]=4)[C:20]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:19]=3[CH:18]=2)=[CH:4][CH:3]=1.[S:58]1[C:62](B(O)O)=[CH:61][C:60]2[CH:66]=[CH:67][CH:68]=[CH:69][C:59]1=2.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>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.C1(C)C=CC=CC=1.C(O)CCC>[S:58]1[C:62]([C:33]2[C:34]3=[N:35][N:36]([C:39]4[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=4)[N:37]=[C:38]3[C:30]([C:23]3[CH:24]=[CH:25][C:26]4[C:27]5[C:19](=[CH:18][C:17]([C:5]6[C:6]7[C:7](=[N:8][N:9]([C:11]8[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=8)[N:10]=7)[C:2]([C:62]7[S:58][C:59]8[CH:69]=[CH:68][CH:67]=[CH:66][C:60]=8[CH:61]=7)=[CH:3][CH:4]=6)=[CH:29][CH:28]=5)[C:20]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:21]=4[CH:22]=3)=[CH:31][CH:32]=2)=[CH:61][C:60]2[CH:66]=[CH:67][CH:68]=[CH:69][C:59]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: CCCCCCC1(CCCCCC)c2cc(-c3ccc(Br)c4nn(-c5ccncc5)nc34)ccc2-c2ccc(-c3ccc(Br)c4nn(-c5ccncc5)nc34)cc21
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: CCCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCC1(CCCCCC)c2cc(-c3ccc(-c4cc5ccccc5s4)c4nn(-c5ccncc5)nc34)ccc2-c2ccc(-c3ccc(-c4cc5ccccc5s4)c4nn(-c5ccncc5)nc34)cc21
Reaction time: 1 h

Procedure:
A mixture of Intermediate E (90%, 488 mg, 0.50 mmol),), benzo[b]thiophen-2-ylboronic acid (356 mg, 2.00 mmol), sodium carbonate (530 mg, 5 mmol) in water (4 mL), tetrakis(triphenylphosphine)palladium (0) (240 mg, 0.20 mmol), n-butanol (15 mL), and toluene (15 mL) was heated under argon at 110° C. for 24 hours. The reaction mixture was poured into water (200 mL), treated with 5N NaOH (25 mL), stirred for 1 hour, and extracted with dichloromethane (3×200 mL). The volatiles were removed under reduced pressure, and the residue was chromatographed (silica gel, dichloromethane/tetrahydrofuran 9:1). The obtained product was washed with ethyl acetate and dried in a vacuum oven to give 2,7-bis(7-(benzo[b]thiophen-2-yl)-2-(pyridin-4-yl)-2H-benzo[d][1,2,3]triazol-4-yl)-9,9-dihexyl-9H-fluorene (Example 24), orange crystals, 430 mg (87%). 1H NMR (400 MHz, CDCl3): δ 8.89 (m, 4H, pyridine), 8.56 (s, 2H, benzothiophene), 8.44 (m, 4H, pyridine), 8.21 (s, 2H, fluorene), 8.14 (d, 2H, J=8.8 Hz, fluorene), 7.88-7.98 (m, 8H, benzothiophene, fluorene and benzotriazole), 7.79 (d, J=7.3 Hz, 2H, benzotriazole), 7.41 (m, 4H, benzothiophene), 2.20 (m, 4H, hexyl), 1.20 (m, 4H, hexyl), 1.14 (m, 8H, hexyl), 0.95 (m, 4H, hexyl), 0.74 (t, J=6.5 Hz, 6H, hexyl). UV-vis spectrum (dichloromethane): λmax=440 nm. Fluorimetry (dichloromethane): λmax=515 nm.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].[CH3:9][C:10]1([CH3:43])[N:14](CCCC(O)=O)[C:13](=[O:21])[N:12]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:38]=[CH:37][C:29]3[C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][O:32][C:28]=3[C:27]=2[CH2:39][CH2:40][CH3:41])[C:11]1=[O:42]>>[CH3:43][C:10]1([CH3:9])[N:14]([CH:3]([CH3:2])[CH2:4][CH2:5][C:6]([OH:8])=[O:7])[C:13](=[O:21])[N:12]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:38]=[CH:37][C:29]3[C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][O:32][C:28]=3[C:27]=2[CH2:39][CH2:40][CH3:41])[C:11]1=[O:42]
Reactant: CCCc1c(OCCCN2C(=O)N(CCCC(=O)O)C(C)(C)C2=O)ccc2c(C(F)(F)F)noc12
Reactant: O=C([O-])CCCCBr
Product: CCCc1c(OCCCN2C(=O)N(C(C)CCC(=O)O)C(C)(C)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
4-[5,5-Dimethyl-2,4-dioxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]pentanoic acid was prepared as for Example 37, substituting 5-bromovalerate for the 4-bromobutyrate of Example 37.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:12]C(C)(C)C)=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[CH:5]=[N:6]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CCC>[Br:1][C:2]1[C:3]2[S:12][N:6]=[CH:5][C:4]=2[CH:8]=[CH:9][C:10]=1[I:11]
Reactant: CC(C)(C)Sc1c(C=NO)ccc(I)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: Brc1c(I)ccc2cnsc12
Yield: 28.2 %

Procedure:
A mixture of 3-bromo-2-tert-butylsulfanyl-4-iodo-benzaldehyde oxime (1.0 g, 2.4 mmol) and p-toluenesulfonic acid (0.19 g, 1 mmol) in n-butanol (50 mL) were heated to reflux for 16 h. The reaction mixture was cooled and concentrated. Water (40 mL) was added to the residue, followed by saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (3×40 mL). The combined organic fractions were washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by column chromatography (5% ethyl acetate:hexanes) afforded 0.23 g (28%) of the title compound as a solid. 1H NMR (300 MHz, CDCl3): δ 7.36 (d, J=7.8 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 8.99 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]([CH2:32][CH3:33])[C:29](=[O:31])[CH3:30])=[CH:24][C:23]=1[C:34]([F:37])([F:36])[F:35].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:19])[CH:17]=[CH2:18])=[N:7][C:2]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH2:32][CH3:33])[C:29](=[O:31])[CH3:30])=[CH:24][C:23]=2[C:34]([F:35])([F:36])[F:37])=[N:3][CH:4]=1
Reactant: C=CC(=O)Nc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN(C(C)=O)c1ccc(N)c(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccccc1Nc1nc(Nc2ccc(N(CC)C(C)=O)cc2C(F)(F)F)ncc1Cl

Procedure:
To a stirred solution of Intermediate 1 from Example 162 (100 mg, 0.3246 mmol) in tetrahydrofuran (5 mL), N-(4-amino-3-(trifluoro methyl)phenyl)-N-ethylacetamide (80 mg, 0.3246 mmol) and cesium carbonate (316 mg, 0.9738 mmol) were added and degassed for 10 min. To the reaction mixture palladium acetate (38 mg, 0.1623 mmol) and xanthphos (36.8 mg, 0.0973 mmol) were added and again degassed for another 5 min. The mixture was irradiated by microwave at 80° C. for 20 min. TLC showed completion of starting material (TLC system: 10% methanol/chloroform, (Rf): 0.5). The reaction was quenched with water (15 mL) and extracted with ethyl acetate (3×10 mL). The organic layer was separated, dried over sodium sulfate and concentrated. The crude compound was purified by prep-HPLC to obtain the title compound as yellow solid. (30 mg, 17%). 1HNMR (DMSO-d6) δ 0.98 (m, 3H), 1.70 (m, 3H), 1.85 (s, 1H), 3.63 (m, 2H), 5.77-5.80 (dd, 1H J=1.8 Hz and 10.2 Hz), 6.26-6.31 (dd, 1H J=1.8, 17 Hz), 6.44-6.51 (dd, 1H J=10.2, 17 Hz), 7.09-7.17 (m, 2H), 7.32-7.35 (dd, 1H J=1.7, 7.5 Hz), 7.48 (d, 1H J=7.1 Hz), 7.55 (s, 1H), 7.63 (d, 1H J=8.2 Hz), 7.72 (d, 1H J=8.2 Hz), 8.08 (s, 1H), 8.49 (s, 1H), 10.12 (s, 1H). MS m/z: 519.5 (ES+, M+H).
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]#[N:11].C(O)C[OH:18].[OH-].[K+]>O>[CH:7]1[CH:8]=[CH:9][N:5]2[CH2:4][C:3]3[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=3[NH:11][C:10](=[O:18])[C:6]=12
Reactant: OCCO
Reactant: N#Cc1cccn1Cc1ccccc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1Nc2ccccc2Cn2cccc21

Procedure:
A mixture of 10 g. of 1-(o-aminobenzyl)-2-pyrrolecarbonitrile [M. Artico et al., I1 Farmaco Ed. Sci., 24 (11), 980 (1969)], 60 ml. of ethylene glycol and 8 g. of 85% potassium hydroxide is heated in an oil bath at 180° C. for 2 hours, cooled and then diluted with 100 ml. of water. The crystals which form are collected by filtration and recrystallized from 95% ethanol, giving pure 5,10-dihydro-11H-pyrrolo[2,1-c][1,4]-benzodiazepin-11-one. The aqueous mother liquor, when treated with acetic acid to pH 4-5, gives 1-o-aminobenzyl-2-pyrrolecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[NH:9][C:10](=[O:11])[NH:8]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ncnc(Cl)c1N
Solvent: C1COCCO1
Product: O=c1[nH]c2ncnc(Cl)c2[nH]1
Reaction time: 1 h
Yield: 95.8 %

Procedure:
Combine 6-chloro-pyrimidine-4,5-diamine (7.46 mmol; 1.08 g); 1,1′-carbonyldiimidazole (2 equiv; 14.92 mmol; 2.42 g) and 1,4-dioxane (20 mL) and heat to reflux under nitrogen for 50 min. Evaporate the yellow solution to an oil. Add DCM (80 mL), let sit 1 h, filter and dry in vacuum oven at 45° C. to provide the title compound (1.22 g; 7.15 mmol; 96%) MS (ES+): m/z=169 (M−H).
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[C:9]([O:11][CH:12]1[CH:19]2[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:21][CH:13]1[CH2:14]3)[CH2:18]2)=[O:10]>>[CH:19]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:21][CH:13]([CH2:14]3)[CH:12]1[O:11][C:9]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:10])[CH2:18]2
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: COP(OC)OC
Product: COP(=O)(OC)C(=O)OC1C2CC3CC(C2)CC1C3

Procedure:
From 1.5 g (12 mmole) of trimethylphosphite and 2.0 g (9.3 mmole) of 2-adamantyl chloroformate: (100°-110° C., 2 hrs). Yield 1.0 g (37%). Bp0.3 160° C.
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:3])[CH3:2].[OH-].[Na+].Cl[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1.ICCCCCOC1C=CC(C#N)=CC=1>C(OC(=O)C)C.CN(C)C=O>[CH:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]#[N:31])=[CH:32][CH:33]=2)=[CH:14][CH:15]=1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2ccc(O)cc2)c(C(C)C)s1
Reactant: N#Cc1ccc(OCCCCCCl)cc1
Agent: N#Cc1ccc(OCCCCCI)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(OCCCCCOc3ccc(C#N)cc3)cc2)c(C(C)C)s1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
While 72.6 g of 4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenol (6) prepared in Example 4 were added to 850 ml of dimethylformamide and stirred, 15.0 g of sodium hydroxide were added. The reaction temperature was gradually increased and stirring was continued at 50-55° C. for 30 min. Thereafter, 70.0 g of 4-(5-chloro-pentoxy)-benzonitrile (8), prepared in Example 5, or 95.3 g of 4-(5-iodo-pentoxy)-benzonitrile (9), prepared in Example 6, were added. The reaction temperature was gradually increased and stirring was continued at 80-90° C. for 3 hr. After the reaction was completed, the temperature was decreased to room temperature, and the resultant reaction mixture was added with 850 ml of ethylacetate, and then washed with water and brine. Subsequently, the ethylacetate layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residual solution was crystallized with ethylacetate and n-hexane, thus obtaining 114 g (yield: 90%) of a title compound as a light yellow solid through the reaction with the compound (8), or 119.6 g (yield: 94%) of a title compound as a light yellow solid through the reaction with the compound (9).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]([OH:25])=[O:24])=[CH:15]1.CI>C1COCC1.O.CCCCCC>[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]([OH:25])=[O:24])=[C:15]1[CH3:1]
Reactant: CC(C)NC(C)C
Reactant: Cn1cc(C(=O)O)c2ccccc21
Agent: [Li]CCCC
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)c2ccccc2n1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
Diisopropylamine (2.83 ml, 20.0 mmol) was dissolved in THF (35 ml). Under stirring at −78° C., n-butyl lithium (12.7 ml, 20.0 mmol, a 1.57M hexane solution) was added to the resulting solution. After stirring at 0° C. for 15 minutes, the reaction mixture was cooled again to −78° C. Under stirring, a solution of 1-methyl-1H-indole-3-carboxylic acid (1.75 g, 10.0 mmol) in THF (5 ml) was added. After the reaction mixture was stirred at the same temperature for 30 minutes, methyl iodide (3.42 ml, 55.0 mmol) was added. The reaction mixture was caused to rise back to room temperature over 30 minutes. The reaction mixture was poured into water and the mixture was stirred for 18 hours at room temperature. The reaction mixture was washed with ether. The water layer was acidified with 1M HCl, followed by extraction with ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (middle pressure, linear gradient of chloroform/methanol from 10:0 to 20:1, 20 ml/min, φ 50×300 mm) to give 1,2-dimethyl-1H-indole-3-carboxylic acid (180 mg, 10%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:16][CH2:17][C:18](Cl)=[O:19]>CC(N(C)C)=O>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH:15][C:18](=[O:19])[CH2:17][Cl:16])[S:13][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(=NOC)c1csc(NC(=O)CCl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 10 g of ethyl α-methoxyimino-α-(2-aminothiazol-4-yl)acetate in 100 ml of dimethylacetamide is dropwise added 5.91 g of chloroacetyl chloride under ice-cooling. After the stirring for 1 hour at room temperature, the reaction mixture is poured into ice-water and the resultant solution is extracted with ethyl acetate. The organic layer is washed and dried, followed by the distillation of solvent to give 12.66 g of ethyl α-methoxyimino-α-[2-(chloroacetamido)thiazol-4-yl]acetate is a crystal.
Reaction SMILES: C([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH:29][C:30](=[O:41])[C:31]3[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([O:39][CH3:40])[CH:32]=3)=[CH:13][CH:14]=2)[CH:9]=1)(=[O:7])=[O:6])(C)C.[I-].[Na+]>CC(=O)CC>[CH3:38][O:37][C:35]1[CH:36]=[C:31]([CH:32]=[C:33]([O:39][CH3:40])[CH:34]=1)[C:30]([NH:29][C:12]1[CH:11]=[C:10]2[C:15]([C:16]([OH:28])=[C:17]([N:18]=[N:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:8]([S:5]([OH:7])(=[O:4])=[O:6])=[CH:9]2)=[CH:14][CH:13]=1)=[O:41]
Reactant: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(NC(=O)c4cc(OC)cc(OC)c4)ccc3c2O)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1ccc(N=Nc2c(S(=O)(=O)O)cc3cc(NC(=O)c4cc(OC)cc(OC)c4)ccc3c2O)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 89.5 %

Procedure:
7-(3,5-Dimethoxy-benzoylamino)-4-hydroxy-3-(4-methoxy-phenylazo)-napthalene-2-sulfonic acid isopropyl ester (Example 13, 96 mg, 0.19 mmol) was suspended in 2-butanone (3 mL) and sodium iodide (57 mg, 0.38 mmol) was added. The reaction mixture was allowed to stir under nitrogen at 60° C. for 24 h. The solvent was removed under a stream of nitrogen, acetone was added and the suspension was filtered to provide the title compound (86 mg, 0.17 mmol, 91%) as a red solid: NMR (DMSO-d6): δ 16.34 (s, 1H), 10.47 (s, 1H), 8.27 (d, 9 Hz, 1H), 8.18 (m, 1H), 7.95 (d, J=9 Hz, 1H), 7.83 (d, J=9 Hz, 2H), 7.51 (s, 1H), 7.17 (d, J=3 Hz, 2H), 7.08 (d, J=9 Hz, 2H), 6.74 (t, J=2 Hz, 1H), 3.78 (m, 9H); Analytical HPLC: 94% pure; MS (ES-NEG): [M−H] 536; Anal. Calc. for C26H23N3O8SNa: C, 55.81, H, 3.96, N, 7.51. Found: C, 52.65, H, 4.45, N, 5.99.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25]CC)=[O:24])[CH:16]=[N:15]3)[N:9]=2)=[CH:6][C:5]([CH3:28])=[CH:4][N:3]=1.[CH3:29][C:30]1[CH:31]=[C:32]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)[CH:33]=[CH:34][C:35]=1[CH2:36][OH:37]>>[CH3:28][C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[C:18]([C:19]([F:21])([F:22])[F:20])=[C:17]([C:23]([OH:25])=[O:24])[CH:16]=[N:15]3)[N:9]=2)[C:2]([O:37][CH2:36][C:35]2[CH:34]=[CH:33][C:32]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=3)=[CH:31][C:30]=2[CH3:29])=[N:3][CH:4]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)cnc3F)n2)c1C(F)(F)F
Product: Cc1cnc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2C)c(-c2cccc(-n3ncc(C(=O)O)c3C(F)(F)F)n2)c1

Procedure:
The title compound was prepared according to the procedure described in Example 237 Step B, by reaction of the title compound from Example 238 Step B with [3-methyl-4′-(trifluoromethyl)biphenyl-4-yl]methanol (PCT Publication WO2005118542): LCMS m/z 612.9 [M+H]+; 1H NMR (500 MHz, acetone-d6) δ 8.18 (m, 2H), 7.91 (d, J=8.2 Hz, 2H), 7.80 (m, 3H), 7.63 (m, 2H), 5.66 (s, 2H), 2.51 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Br.[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1>>[N:13]1[CH:14]=[CH:15][C:10]([NH:9][C:3]2[C:2]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:11][CH:12]=1
Reactant: Brc1ccccc1Br
Reactant: Nc1ccncc1
Product: c1ccc(Nc2ccncc2)c(Nc2ccncc2)c1
Yield: 73.3 %

Procedure:
The synthesis is carried out in accordance with the general procedure of Example 2 from 56.6 g (240 mmol) of 1,2-dibromobenzene and 47.5 g (505 mmol) of 4-aminopyridine. The precipitated solid is recrystallised from toluene/acetonitrile (5:1), and the residue is washed with MeOH, giving 46.2 g (176 mmol) of a crystalline solid. The total yield is 73%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH:14]=O)[C:7]=2[N:16]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:17]3[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]3)[C:7]=2[N:16]=1
Reactant: COc1ccc2ncc(=O)n(CC=O)c2n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
To a solution of 0.18 g of (6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde in 4 mL of dichloromethane, 0.16 g of tert-butyl (piperidin-4-yl)carbamate and 47 μL of acetic acid and 0.26 g of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 3 hours. Chloroform and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resultant residue, diethyl ether, methanol and hexane were added, and the solid was filtered off to obtain 0.23 g of tert-butyl (1-(2-(6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamate as a light brown solid.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH:6]=1.[F:16][C:17]([F:35])([F:34])[C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Cl)[CH:25]=2)=[CH:20][CH:19]=1>>[F:16][C:17]([F:34])([F:35])[C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=2)[CH2:30][O:14][C:12]2[CH:11]=[CH:10][C:9]3[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[CH:6][O:7][C:8]=3[CH:13]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Reactant: FC(F)(F)c1ccc(COc2cccc(CCl)c2)cc1
Product: O=C(O)Cc1coc2cc(OCc3cccc(OCc4ccc(C(F)(F)F)cc4)c3)ccc12

Procedure:
The title compound was prepared in the manner analogous to step 1 of Example 80 using (6-hydroxy-benzofuran-3-yl)-acetic acid methyl ester and 1-(4-trifluoromethyl-benzyloxy)-3-chloromethyl-benzene. MS m/z 471 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH2:18]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])[CH3:19]>>[CH2:18]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)[CH3:19]
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Reactant: CCc1cccc(N)c1
Product: CCc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol) and 3-ethylaniline (18 μl, 0.144 mmol) similar to Example 92 and isolated as a yellow oil (12 mg, 36%). 1H NMR (CDCl3): 8.84–8.82 (m, 1H), 8.57–8.54 (m, 1H), 7.89–7.84 (m, 1H), 7.72 (s, 1H), 7.44–7.40 (m, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.14–7.11 (m, 3H), 7.01 (s, 1H), 2.69 (q, J=7.8 Hz, 2H), 1.27 (t, J=7.8 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]=[CH:5][CH:6]=[C:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15].[OH-].[Na+]>CO>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:24])=[O:2]
Reactant: COC(=O)C=CC=C(c1ccccc1OC)c1ccccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1C(=C/C=C/C(=O)O)c1ccccc1OC
Yield: 84.6 %

Procedure:
In the manner described in Example 99, 5,5-bis(2-methoxyphenyl) -2,4-pentadienoic acid methyl ester (6.3 g) was saponified in a refluxing mixture of methanol (50 mL) and 1N NaOH (50 mL). After 45 minutes the crude acid was isolated in the normal manner and the crystallized from 2-propanol to yield 5.1 g of (E)-5,5-bis(2-methoxyphenyl)-2,4-pentadienoic acid, mp 196°-197° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[C:13](=O)([O-])[O-:14].[K+].[K+]>CO>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[C:4]([O:14][CH3:13])[N:3]=[C:2]([Cl:1])[N:7]=1)=[O:9]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(OC)nc(Cl)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methyl 2,6-dichloropyrimidine-4-carboxylate (1 g) was combined with MeOH (20 ml) to give a light yellow solution. Potassium carbonate (668 mg) was added and the reaction mixture was stirred at RT for 6 h. The solvent was concentrated in vacuo and the residue was stirred in Et2O. The suspension was filtered and the filtrate was concentrated in vacuo to afford title compound as a white solid. MS (ISP): 203.3 ([M+H]+)
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.C([O:14][C:15](=O)[CH:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:17])C.OS(O)(=O)=O>O>[CH2:19]([O:18][CH:16]([CH3:17])[CH2:15][OH:14])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCOC(C)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCCOC(C)CO
Reaction time: 4 h

Procedure:
1.9 g of LiAlH4 was added to 70 ml of ether and the mixture was stirred for 4 hours. To the mixture was added dropwise 16.9 g of (-)-ethyl-2-dodecyloxypropionate in the same manner as in Example 3, and the mixture was stirred for 15 minutes. Then, 50 ml of deionized water and further 50 ml of 10% H2SO4 aqueous solution were added thereto. The ether layer was separated, dried with MgSO4 and filtered. Ether was distilled off to obtain the objective product at an yield of 12.0 g. The product showed the following properties: