Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1[NH:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=3)=[CH:7][CH:8]=2)[NH:3]1.NC1C=C(Br)C=CC=1C#N.B([O-])[O-]>>[NH2:3][C:4]1[CH:5]=[C:6]([C:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=2)[CH:7]=[CH:8][C:9]=1[C:10]#[N:11]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)NC(=O)NC3)CC1
Agent: N#Cc1ccc(Br)cc1N
Agent: [O-]B[O-]
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C#N)c(N)c2)CC1
Yield: 62 %

Procedure:
Following the same procedure adopted for the synthesis of 22, the reaction of nitrile 11 with boronic ester 21 afforded the title compound 24 as an off-white solid (62%). IR (KBr) νmax. cm−1: 3421, 3318 (NH2), 3072 (Ar—H), 2247 (CN), 1691 (C═O), 1616, 1510, 1412 (C═C). 1H-NMR (500 MHz, CDCl3) δ=1.49 (s, 9H, (CH3)3C); 1.71 (br. s, 2H, CH2); 2.45 (br. s, 2H, CH2); 3.61 (m, 2H, CH2); 4.07 (s, 2H CH2); 4.43 (br. s, 2H, NH2); 6.10 (br. s, 1H, CH); 6.71 (d, J=2.2 Hz, 1H, H-2); 6.75 (dd, 1H, J=2.3, 8.6 Hz, H-6); 7.33 (d, J=8.5 Hz, 1H, H-5); 8.01 (br. s, 1H, NH); 13C NMR (125.7 MHz, CDCl3) δ=27.35 (CH2), 28.47 (CH3)3C), 29.73 (CH2), 41.96 (CH2), 79.91 (CH3)3C), 94.63 (aromatic-C), 115.12 (aromatic-C), 117.69 (CN), 133.67 (aromatic-C), 147.42 (aromatic-C), 150.47 (aromatic-C), 155.33 (C═O). Calculated (%) for C17H21N3O2 (299.16); C, 68.20; H, 7.07; N, 14.04. found (%; C, 68.16; H, 7.13; N, 13.97.
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[NH:6][C:7](=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[C:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[Cl:26])[NH2:22])#[CH:18]>CN(C=O)C.CC(N(C)C)=O>[C:17]([C:19]1[CH:20]=[C:21]([NH:22][C:9]2[C:4]3[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:23]=[CH:24][C:25]=1[Cl:26])#[CH:18]
Reactant: O=c1ncc2cc(F)ncc2[nH]1
Reactant: C#Cc1cc(N)ccc1Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: C#Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.4 %

Procedure:
A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.65 g, 10.0 mmol), thionyl chloride (20 mL) and a catalytic amount of DMF (2 drops) was stirred under reflux for 24 h to give a homogeneous mixture. It was evaporated under reduced pressure at 45° C. (bath temperature) to give a light brown solid. To this solid was added a solution of 3-ethynyl-4-chloroaniline (J. Org. Chem., 1981, 46, 2280-2286) (1.67 g, 11.0 mmol) and dry DMA (15 mL). The residue of 3-ethynyl-4-chloroaniline was washed down with more DMA (2×2 mL). The reaction mixture was stirred at room temperature for 24 h. It was poured into water (300 mL) and the residue washed down with MeOH. The pH was adjusted to ca. 9 using an aqueous solution of Na2CO3 at room temperature. Petroleum ether (300 mL) was added and stirred at room temperature for 30 min. The petroleum ether layer was decanted. It was repeated once more with petroleum ether (300 mL). The solid was collected by filtration and washed with water (5×25 mL); ethyl acetate/petroleum ether (1:10) (4×25 mL) and dried to give N-(3-ethynyl-4-chlorophenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (209) (3.0 g, 100%) as a pale brown solid, mp 218-222° C.; 1H NMR δ [(CD3)2SO] 10.13 (s, 1H), 8.98 (s, 1H), 8.77 (s, 1H), 8.32-8.22 (m, 2H), 7.95 (dd, J=8.8, 2.6 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 4.60 (s, 1H). Anal. Calcd for C15H8ClFN4.0.5H2O.0.5MeOH: C, 57.51; H, 3.43; N, 17.31. Found C, 57.33; H, 3.13; N, 17.10.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[CH:5][CH:4]=1.N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[Si:20]([O:1][CH2:2][C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[CH:5][CH:4]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(=O)c1ccc(CO)s1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)s1
Temperature: 0 °C

Procedure:
To a solution of 1-[5-(hydroxymethyl)thien-2-yl]ethanone prepared in the above step in DMF (84 ml) was added imidazole (27.11 g) and thereto was dropped under ice cooling tert-butyldimethylchlorosilane (30.01 g). Thirty minutes later, thereto was added ice water (250 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 1-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)thien-2-yl]ethanone (46.53 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][C:16]([F:19])([F:18])[CH2:15][N:14]3C(OC(C)(C)C)=O)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][C:16]([F:18])([F:19])[CH2:15][NH:14]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC1(F)CN[C@H](c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Reaction time: 2 h

Procedure:
In a 10 ml, pear-shaped flask, (S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4,4-difluoropyrrolidine-1-carboxylate (1.0 g, 2.33 mmol) was combined with CH2Cl2 (6 ml) to give a light yellow solution. TFA (2.96 g, 2 mL, 26.0 mmol) was added and stirred for 2 hr. It was concentrated in vacuo to afford (S)-5-(4-bromophenyl)-2-(4,4-difluoropyrrolidin-2-yl)-1H-imidazole as a viscous oil and used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:12](CC3C=CC(OC)=CC=3)[CH2:11][CH2:10][CH2:9][C:8]([C:22]([O:24][CH3:25])=[O:23])=[CH:7][C:6]=2[CH:26]=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][CH2:11][CH2:10][CH2:9][C:8]([C:22]([O:24][CH3:25])=[O:23])=[CH:7][C:6]=2[CH:26]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(Cc2ccc(OC)cc2)CCC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1=Cc2cc(Br)ccc2NCCC1
Temperature: 65 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a solution of methyl 8-bromo-1-(4-methoxybenzyl)-1,2,3,4-terahydro-1-benzoazocine-5-carboxylate (10.0 g), in toluene (50 ml) was added trifluoroacetic acid (50 ml), and the mixture was stirred at 65° C. for 2 hours. After distilling off the solvent under reduced pressure, water was added at 0° C. and the reaction mixture was neutralized with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution and saturated brine, after which it was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=9:1). The resulting solid was washed with hexane to give methyl 8-bromo-1,2,3,4-terahydro-1-benzoazocine-5-carboxylate (6.59 g) as yellow crystals.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.OC1C2N=NNC=2C=CC=1.[CH2:39]([S:46][CH:47]1[N:50]([CH2:51][C:52](O)=[O:53])[C:49](=[O:55])[CH2:48]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:52](=[O:53])[CH2:51][N:50]2[CH:47]([S:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:48][C:49]2=[O:55])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCCCCc1ccccc1
Reactant: O=C(O)CN1C(=O)CC1SCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CN1C(=O)CC1SCc1ccccc1)NCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of 6-phenylhexylamine (Morse M. A. et al., Cancer Research, 1991, 1846), (7.0 g, 40 mmol) in DMF (20 ml) was added to DCC (8.2 g, 40 mmol), hydroxybenzotriazole (5.3 g, 39 mmol) and (4-benzylthio-2-oxoazetidin-1-yl)acetic acid (10 g, 39 mmol) and the mixture stirred for 2 hours at room temperature. Ethyl acetate (250 ml) was added, the precipitate filtered, the filtrate washed with dil NaHCO3, water (×2), dried (MgSO4) and evaporated to an oil which was purified by flash chromatography on silica gel using hexane/ethyl acetate (1:1). Evaporation of the appropriate fractions followed by treatment with hexane gave a white solid (11.2 g, 70%), mp 65-70° C.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C@@H:20]([OH:32])[CH2:21][C@@H:22]([C:28]([OH:31])([CH3:30])[CH3:29])[C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.[CH2:40]([C@H:47]([CH2:51][C:52]([N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)=[O:53])C(O)=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>>[CH2:40]([C@H:47]([CH2:51][C:52]([N:54]1[CH2:55][CH2:56][O:57][CH2:58][CH2:59]1)=[O:53])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:33][CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)[C@@H:20]([OH:32])[CH2:21][C@@H:22]([C:28]([OH:31])([CH3:30])[CH3:29])[C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1)C(C)(C)O
Yield: 32 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 100 mg (0.176 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-ethylhexanamide [prepared as described in Example 14(a)], 50 mg (0.18 mmoles) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid, 0.28 ml (2 mmoles) of triethylamine, and 0.029 ml (0.18 mmoles) of diethyl cyanophosphate were used, to obtain 41 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18](=O)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3F)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.O.[NH2:35][NH2:36]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:19]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:36][N:35]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccccc1F)C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Solvent: O
Product: Fc1ccc(C(CCCN2CCC(c3n[nH]c4ccccc34)CC2)c2ccc(F)cc2)cc1
Yield: 47.4 %

Procedure:
A solution of 8.0 g of 1-[4,4-bis(4-fluorophenyl)-1-butyl]-4-(2-fluorobenzoyl)piperidine and 110 ml of hydrazine hydrate was heated at 150° in an autoclave for 20 hrs, with stirring. The resultant solid was diluted with water, and the mixture extracted with dichloromethane. The dichloromethane was evaporated in vacuo to yield a solid. The solid was recrystallized from toluene to give 3.8 g (47.4%) of product, mp 154°-156° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([N+:15]([O-])=O)[CH:3]=1.[H][H]>[Pd].C(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([NH2:15])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1Oc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: Nc1cc(F)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
The atmosphere over a stirred solution of 11,6 g (50 mmol) 4-fluoro-2-nitro-1-phenoxy-benzene and catalytic amount of palladium on carbon in 150 ml iso-propanol at 20° C. was saturated with hydrogen. The reaction mixture was stirred vigorously at 25° C. for 8 h. The reaction mixture was filtered over celite. The filtrate was evaporated. 200 ml water and 200 ml dichloromethane were added. The organic phase was separated. The aqueous phase was extracted three times with 100 ml dichloromethane each. The combined organic phases were washed with 50 ml water and 50 ml brine. The organic phase was dried with magnesium sulfate and evaporated. The crude product 1b was used without purification. The desired crude product 1b was obtained in 94% yield (9.54 g, 47 mmol) as yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:15])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.[ClH:23].O1CCOCC1>>[ClH:23].[ClH:23].[CH3:14][N:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:15])=[O:5])[CH2:13][CH2:12]1
Reactant: CN1CCN(CC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
tert-Butyl(4-methylpiperazin-1-yl)acetate (3.50 g, 16.3 mmol) was suspended in 4N hydrogen chloride/1,4-dioxane (35 mL) solution, trifluoroacetic acid (60 mL) was added to give a solution, and the solution was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, 4N hydrogen chloride/ethyl acetate (30 mL) was added to the obtained oily residue to give a suspension, and the suspension was stirred at room temperature for 2 hr. The obtained precipitate was collected by filtration, washed with ethyl acetate and diisopropyl ether on filter paper, and dried to give the title compound (3.33 g, 88%) as a colorless powder. The compound was used for the next reaction without further purification operation.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([Cl:10])[C:7]([OH:11])=[C:6](I)[CH:5]=1)(=[O:3])[CH3:2].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)(Cl)Cl.O1CCCC1.C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:4]1[N:9]=[C:8]([Cl:10])[C:7]([OH:11])=[C:6]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)c1cc(I)c(O)c(Cl)n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(C#C[Si](C)(C)C)c(O)c(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
6-Acetyl-2-chloro-3-hydroxy-4-iodo-pyridine (6.12 g, 20.6 mmole) was combined with trimethylsilyl acetylene (3.5 ml, 24.7 mmole), bis (triphenylphosphine) palladium dichloride (730 mg, 10 mmole) and cuprous iodide (99 mg, 0.52 mmole) in 37 ml of 2:1 chloroform/tetrahydrofuran in a 100 ml one neck round bottom flask under nitrogen. The suspension was treated with triethylamine (6 ml, 43 mmole) and the reaction was stirred for 2 h at room temperature. The mixture was diluted with 150 ml of ethyl acetate and was washed with 2×50 ml of 5% hydrochloric acid. The organics were dried over anhydrous magnesium sulfate, treated with 10 g of silica gel (230-400 mesh), and concentrated to dryness. The plug was chromatographed over 200 g of silica gel (230-400 mesh), eluting with 25% ethyl acetate/hexane+0.1% acetic acid, while collecting 50 ml fractions. Fractions 10-18 were combined and concentrated to give 4.88 g (88%) of 6-acetyl-2-chloro-3-hydroxy-4-(2-trimethylsilylethynyl)pyridine as a pale tan solid. 1H NMR (d6DMSO): δ 8 0.26 (s, 9), 2.51 (s, 3), 7.78 (s, 1) ppm.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[NH:10][NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(Cl)(Cl)Cl>[CH3:15][C:14]([N:10]1[C:11](=[O:12])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:13])[NH:9]1)=[O:16]
Reactant: O=c1[nH][nH]c(=O)n1-c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)n1[nH]c(=O)n(-c2ccccc2)c1=O
Yield: 54 %

Procedure:
To a suspension of 5.3 g (30 mmol) of 4-phenyl-1,2,4-triazolidine-3,5-dione in 175 ml of chloroform was added dropwise over a 15 minute period 45.9 g (450 mmol) of acetic anhydride with stirring. The reaction mixture was stirred at room temperature for five days. The reaction mixture was filtered to remove a white precipitate which was washed with 30 ml of chloroform to give 3.55 g (54.0%) of 1-methylcarbonyl-4-phenyl-1,2,4-triazolidine-3,5-dione as white solid, m.p. 215°-218.5° C. The filtrate was washed with three 100 ml portions of water and three 80 portions of 10% sodium carbonate. The carbonate washings were acidified with concentrated hydrochloric acid. No precipitate was formed. The chloroform solution was dried (Na2SO4) and evaporated under reduced pressure to give a liquid residue containing acetic anhydride. The filtered solid was recrystallized from 95% to ethanol to yield pure 1 -methylcarbonyl-4-phenyl-1,2,4-triazolidine-3,5-dione; m.p. 216.5°-218.5° C.; IR (Nujol) 1726, 1710, 1688 cm-1 (CO); 1H NMR (60 MHz, CDCl3)δ7.90 (s, 5H) 2.55(s, 3H). Found C, 54.5; H, 4.2: N, 19.4. C10H9N3O3 requires C, 54.8; H, 4.2; N, 19.4
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[CH:17]([F:19])[F:18].[Li]CCCC.CN([CH:28]=[O:29])C.[NH4+].[Cl-]>C1COCC1>[F:18][CH:17]([F:19])[C:3]1[CH:4]=[C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:15]=[CH:16][C:2]=1[CH:28]=[O:29]
Reactant: CN(C)C=O
Reactant: FC(F)c1cc(OCCN2CCOCC2)ccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCN2CCOCC2)cc1C(F)F
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a solution of 4-(2-(4-bromo-3-(difluoromethyl)phenoxy)ethyl)morpholine (123; 2.8 g, 8.38 mmol) in THF (90 mL) was added n-BuLi (1.6 M solution in hexanes, 7 mL, 11.2 mmol) at −78° C. The resulting reaction mixture was stirred at the same temperature for 1 h and DMF (1.24 g, 17 mmol) was added dropwise. After stirring the mixture at −78° C. for an additional 30 min, saturated aqueous NH4Cl was added and the mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography afforded 2-(difluoromethyl)-4-(2-morpholinoethoxy)benzaldehyde 124 (1.6 g, 67%) as a brown yellow oil.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][CH2:10][CH:11]=O)[CH2:7][CH2:6][N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH2:4][CH2:3]1.[C:23]1([C:29]2([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.B.N1C=CC=CC=1.CC(O)=O>ClCCCl.CCO>[OH:35][C:29]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:34][CH2:33][N:32]([CH2:11][CH2:10][CH2:9][N:8]2[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH2:6][CH2:7]2)[CH2:31][CH2:30]1
Reactant: O=CCCN1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reactant: OC1(c2ccccc2)CCNCC1
Agent: B
Solvent: ClCCCl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1CCN(c2cccc(C(F)(F)F)c2)CCN1CCCN1CCC(O)(c2ccccc2)CC1
Reaction time: 16 h
Yield: 42.1 %

Procedure:
To a solution of 3-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-propionaldehyde 0.016 g (0.05 mmol) and 4-phenyl-piperidin-4-ol 0.018 g (0.10 mmol) in DCE/EtOH 1:1 (0.5 ml) was added pyridine-borane complex (25 μL of 8 M solution in pyridine, 0.2 mmol) and AcOH (25 μL, 0.4 mmol) and the mixture stirred for 16 h. The mixture was then evaporated to dryness and purified by preparative HPLC, affording the title compound 0.01 g (44%) as a white solid. MS: 476.2 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[F:12])=O.[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][N:23]=1)[C:17]([O:19][CH3:20])=[O:18]>C(O)C>[F:12][C:6]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=1[C:3]1[N:13]=[C:14]2[CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[CH:21]=[CH:22][N:23]2[CH:2]=1
Reactant: COC(=O)c1ccnc(N)c1
Reactant: O=C(CBr)c1cc(F)ccc1F
Solvent: CCO
Product: COC(=O)c1ccn2cc(-c3cc(F)ccc3F)nc2c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 135.9 %

Procedure:
2-Bromo-1-(2,5-difluorophenyl)ethanone (1.5 g) was added to an ethanol (8.2 ml) solution of methyl 2-aminoisonicotinate (1.0 g), and the obtained mixture was then stirred in a nitrogen atmosphere at 60° C. for 18 hours. Thereafter, 2-bromo-1-(2,5-difluorophenyl)ethanone (0.77 g) was added to the reaction solution, and the obtained mixture was then stirred for 6 hours at the same temperature as described above. Thereafter, the reaction solution was concentrated under reduced pressure, and ethyl acetate (10 ml) was then added to the obtained residue. The precipitated solid was collected by filtration, and it was washed with ethyl acetate (15 ml) and heptane (6 ml) and was then dried, so as to obtain the title compound (2.5 g) in the form of a pink solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1.[C:17](O)([CH3:20])([CH3:19])[CH3:18].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:9])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: CC(C)(C)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reaction time: 96 h

Procedure:
Commercially available 2-nitro-terephthalic acid 4-methyl ester (4.84 g, 21.49 mmol) in DCM (54 mL) was treated with tert-butanol (4.05 mL, 42.99 mmol), di-tert-butyl dicarbonate (12.19 g, 55.87 g) and DMAP (0.79 g, 6.45 mmol). After 4 days at room temperature, the reaction was diluted with DCM (100 mL), washed with 1N HCl (100 mL), aqueous NaHCO3 and finally with water. After drying over sodium sulphate and evaporation of the volatiles, the title compound was obtained as a brownish oil in more than quantitative yield (6.51 g). The crude was employed in the following step with no further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8](Cl)[N:9]=2)[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:18]3[CH:19]=[CH:20][S:16][CH:17]=3)[N:9]=2)[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: OB(O)c1ccsc1
Reactant: COC(=O)c1sc2ncc(Cl)nc2c1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc2ncc(-c3ccsc3)nc2c1N
Temperature: 95 °C
Yield: 88 %

Procedure:
A solution of the methyl 7-amino-2-chloro-thieno[2,3-b]pyrazine-6-carboxylate prepared as described in Example 10C (0.190 g), thiophene-3-boronic acid (0.100 g), Pd(dppf)C12 (0.032 g) and triethylamine (0.22 mL) in degassed DMF was heated to 95° C. for 4 h, cooled, quenched in water and extracted with 1:1 Et2O/EtOAc (3×). The organics were washed 3× with water, brine, dried (Na2SO4), filtered and solvent evaporated to give 0.200 g (88%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.95 (3H, s), 6.23 (2H, br s), 7.50 (1H, dd), 7.79 (1H, dd), 8.05 (1H, dd), 9.00 (1H, s).