Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.[CH2:23]([O:30][CH2:31][C:32]1([C:36]2[CH:41]=[CH:40][C:39](Br)=[CH:38][CH:37]=2)[CH2:35][O:34][CH2:33]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C(O)C>[CH2:23]([O:30][CH2:31][C:32]1([C:36]2[CH:41]=[CH:40][C:39]([C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][C:2]=3[Cl:1])[NH:8][CH:7]=[C:6]4[C:11]([O:13][CH3:14])=[O:12])=[CH:38][CH:37]=2)[CH2:33][O:34][CH2:35]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Reactant: Brc1ccc(C2(COCc3ccccc3)COC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(COCc5ccccc5)COC4)cc3)cc12
Temperature: 25 °C
Yield: 62.1 %

Procedure:
A mixture of methyl 6-Chloro-5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-1H-indole-3-carboxylate (241 mg, 0.75 mmol), 3-Benzyloxymethyl-3-(4-bromo-phenyl)-oxetane (250 mg, 0.75 mmol), 2M aqueous potassium carbonate (1.51 mL, 3 mmol), toluene (9 mL), and ethanol (3 mL) was sparged with N2 for 10 minutes, then treated with [1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (29 mg, 0.035 mmol). The reaction mixture was heated to 100 degrees and stirred. After 2 hours the reaction was cooled to room temperature, diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a brown oil, which was purified by flash chromatography (40 g silica, 10-60% ethyl acetate/heptane, 17 column volumes). Product fractions were combined and concentrated in vacuo to afford the title compound as a colorless solid (215 mg, 62% yield). MS (ES+) 462 (M+H)+; 1H NMR (500 MHz, CD3OD) δ ppm 8.04 (s, 1 H), 8.02 (s, 1 H), 7.99 (s, 1 H), 7.43-7.57 (m, 4 H), 7.23-7.34 (m, 5 H), 4.90-5.01 (m, 4 H), 4.58 (s, 2 H), 3.90 (s, 3 H), 3.88 (s, 2 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4]C(=O)C.C(N(CC)CC)C.[CH3:15][S:16]([Cl:19])(=[O:18])=[O:17]>ClCCl>[ClH:19].[NH2:1][CH2:2][CH2:3][NH:4][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: CC(=O)NCCN
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCN
Product: Cl
Temperature: 110 °C
Reaction time: 3 h

Procedure:
40 g (0.392 mol) of N-(2-aminoethyl)acetamide and 59.4 g (0.587 mol) of triethylamine were dissolved in 600 ml of dichloromethane. The solution was cooled down to 0 . . . +5° C. after which 67.2 g (0.587 mol) of methanesulfonyl chloride was added during a period of 1-1.5 h under continuous stirring, while keeping the temperature not higher than +5° C. during the addition. When the addition was finished the reaction mixture was stirred for another 3 hours while the temperature was allowed to rise to room temperature. After the reaction was completed the reaction mixture was evaporated to dryness. Dichloromethane saturated with ammonia (2000 ml) was added to the evaporation residue and the mixture was triturated for 15-30 min at room temperature. The formed precipitate was filtered off and the filtrate was evaporated to dryness. The evaporation residue was dissolved in 6 M hydrochloric acid (980 ml). The solution was heated to reflux (approx. 110° C.) and stirred at this temperature for 2 h. When the reaction was finished the reaction mixture was allowed to cool down to 60° C. and then evaporated to dryness under reduced pressure. The evaporation residue was dissolved in 460 ml of methanol and then again evaporated to dryness to remove traces of water. The residue was dissolved in another 460 ml of methanol after which 3 g of −activated carbon (Norit® SX1) was added. The mixture was stirred for 15 min at 30° C., and filtered. The methanol solution was concentrated to about one third of the original mass. The crystallization was initiated by adding 85 ml of dichloromethane during 1 h under constant stirring. The solution was seeded by adding approximately 200 mg of seeding material N-(2-aminoethyl)methanesulfonamide hydrochloride. The solution was stirred for 15 min after which slow dichloromethane addition (1600 ml) was continued over a period of 6 hours under constant stirring. The mixture was cooled to 5° C. and stirred at this temperature for another 3 hours. The crystals were filtered and washed with 2×70 ml of cold acetone. The product was dried under vacuum at 30° C. overnight. The yield was typically in the range of 70-80%.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]Br.[S:8]([O-:11])([O-:10])=[O:9].[Na+:12].[Na+].C(O)C.BrCCS([O-])(=O)=O.[Na+]>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:8]([O-:11])(=[O:10])=[O:9].[Na+:12]
Reactant: BrCCCCCBr
Reactant: O=S([O-])[O-]
Agent: O=S(=O)([O-])CCBr
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCCCCBr

Procedure:
1,5-Dibromopentane (16.4 g, 71 mmol), sodium sulfite (3 g, 24 mmol), ethanol (25 mL) and water (20 mL) were reacted and worked up analogously to sodium 2-bromoethane sulfonate. Yield: 7.4 g (41%) colorless solid. IR (ATR): {tilde over (ν)}=3485 (m), 3411 (w), 2978 (w), 2930 (m), 2908 (w), 2895 (w), 2867 (w), 2851 (w), 1636 (w), 1616 (w), 1487 (w), 1466 (m), 1410 (w), 1390 (w), 1329 (w), 1314 (w), 1293 (w), 1262 (w), 1224 (m), 1207 (s), 1180 (s), 1044 (s), 988 (w), 938 (w), 823 (w), 804 (w), 792 (w), 729 (w), 618 cm−1 (w). HRMS (ESI) (C5H11BrNaO3S+): calculated 252.9504. found 252.9820, Δ=31.6 mmu.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>CS(C)=O.CCOCC>[CH3:9][O:10][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: COc1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 92.4 %

Procedure:
To a solution of 2,5-dibromopyridine (20 g, 84 mmol) in DMSO (84 mL) is added (25 wt %) sodium methoxide (21.2 mL, 93 mmol). The resulting solution is heated to 80° C. and stirred for 45 min then cooled to 20° C., diluted with ether, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 10% ether in hexanes) to give 14.6 g of title compound as a colorless oil. 1H NMR (CDCl3) δ 3.90 (s, 3H), 6.66 (d, J=9 Hz, 1H), 7.63 (dd, J=9, 3 Hz, 1H), 8.20 (d, J=3 Hz, 1H). MS (EI) m/z 187/189 (M+, Br).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][OH:5].BrCCC.[OH-].[Na+].[CH2:13]([C:15](C)=[O:16])[CH3:14]>[Cl-].[Na+].O>[CH2:15]([O:16][CH:4]([OH:5])[CH2:3][CH2:2][CH3:1])[CH2:13][CH3:14]
Reactant: CCC(C)=O
Reactant: OCCCCO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCBr
Solvent: O
Product: CCCOC(O)CCC
Temperature: 130 °C
Yield: 46.5 %

Procedure:
"PPAE-2" was prepared from the alkylation of 1,4-butane diol (1.25 kg, 13.9 moles) with bromopropane (0.5 kg, 4.1 moles) by addition of 50 wt-% sodium hydroxide (1 kg, 12.6 moles NaOH) at 65° C. and heating at 130° C. for two hours. The reaction mixture was cooled and methyl ethyl ketone (0.5 kg) and a 10 wt-% brine solution (1.1 kg) was added. Top phase (1.57 kg) was further washed with an additional 10 wt-% brine solution (1.1 kg). Top phase (940 g) was vacuum distilled to yield propoxybutanol (426 g, 86% yield), b.p. 112-118° C./14mm. Acetic anhydride (460 g) was added to the alcohol at 120° C. over one hour and heated at 130° C. for an additional hour. Acetic acid and excess acetic anhydride were distilled out to yield propoxy butyrate (585 g, 95% yield). The butyrate was fluorinated in perfluoromethyl morpholine using a tubular reactor described in U.S. Pat. No. 5,488,142 (Fall). After fluorination, excess methanol was added to provide methyl- 4-perfluoro-propoxybutyl acetate (604 g, 68% yield), b.p. 120-130° C. Saponification and decarboxylation was carried out by adding to the ester, sodium carbonate (23 g) and titration with sodium hydroxide (61 g) in methanol (380 g). Methanol was then removed after addition of"FC-71 FLUORINERT" electronic liquid, available from the 3M Co., St. Paul, Minn. (1.3 kg) under reduced pressure. The mixture was then heated up to 250° C. to yield perfluoropropoxyallyl ether (375 g, 75% yield), b.p. 58-62° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[C:6](Cl)[N:7]=1.[F:10][C:11]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[C:6]([NH:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:11]=2[F:10])[N:7]=1
Reactant: NCc1cccc(F)c1F
Reactant: Clc1nnc(Cl)c(Cl)n1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Fc1cccc(CNc2nc(Cl)nnc2Cl)c1F
Temperature: 25 °C

Procedure:
3,5,6-Trichloro-1,2,4-triazine (520 mg, 2.8 mmol) was dissolved in 5 mL NMP. To it was added 2,3-difluorobenzylamine (0.36 mL, 3.1 mmol) and DIEA (0.54 mL, 3.1 mmol). The mixture was stirred at RT for 20 m. It was diluted with EtOAc, washed with brine twice, dried over MgSO4, concentrated in vacuo, and subjected to flash column to afford 3,6-dichloro-N-(2,3-difluorobenzyl)-1,2,4-triazin-5-amine.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH:15]1([CH2:14][O:12][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]3)[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: Cc1ccc2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc2cccc(OCC3CC3)c2n1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A solution of 2-methylquinolin-8-ol (10.0 g, 62.82 mmol), (bromomethyl)cyclopropane (17.0 g, 125.6 mmol), and K2CO3 (17.80 g, 128.8 mmol) in acetone (50 mL) in a sealed flask was stirred at 88° C. for 2 days. After cooling to ambient temperature, the acetone was removed under reduced pressure. DCM (100 mL) and water (50 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM) to give 8-(cyclopropylmethoxy)-2-methylquinoline (13.2 g, 98.5%) as a solid.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:30]([O:34][C:35]([NH:37][C:38]1[S:42][C:41]([C:43]2[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:44]=2[F:50])=[N:40][C:39]=1[C:51](O)=[O:52])=[O:36])([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:51]([C:39]3[N:40]=[C:41]([C:43]4[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:44]=4[F:50])[S:42][C:38]=3[NH:37][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])=[O:52])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)sc1NC(=O)OC(C)(C)C)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (13.0 mg, 0.032 mmol), 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (13.7 mg, 0.040 mmol), HATU (30.5 mg, 0.080 mmol) in DMF (0.09 mL) and DIPEA (12.5 mg, 0.096 mmol) was stirred at room temperature for 16 h. The reaction mixture was diluted with MeOH and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a white powder (12.4 mg, 52%). LCMS calc. for C36H45F2N6O7S (M+H)+: m/z=743.3. Found: 743.3.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[N:6]=1.[C:19]([N:27]1[CH2:32][CH2:31][CH2:30][C:29]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=2)([CH2:33][CH2:34][CH2:35]OS(C)(=O)=O)[CH2:28]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].[ClH:55]>CN(C=O)C.C(#N)C>[OH2:26].[ClH:47].[ClH:55].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([CH2:35][CH2:34][CH2:33][C:29]3([C:41]4[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=4)[CH2:30][CH2:31][CH2:32][N:27]([C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:28]3)[CH2:11][CH2:12]2)[N:6]=1
Reactant: Nc1nc(C2(c3ccccc3)CCNCC2)cs1
Reactant: CS(=O)(=O)OCCCC1(c2ccc(Cl)c(Cl)c2)CCCN(C(=O)c2ccccc2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Nc1nc(C2(c3ccccc3)CCN(CCCC3(c4ccc(Cl)c(Cl)c4)CCCN(C(=O)c4ccccc4)C3)CC2)cs1
Product: O

Procedure:
A mixture of 1.04 g of 4-(2-aminothiazol-4-yl)-4-phenylpiperidine (compound of PREPARATION 1.4 in the form of the free base), 1.88 g of the compound obtained in step B of EXAMPLE 1 and 1.1 g of K2CO3 in 20 ml of a DMF/acetonitrile mixture (50/50; v/v) is refluxed for 2 hours. The reaction mixture is concentrated under vacuum, the residue is taken up with water and extracted with AcOEt, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a gradient of a DCM/MeOH mixture (98/2; v/v to 95/5; v/v) as the eluent. The product obtained is taken up with ethereal hydrogen chloride and the precipitate formed is filtered off to give 1.2 g of the expected product after crystallization from AcOEt, m.p.=162-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:10]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[O:9])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:29].[N+:35]([O-:38])([OH:37])=[O:36]>C(Cl)Cl.CCOCC>[N+:35]([O-:38])([O-:37])=[O:36].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:10]([N+:19]2[CH:23]=[CH:22][NH:21][CH:20]=2)[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])(=[O:29])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S(c1ccc(Cl)cc1)C(c1ccc(Cl)cc1Cl)n1ccnc1
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1ccc(Cl)cc1Cl)[n+]1cc[nH]c1
Product: O=[N+]([O-])[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5 g (0.013 mole) of 1[α-(4-chlorophenylsulfinyl)-2,4-dichlorobenzyl]imidazole dissolved in 50 ml of methylene chloride is added 2.7 g (0.013 mole) of m-chloroperoxybenzoic acid in small portions at 0°. The reaction mixture is stirred at room temperature overnight. Concentrated nitric acid is added dropwise until the solution becomes acidic. When the reaction mixture is diluted with anhydrous ether, a white precipitate forms which is collected by filtration to give 4 g of desired product, mp 149°-9° (dec.).
Reaction SMILES: [H-].[Na+].CCCCCC.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:14][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (50% w/w dispersion in mineral oil, 3.7 g) was treated under argon with repeated washes of hexane. The oil-free residue was suspended in dry DMF (100 ml) and 4-hydroxyphenylacetic acid (13.0 g) was added portionwise to the stirred cooled (4° C.) mixture. After 30 minutes, benzyl bromide (9.2 ml) was added dropwise and, after a further 1 hour at 4° C., stirring was continued overnight at ambient temperature. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The aqueous phase was re-extracted with further ethyl acetate and the combined organic extracts washed with water and brine, then dried (MgSO4) and evaporated. The crystalline residue gave benzyl 4-hydroxyphenylacetate, 17.8 g, as off-white crystals: m.p. 70°-72° C.; NMR (CDCl3) δ 7.32(5H, m), 7.14(2H, d), 6.76(2H, d), 5.12(2H, s), 3.59(2H, s); m/e 242 (M°)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Mg].[C:16](OC(=O)C)(=[O:18])[CH3:17].[Cl-].[NH4+]>CCOCC>[C:9]1([CH2:8][CH2:7][O:6][CH2:5][CH2:4][CH2:3][CH2:2][C:16](=[O:18])[CH3:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCCCCOCCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)CCCCOCCc1ccccc1
Temperature: 25 °C
Yield: 88 %

Procedure:
[2-(4-Bromobutoxy)ethyl]benzene (10.0 g) in dry ether (80 ml) was added dropwise to magnesium turnings (0.946 g) under nitrogen with stirring to give a gentle reflux. The reaction mixture was refluxed for 1 h, allowed to cool to room temperature and added dropwise to acetic anhydride (8.07 g) in dry ether (55 ml) at -70° under nitrogen with stirring over 1.5 h. The reaction mixture was stirred at -70° for 2 h, allowed to warm to -10° , then treated with saturated ammonium chloride (100 ml). The organic layer was separated and the aqueous layer re-extracted with ER (150 ml). The combined organic extracts were washed with 2N aqueous sodium hydroxide (150 ml), brine (150 ml), dried and evaporated to give an oil (7.54 g) which was purified by FCC eluting with ER-CX (1:3) to give the title compound as a colourless oil (4.34 g). T.l.c. (ER-CX 1:3) Rf 0.25.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc(F)cc1

Procedure:
p-Fluorophenylacetic acid (20 g) was stirred with thionyl chloride (30 ml) at room temperature for 5 hours. The excess of thionyl chloride was then removed under reduced pressure. The remaining oil was dissolved in toluene, and the toluene then removed under reduced pressure. The remaining oil was distilled (b.p. 41°-42°/0.1 mm) to give p-fluorophenylacetyl chloride (19.74 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[N:7]([CH:12]([CH3:14])[CH3:13])[CH2:8][C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.CCN(C(C)C)C(C)C.Cl.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1>C(#N)CC>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([N:42]2[CH2:47][CH2:46][N:45]([CH2:2][C:3]3[CH:16]=[N:15][C:6]4[N:7]([CH:12]([CH3:14])[CH3:13])[CH2:8][C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:44][CH2:43]2)=[CH:40][CH:41]=1
Reactant: CC(C)N1CC(=O)Nc2cc(CO)cnc21
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CC(=O)Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 25.8 %

Procedure:
The 7-(hydroxymethyl)-4-isopropyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (100 mg, 0.452 mmol) was weighed into a vial and taken up as a suspension in propiononitrile (1 mL). Next was added (cyanomethyl)trimethylphosphonium iodide (132 mg, 0.542 mmol) followed by DIEA (0.237 mL, 1.356 mmol). To the stirred white suspension was then added the 1-(4-chlorophenyl)piperazine hydrochloride (116 mg, 0.50 mmol). The reaction was stirred overnight at 90° C. The crude reaction was cooled to room temperature and concentrated to a residue, then taken up in DMSO (3 mL) and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (46.6 mg, 26%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.49 (s, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.21 (d, J=9.1 Hz, 2H), 6.97 (d, J=1.8 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 4.74-4.87 (m, 1H), 3.81 (s, 2H), 3.33 (d, J=2.0 Hz, 2H), 3.01-3.15 (m, 4H), 2.41-2.48 (m, 4H), 1.12 (d, J=6.8 Hz, 6H). [M+H] calc'd for C, 21; H, 26; ClN, 5; O, 400; found, 400.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:56][CH:57]4[CH2:62][CH2:61][O:60][CH2:59][CH2:58]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: NC1CCOCC1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (83 mg, 0.25 mmol) and TBTU (90 mg, 0.28 mmol) in DMF (3.0 mL) was added DIPEA (217 μL, 1.26 mmol). Then 4-aminotetrahydropyran (28 mg, 0.28 mmol) was added and the mixture was stirred at room temperature under Ar for 30 min. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (100 mg, 96%) as a white solid. MS: m/e=412.3 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[O:9])[CH2:24][CH2:25]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3cnccn3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.7 %

Procedure:
0.28 g of 2-pyrazinecarboxylic acid (2.26 mmol) and 0.78 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (2.27 mmol) were dissolved in 30 ml of dichloromethane. Addition of 1.19 g of diisopropylethylamine (9.26 mmol), 0.155 g of hydroxybenzotriazole (HOBt, 1.15 mmol), and 0.487 g of N-ethyl-N′-(3-dimethyl-aminopropyl)-carbodiimide hydrochloride (EDCl, 2.54 mmol) at 0° C. was followed by stirring for 16 h at room temperature. After the addition of 0.24 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride the mixture was stirred for further 4 h. 50 ml of dichloromethane were added. The organic layer was washed with water and saturated aqueous sodium chloride. The dichloromethane phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate and ethyl acetate-methanol (5%). Evaporation of the solvent yielded 0.568 g of the title compound as a white solid.