Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: N#CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: N#CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
4-Hydroxybenzyl cyanide (2.5 g, 18.77 mmol), benzyl bromide (3.8 g, 22.5 mmol) and potassium carbonate (45 mmol) were combined in acetone (50 mL) and heated to reflux for 8 h. The reaction was allowed to cool to rt, diluted with ethyl acetate and filtered to remove the solids. The organic layer was concentrated in vacuo to give an oil. The crude benzyl ether was purified by chromatography on silica gel eluting hexane: ethyl acetate (90:10, v:v) to give 4-benzyloxybenzyl cyanide (4.0 g, 95%) which solidified. MS (M+NH4)+ =241.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=1>C1COCC1.CO.O>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:15])=[N:20][CH:21]=1
Reactant: Clc1ccc(Br)cn1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.6 %

Procedure:
To a solution of [3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (500 mg, 2.41 mmol) in THF (5 mL) at room temperature was added sodium hydride (55% dispersion in mineral oil, 137 mg, 3.1 mmol) and the reaction mixture stirred at room temperature for 1 h. Then a solution of 2-chloro-5-bromo-pyridine (484 mg, 2.41 mmol) in THF (5 mL) was added at room temperature and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with methanol and water and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=9:1 to 4:1) afforded the title compound (128 mg, 15%) which was obtained as a colourless oil. MS: m/e=363.1/365.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])[CH:5]=[CH:6][CH:7]=1.[C:25](=[O:27])=[O:26]>C1COCC1>[OH:12]/[N:11]=[C:10](/[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)\[CH2:9][CH:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:25]([OH:27])=[O:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O/N=C(\CC(c1ccccc1)c1cccc(Br)c1)c1ccncc1
Reactant: O=C=O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(C(C/C(=N\O)c2ccncc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29 %

Procedure:
At −78° C., to a solution of (E)-3-(3-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (60 mg, example 12) in THF (1.5 mL) n-BuLi (1.6 M in hexane, 0.11 mL) was added dropwise. After stirring for 30 mins at that temperature carbon dioxide gas was bubbled into the solution for 5 min at −78° C. The reaction mixture was then warmed up to 0° C. and stirred for 15 min. The reaction was quenched by adding 1N aqueous KHSO4 solution, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Column chromatography on silica gel (CH2Cl2/MeOH 97:3) yielded 3-{3-[(E)-hydroxyimino]-1-phenyl-3-pyridin-4-yl-propyl}-benzoic acid (16 mg, 29%) as a yellow foam, MS (ESI+): m/z=347.1391 ([M+H]+).
Reaction SMILES: BrCCBr.[CH3:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Br:15])=[CH:10][CH:9]=1.S([C:27]#[N:28])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1.[Zn].Cl[Si](C)(C)C>[CH3:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Br:15])=[C:10]([C:27]#[N:28])[CH:9]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COC(=O)c1ccc(CBr)c(C#N)c1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 44.6 %

Procedure:
A suspension of zinc dust (792 mg, 12.12 mmol) and 1,2-dibromoethane (44 μL, 0.51 mmol) in THF (3 mL) was stirred at 70° C. for 10 minutes. The mixture was cooled to room temperature and chlorotrimethylsilane (45 μL, 0.36 mmol) was added. The mixture was cooled to 0° C. and a solution of methyl-4(bromomethyl)benzoate (2.314 g, 10.10 mmol) in THF (11 mL) was added at 0° C. over 2 hours and then stirred for an additional 2 hours at 0° C. The reaction mixture was cooled to −78° C. and a solution of tosyl cyanide (1.556 g, 8.59 mmol) in THF (11 mL) was added and the resultant mixture stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, diluted with CH2Cl2 (100 mL) and saturated aqueous NaHCO3 (15 mL) and filtered. The phases were separated and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (Hexanes/EtOAc, 10:1) afforded the desired nitrile (973 mg) as a 16:1 mixture (desired product/side product).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:14])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.Br[CH:22]([CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:23](Cl)=[O:24].C1(CC(Cl)=O)CCCC1>ClCCl>[CH:26]1([C:22]2[N:3]3[C:4]([CH3:14])=[N:5][N:6]=[C:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]3=[N:1][C:23]=2[OH:24])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(Cl)C(Br)C1CCCC1
Reactant: Cc1nnc(-c2ccccc2)c(N)n1
Agent: O=C(Cl)CC1CCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nnc(-c2ccccc2)c2nc(O)c(C3CCCC3)n12
Temperature: 120 °C

Procedure:
To a solution of 5-amino-3-methyl-6-phenyl-[1,2,4]triazine (0.2 g, 1.07 mmol) in dichloromethane (20 ml) was added pyridine (0.104 ml, 1.28 mmol) followed by dropwise addition of 2-bromo-2-cyclopentylacetyl chloride (0.266 ml, 1.18 mmol; prepared from cyclopentylacetyl chloride by the method of Gleason, Tetrahedron Lett., 1970, 39, 3431). The reaction mixture was stirred for 18 h after which time the dichloromethane was evaporated in vacuo. The residue was dissolved in t-butanol (20 ml) to which was added triethylamine (1 ml) and sodium iodide (0.010 g) and the resultant mixture was heated at 120° C. for 18 h. The n-butanol was evaporated in vacuo and the residue was purified by flash chromatography (SiO2; 60% EtOAc in hexanes) to afford the title compound (0.178 g). δH (400 MHz; d6-DMSO) 1.40-2.20 (8H, m), 2.71 (3H, s), 3.65 (1H, m), 7.49 (3H, m), 8.05 (2H, m). m/z (ES+) 295 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB(/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])O1>C(#N)C.CCO.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>[C:11]([O:10][C:9]([NH:8][C:6]1[CH:7]=[C:2](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:3]=[CH:4][C:5]=1[Cl:16])=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccc1Cl
Reactant: CCOC(=O)/C=C/B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)/C=C/c1ccc(Cl)c(NC(=O)OC(C)(C)C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 5-bromo-2-chlorophenylcarbamate (1) (1.0 equiv.) in acetonitrile (0.3M) and EtOH (0.5M) was added K2CO3 (2.0 equiv.). The reaction was degassed and flushed with N2, then added (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (2) (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.). The reaction was flushed again with N2 and stirred at 100° C. overnight. After cooling to room temperature, hexane was added, and the mixture was filtered through a pad of silica, eluting with EA/Hex (1:1) until the product was completely eluted. The filtrate was concentrated and purified on Combiflash, eluting with 0-15% EA in Hex to give (E)-ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)acrylate (3) as a white solid.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[CH2:27][CH3:28]>CN(C=O)C>[CH2:27]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:21]=1[CH2:20][S:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[N:3]=1)[CH3:28]
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Reactant: CCc1cnccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cnccc1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (1.56 g, 8.0 mmol) was dissolved in anhydrous DMF (50 mL), and then potassium carbonate (3.3 g, 23.9 mmol) and 4-(bromomethyl)-3-ethylpyridine (10.3 mmol) in DMF (10 mL) were added. The reaction mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 3-12% DCM/MeOH to afford 2-{[(3-ethylpyridin-4-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (357 mg, 14% yield for 3 steps); 1H NMR (500 MHz, DMSO-d6): δ 1.21 (t, J=7.5 Hz, 3H), 2.75 (q, J=7.5 Hz, 2H), 4.46 (s, 2H), 6.65 (s, 1H), 7.41 (d, J=5.1 Hz, 1H), 8.34 (d, J=5.0 Hz, 1H), 8.42 (s, 1H); LRMS (ES+) m/z 316 (100%, M+1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: Cc1cccc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1-c1ncccn1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: Cc1cccc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)c1-c1ncccn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A298 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 471 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].CC[O-].[Na+].[CH:14]([CH:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH2:15].Cl>CC(C)=O.COCCO.C(O)CO>[OH:1][CH2:2][CH2:3][N:4]([CH:16]([CH:14]=[CH2:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: C=CC(Cl)c1ccccc1
Reactant: O=C(O)CCNCCO
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: OCCO
Solvent: CC(C)=O
Solvent: COCCO
Product: C=CC(c1ccccc1)N(CCO)CCC(=O)O
Reaction time: 2 h

Procedure:
Into the flask as in Example 1, N-(2-hydroxyethyl)-β-alanine (117 parts), sodium ethylate (68 parts), ethylene glycol (300 parts) and ethylene glycol monomethyl ether (150 parts) are charged, and the resultant mixture is heated at 100° C. under stirring. A mixture of vinylbenzyl chloride (152 parts) and ethylene glycol monomethyl ether (100 parts) is dropwise added thereto in 2 hours. Stirring under heating is further continued for 6 hours. The reaction mixture is neutralized with hydrochloric acid, and acetone is added thereto to precipitate a white solid substance. The white solid substance is collected by filtration and dried under reduced pressure to give N-(2-hydroxyethyl)-N-(vinylbenzyl)-β-alanine (191 parts) of the formula: ##STR21## of which the NMR chart is shown in FIG. 8.
Reaction SMILES: I[CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:7][C:8]1[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][CH:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:9]=1
Reactant: IC1CCCC1
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1cccc(SC2CCCC2)c1
Reaction time: 1.5 h

Procedure:
Iodocyclopentane (3.93 ml) was added to a mixture of 3-bromobenzenethiol and potassium carbonate (5.4 g) in acetone (50 ml) and the reaction was stirred under nitrogen for 1.5 h. A further portion of iodocyclopentane (2 ml) was added and the mixture was stirred for 1 h. The solvent was evaporated and the residue was partitioned between water and EtOAc. he combined organic extracts were washed with NaOH (2N), brine and dried (Na2SO4). The resulting oil was purified using biotage™ chromatography on silica using cyclohexane as eluant to give the title compound (3.6 g). LCMS RT=4.1 min
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[O:6])[CH2:2]1.[F:27][C:28]1[N:29]=[N:30][C:31](F)=[CH:32][CH:33]=1.ClC1N=NC(Cl)=CC=1>>[F:27][C:28]1[N:29]=[N:30][C:31]([N:1]2[CH2:4][CH:3]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([CH:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]4)=[CH:10][CH:9]=3)=[O:6])[CH2:2]2)=[CH:32][CH:33]=1
Reactant: Fc1ccc(F)nn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)C3CNC3)cc2)CC1
Agent: Clc1ccc(Cl)nn1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)C3CN(c4ccc(F)nn4)C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 147A, substituting tert-butyl 4-(4-(azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate for tert-butyl 4-(4-(azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate and 3,6-difluoropyridazine for 3,6-dichloropyridazine.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:33][CH2:34][O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=O)=O.C(OCC)(=O)C>CN(C=O)C>[C:36]([O:35][CH2:34][CH2:33][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OCCOS(C)(=O)=O
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 70 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 2-tert-butoxyethyl methanesulfonate (0.218 g, 1.11 mmol) in DMF (5.3 mL). Heat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+384.2 (M+H)+, HRMS calcd for C22H30N3O3 384.2287 (M+H)+, found 384.2276, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=10.5 min, 97.7% purity.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20].[H-].[Na+]>CN(C=O)C>[Cl:11][C:9]1[C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[N:10]=1
Reactant: NC(=O)c1cc(C2CC2)c(Cl)nc1Cl
Reactant: CC(=O)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)CCCOc1nc(Cl)c(C2CC2)cc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
To a mixture of 2,6-dichloro-5-cyclopropylnicotinamide (2.00 g, 8.66 mmol) and 5-hydroxypentan-2-one (883 mg, 8.66 mmol) in DMF (30 mL) was added and NaH (416 mg, 10.4 mmol) in portions at 0° C. The mixture was stirred at r.t. overnight, quenched by water, extracted by EtOAc. The separated organics was dried, concentrated and purified by column chromatography (Petroleum ether:EtOAc=10:1-1:1) to give 6-chloro-5-cyclopropyl-2-(4-oxopentyloxy)nicotinamide (500 mg, 19.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[CH3:24])=[CH:18]/[C:19](OCC)=[O:20])=[CH:13][CH:12]=1.CC(C[AlH]CC(C)C)C>>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:11]1[CH:12]=[CH:13][C:14](/[C:17](/[CH3:24])=[CH:18]/[CH2:19][OH:20])=[CH:15][CH:16]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2c(OC)cccc2OC)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: COc1cccc(OC)c1-c1ccc(/C(C)=C/CO)cc1

Procedure:
(E)-Ethyl 3-(2′,6′-dimethoxy-biphenyl-4-yl)-but-2-enoate (0.90 g, 2.76 mmol) was reduced with DIBAL-H by a procedure analogous to that described in example 52b to give (E)-3-(2′,6′-dimethoxy-biphenyl-4-yl)-but-2-en-1-ol as a colourless solid; 0.82 g (100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH3:17])[C:15]([C:18]#[N:19])=[CH:14][C:13]=3[CH3:20])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:21])[O:3]1.[Br:23]N1C(=O)CCC1=O.N1C=CC=CC=1.O>C1COCC1>[CH3:1][C:2]1([CH3:22])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH3:17])[C:15]([C:18]#[N:19])=[C:14]([Br:23])[C:13]=3[CH3:20])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:21])[O:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C#N)n(C)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Br)c(C#N)n(C)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Reaction time: 16 h

Procedure:
To a solution of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,4-dimethyl-1H-pyrrole-2-carbonitrile (1 eq, 0.15 g, 0.51 mmol) in THF (5 mL) at −78° C. was added N-bromosuccinimide (1.1 eq, 0.1 g, 0.56 mmol). The solution was allowed to warm and stir for 16 hours. Pyridine (1 mL) was added and the mixture was poured into water (15 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (3×10 mL) and the combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The product, 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-bromo-1,4-dimethyl-1H-pyrrole-2-carbonitrile was obtained by crystallization from 20% ethyl acetate/hexane as a white crystalline solid. 1H NMR (300 MHz, d6-DMSO) δ 1.64 (s, 6H), 1.93 (s, 3H), 3.57 (s, 3H), 7.01 (d, 1H, J=8 Hz), 7.31 (dd, 1H, J=1.95, 8 Hz), 7.35 (s, 1H), 10.43 (s, 1H). MS m/z (ESI (−)) 372/374 (M−H)−. Anal. calcd for C17H16N3O2, C, 54.6, H, 4.31, N, 11.2. Found, C, 54.8, H, 4.42, N, 11.1.
Reaction SMILES: [NH2:1][C:2](=[NH:15])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O=[C:17]1[CH2:22][CH2:21][O:20][CH2:19][CH:18]1[C:23](OC)=[O:24].C(=O)([O-])[O-].[K+].[K+]>CO>[O:24]=[C:23]1[NH:1][C:2]([CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:15][C:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]1=2
Reactant: COC(=O)C1COCCC1=O
Reactant: N=C(N)CNC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(NCc1nc2c(c(=O)[nH]1)COCC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.5 %

Procedure:
To benzyl 2-amino-2-iminoethylcarbamate (1.77 g, 8.54 mmol) in methanol (67.5 mL) was added methyl 4-oxotetrahydro-2H-pyran-3-carboxylate (1.35 g, 8.54 mmol) and potassium carbonate (3.54 g, 25.6 mmol). The reaction mixture was stirred 15 h at room temperature. The solution was filtered and concentrated under vacuum. Purification was accomplished on a 100 g Isco column with 0% to 10% methanol in dichloromethane over 20 column volumes to give title compound (1.63 g, 59% yield). Exact mass calculated for C16H17N3O4 315.3. found 316.2 (ESI, M+H); 1H NMR (400 MHz, MeOD) δ ppm 7.17-7.46 (m, 5H) 5.11 (s, 2H) 4.47 (br. s., 2H) 4.22 (s, 2H) 3.92 (t, J=5.31 Hz, 2H) 2.65 (br. s., 2H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][S:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([S:13][CH2:14][CH2:15][C:16]#[N:17])=[CH:8][C:7]=1[NH2:18])#[N:2].[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].O>CN1C(=O)CCC1>[C:1]([CH2:3][CH2:4][S:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([S:13][CH2:14][CH2:15][C:16]#[N:17])=[CH:8][C:7]=1[NH:18][C:26](=[O:27])[C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=1)#[N:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: N#CCCSc1cc(N)c(SCCC#N)cc1N
Solvent: CN1CCCC1=O
Solvent: O
Product: N#CCCSc1cc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(SCCC#N)cc1N
Reaction time: 0.17 h
Yield: 61.3 %

Procedure:
2,5-Bis[(cyanoethyl)thio]-1,4-phenylenediamine (13.9 g, 50 mmol) was dissolved in 90 mL of NMP in a 250 mL 3-necked round-bottom flask under nitrogen purge. The resultant clear red solution was cooled to 0˜5° C. in an ice bath, followed by addition of freshly distilled triethylamine (TEA) by syringe. After stirring for 10 minutes, a mixture of 4-nitrobenzoyl chloride (10.2 g, 55 mmol) and 90 mL of NMP was added into the stirred red solution drop by drop over a period of 0.5 h. The resultant solution was stirred at 0˜5° C. for 2 h and at room temperature for 1 h, followed by addition of 800 mL of water with stirring. The resultant yellow precipitate was collected by filtration, followed by washing with 800 mL of deionized water twice and 300 mL of methanol once. The obtained product was extracted with methanol using a Soxhlet extractor for 24 h. A yellow solution was collected and evaporated, followed by drying at 60° C. under vacuum overnight, giving the title compound as a red powder (13.1 g, yield 61%).
Reaction SMILES: [C:1]([NH2:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:23](O)(=O)C.[CH2:27]([O:34][P:35]([O-:44])[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:1]([NH:20][CH2:23][P:35](=[O:44])([O:34][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: CC(=O)O
Agent: C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=P(CNC(c1ccccc1)(c1ccccc1)c1ccccc1)(OCc1ccccc1)OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 1.00 g tritylamin in 20 ml of toluene is combined with 127 mg paraformaldehyde and 50 μl acetic acid and stirred for one hour at 80° C. Then 0.85 ml dibenzylphosphite are added and the reaction mixture is refluxed for three hours. Then 200 μl triethylamine are added and the reaction mixture is evaporated down in vacuo using the rotary evaporator. The flask residue is chromatographed through a silica gel column.