Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]4)[N:12]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:28](#[N:31])[CH:29]=[CH2:30].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:26][C:20]1([CH3:27])[CH2:19][CH:18]([NH:17][C:13]2[N:12]=[C:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2](/[CH:30]=[CH:29]/[C:28]#[N:31])=[CH:3][CH:4]=4)[NH:8][CH:7]=3)[CH:16]=[CH:15][N:14]=2)[CH2:23][C:22]([CH3:24])([CH3:25])[NH:21]1
Reactant: C=CC#N
Reactant: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(Cl)ccc34)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(/C=C/C#N)ccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared by the general Heck procedure described in Example 256, using the SEM-protected intermediate of Example 229 and acrylonitrile, followed by TBAF deprotection of the SEM group.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:25])=O>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C:10]([Cl:25])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)Cl

Procedure:
(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid (I) is dissolved in THF and stirred at 20-250. Oxalyl chloride (1 equivalent) is added and the mixture stirred for about 15 min to give t-butyl-(1S)-2-chloro-1-[3,5-difluorobenzyl]-2-oxoethylcarbamate (XI). The mixture is cooled to <0° and LiCHICl (greater than 2 equivalents) is added. The mixture is stirred until the reaction is complete. The reaction is quenched with water and the product is extracted into ethyl acetate. The combined organic phases are washed with saline, dried over sodium sulfate and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]([C:17]1[CH:18]=[CH:19][N:20]2[C:25]=1[C:24](=[O:26])[N:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]([CH:34](OS(C)(=O)=O)[CH2:35][CH3:36])=[N:21]2)=[O:16].C(N(CC)CC)C>CN(C=O)C>[CH3:13][O:14][C:15]([C:17]1[CH:18]=[CH:19][N:20]2[C:25]=1[C:24](=[O:26])[N:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]([CH:34]([NH:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:12])[CH2:35][CH3:36])=[N:21]2)=[O:16]
Reactant: CCC(OS(C)(=O)=O)c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(NCCCNC(=O)OC(C)(C)C)c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1
Temperature: 75 °C
Yield: 12.4 %

Procedure:
(3-Amino-propyl)-carbamic acid tert-butyl ester (Fluka, 0.054 ml, 0.31 mmol) was added to a solution of 3-benzyl-2-(1-methanesulfonyloxy-propyl)-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxyic acid methyl ester (0.086 g, 0.21 mmol) and triethylamine (0.086 mL, 0.616 mmol) in DMF (1.0 mL) and the reaction mixture was heated to 75° C. for 4 h. The reaction mixture was quenched with saturated NaHCO3 (2 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with 10% LiCl (4×10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 8/1 to 1/1 hexane/EtOAc to afford the title compound (0.013 g, 14%) as a solid: 1H NMR (CDCl3) δ 6.98–7.26 (m, 8H), 5.75 (m, 1H), 4.95 (m, 2H), 3.86 (s, 3H), 3.65 (m, 1H), 3.00 (m, 2H), 2.45 (m, 1H), 2.00 (m, 1H), 1.50–1.75 (m, 4H) 1.36 (s, 9H), 0.88 (m, 3H); MS (ESI+) 498 (M++H); HRMS (ESI+) calculated: 498.2716 (M++H), found: 498.2720 (M++H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:22]([OH:24])=O)[CH3:3].C(N1C=CN=C1)([N:27]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.O>[CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:22]([NH2:27])=[O:24])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)Oc1c(C(=O)O)oc2ccc(OCc3ccccc3)cc12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1c(C(N)=O)oc2ccc(OCc3ccccc3)cc12
Yield: 51.9 %

Procedure:
A mixture of 3-(1-methylethoxy)-5-(phenylmethoxy)-2-benzofurancarboxylic acid (0.53 g, 1.6 mmol) and 1,1'-carbonyldiimidazole (0.29 g, 1.8 mmol) in 20 mL of tetrahydrofuran is stirred at reflux for 2 hours. The cooled reaction mixture is treated with 3.0 mL of ammonium hydroxide solution and stirred at room temperature for an additional 2 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried (anhydrous magnesium sulfate), and evaporated. Purification of the residue by flash chromatography (silica gel, 50% ethyl acetate in hexane elution) gives 0.27 g (53%) of product; mp=158°-160° C.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[OH:10][CH2:9][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:8]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Nc1ccc(CO)cc1Br
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: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cc(CO)ccc2N)cc1
Yield: 138 %

Procedure:
To a degassed solution of crude 2-bromo-4-hydroxymethylaniline (3.2 g, 15.8 mmol), 4-methoxybenzeneboronic acid (2.89 g, 19 mmol) and potassium carbonate (4.77 g, 34.8 mmol) in toluene/ethanol 2/1 (45 mL) a catalytic amount of Pd(PPh3)4 (0.2 g, 1 mmol %) was added and the mixture was heated at 90 C for 5 hours. The residue was extracted into ethyl acetate and washed with water and then saturated brine and dried over sodium sulphate. The solvent was removed under reduced pressure to afford 5 g of crude product. C14H15BNO2 Mass (calculated) [229.28]; (found) [M+H+]=230 Lc Rt=0.88, 89%. NMR (400 MHz, CDCl3): 3.75 (3H, s, MeO); 4.5 (2H, s, CH2O); 6.65 (1H, d, J=8.5 Hz, aryl-H); 6.9 (2H, d, J=8.5 Hz, aryl-H); 7–7.1 (2H, m, aryl-H); 7.25 (2H, d, J=8.5 Hz, aryl-H).
Reaction SMILES: OS(O)(=O)=O.[CH3:6][O:7][C:8]1[C:9](=[O:20])[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([CH3:19])[CH:13]=[CH:12][CH:11]=2.[N-:21]=[N+]=[N-].[Na+].CO>O>[CH3:6][O:7][C:8]1[C:9](=[O:20])[NH:21][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:19])[C:15]=2[C:16](=[O:18])[CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC1=CC(=O)c2c(C)cccc2C1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(=O)c2c(C)cccc2[nH]c1=O
Yield: 93 %

Procedure:
To stirred, ice bath cold, concd H2SO4 (12 mL, Baker), there was added 2-methoxy-5-methylnaphthalene-1,4-dione (800 mg, 3.96 mmol) in portions. A deep red solution resulted. To this cold solution, NaN3 (515 mg, 7.92 mmol, Aldrich) was added in portions over one min. The ice bath was removed and the reaction was allowed to stir at rt for 18 h under N2. Nitrogen evolution was noted. The reaction was added to crushed ice (50 mL) to give a thick green suspension. This was diluted with H2O (30 mL) and vigorously stirred with 30% MeOH/70% CHCl3 (60 mL) until all the solid had dissolved. The layers were separated and the aqueous portion was extracted with 30% MeOH/70% CHCl3 (2×30 mL). The combined red organic portion was washed with water (1×30 mL), saturated NaHCO3 (1×30 mL) and brine (1×30 mL), filtered through cotton and the solvent removed in vacuo to give a red solid (800 mg). Crystallization from 95% EtOH (dissolved in 30 mL, hot filtered, concd to 20 mL, allowed to cool to rt then in an ice bath) a gave colorless fluffy needles (564 mg, 66%, pure by 1H NMR); mp 215.5° -217° C.; 1H NMR (DMSO-d6) δ2.32 (s, 3H), 3.71 (s, 3H), 6.32 (s, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 11.00 (s, 1H); IR (KBr) 3195 (m), 3134 (m), δ3061 (m), 2999 (m), 2967 (m), 2939 (m), 1691 (s), 1649 (s), 1616 (s), 1212 (m), 834 (m), 783 (m); MS (m/z) 217 (M+, 100).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][S:11](Cl)(=[O:13])=[O:12].[C:15]1([S:21]([N:24]2[C:28]3=[N:29][CH:30]=[C:31]([NH:40][C:41](=[O:48])[CH2:42][CH:43]4[CH2:47][CH2:46][CH2:45][CH2:44]4)[C:32]([NH:33][CH:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)=[C:27]3[CH:26]=[CH:25]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:15]1([S:21]([N:24]2[C:28]3=[N:29][CH:30]=[C:31]([NH:40][C:41](=[O:48])[CH2:42][CH:43]4[CH2:44][CH2:45][CH2:46][CH2:47]4)[C:32]([NH:33][CH:34]4[CH2:35][CH2:36][N:37]([S:11]([CH3:10])(=[O:13])=[O:12])[CH2:38][CH2:39]4)=[C:27]3[CH:26]=[CH:25]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CC1CCCC1)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Nc2c(NC(=O)CC3CCCC3)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisopropylethylamine (0.166 ml, 0.954 mmol) and methanesulfonyl chloride (0.027 ml, 0.350 mmol), were added sequentially to a solution of crude N-[1-benzenesulfonyl-4-(piperidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-cyclopentyl-acetamide (hydrochloride salt) (0.382 mmol, obtained in preceding step) in CH2Cl2 (10 ml) at 25° C. The reaction mixture was stirred for 30 min at 25° C., then was partitioned between half-saturated NaHCO3 (75 ml) and CH2Cl2 (100 ml). The organic layer was dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to afford N-[1-benzenesulfonyl-4-(1-methanesulfonyl-piperidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-cyclopentyl-acetamide as a white foam. LCMS (Method G, ESI): RT=0.93 min, m+H=560.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [I-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][N:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][CH:35]=[CH:34]2.[ClH:41]>C(OCC)(=O)C.CN(C=O)C>[ClH:3].[ClH:41].[ClH:3].[CH3:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][N:7]([CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:6][CH2:5][CH2:4][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][CH:35]=[CH:34]2
Reactant: Cc1ccccc1CN(CCCCl)CCc1cccnc1
Reactant: Oc1ccc2ncccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccccc1CN(CCCOc1ccc2ncccc2c1)CCc1cccnc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Sodium iodide (113 mg) was added to a DMF solution (5 ml) of N-(3-chloropropyl)-N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)amine (151 mg), and stirred at 60° C. for 1 hours. The reaction mixture was cooled to room temperature. Potassium carbonate (104 mg) and 6-hydroxyquinoline (87 mg) were then added to the reaction mixture and stirred at 60° C. for 24 hours. The reaction mixture was added to ice water, and the extraction with ethyl acetate was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→0:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride in ethyl acetate solution (0.014 ml) was added to a ethyl acetate solution (1 ml) of the residue, and the liquid was stirred at room temperature. The precipitated insoluble product was separated, washed with ether, and dried to give the title compound (7.6 mg) as a brown powder.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:11]=2)[CH2:8][CH2:7][NH:6][C:5]1=[O:21].Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.Cl.ClCCCN1CCCCC1>CC(N(C)C)=O.C1(C)C=CC=CC=1>[CH3:3][CH:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:11]=2)[CH2:8][CH2:7][N:6]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:5]1=[O:21]
Reactant: CC1C(=O)NCCN1c1cccc(OC(F)(F)F)c1
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CC1C(=O)N(CCCN2CCCCC2)CCN1c1cccc(OC(F)(F)F)c1
Temperature: 75 °C
Yield: 84 %

Procedure:
NaH (55% dispersion in mineral oil, 36 mg, 0.82 mmol) was added portionwise at RT to a solution of 3-methyl-4-(3-trifluoromethoxy-phenyl)-piperazin-2-one (150 mg, 0.55 mmol) in DMA (3 mL), then after 1 h a solution of 1-(3-chloropropyl)-piperidine in toluene [prepared from commercially available 1-(3-chloropropyl)-piperidine hydrochloride (542 mg, 2.74 mmol) by partitioning between toluene (4 ml) and 1 M aq. sodium hydroxide solution (4 ml) and drying of the organic layer with MgSO4] was added. The reaction mixture was heated at 75° C. for 1 h, then partitioned between sat. aq. NaHCO3 solution and CH2Cl2. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (IST Isolute® Flash NH2; EtOAc) afforded the title compound (184 mg, 84%). Light yellow oil, MS: 400.3 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:16]4[C:17]=3[C:12](=[CH:13][CH:14]=[CH:15]4)[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.Cl.N1(CCCNC2C3C=CC=C4C=3C(=CC=C4)N=2)C=CN=C1.[C:45]1([N:51]=[C:52]=[O:53])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>ClCCl>[N:11]1[C:12]2[C:17]3[C:16](=[CH:21][CH:20]=[CH:19][C:18]=3[C:10]=1[N:9]([CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:52]([NH:51][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:53])[CH:15]=[CH:14][CH:13]=2
Reactant: O=C=Nc1ccccc1
Reactant: c1cc2c3c(cccc3c1)C(NCCCn1ccnc1)=N2
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N(CCCn1ccnc1)C1=Nc2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.7 g of N-(3-(1H-imidazol-1-yl)propyl)benz(cd)indol-2-amine (free base of the compound of Example 1) was dissolved in 50 ml of dichloromethane, and the solution then treated with 2.4 grams of phenylisocyanate. The mixture was stirred at room temperature overnight and then washed with 50 ml of saturated NaCHO3 solution. The dichloromethane layer was dried over MgSO4. Removal of the dichloromethane in vacuo left 3.7 grams of the desired compound, melting at 240° C.-250° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[C:6](Cl)=[N:5]2.[NH2:16][CH2:17][CH2:18][CH2:19][OH:20]>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[C:6]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])=[N:5]2
Reactant: Clc1nc2cc(Br)ccc2n2ccnc12
Reactant: NCCCO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: OCCCNc1nc2cc(Br)ccc2n2ccnc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 87.5 %

Procedure:
To a solution of 7-bromo-4-chloro-imidazo[1,2-a]quinoxaline (2.75 g; 9.6 mmol; 1 eq) in anhydrous dioxane (421 mL), 3-aminopropanol (1.83 mL; 24.1 mmol; 2.5 eq) is added under argon atmosphere. After 17 hours of stirring under reflux, the reaction mixture is cooled to room temperature and diluted in ethyl acetate (250 mL). The organic phase is washed three times with a molar solution of sodium hydroxide (3×150 mL). The recombined water phases are extracted one more time with ethyl acetate (300 mL) and the combined organic phases dried over sodium sulfate and concentrated under vacuum. The resulting beige powder is further washed with ether (200 mL) to provide the title compound (2.70 g; 8.4 mmol; 89%) as a grey powder.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]#[N:15])=[N:6]1.C[O-].[Na+].C(O)(=O)C.[Cl-].[NH4+:26]>CO>[F:17][C:2]([F:1])([F:16])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:26])[NH2:15])=[N:6]1
Reactant: N#Cc1nn(CCC(F)(F)F)c2ncccc12
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)c1nn(CCC(F)(F)F)c2ncccc12
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To the intermediate from Step A above (44.4 g, 185 mmol) in MeOH (16 mL) at rt was added sodium methoxide (13.98 g, 259 mmol). After stirring for 3 hours, acetic acid (42.3 mL, 739 mmol) and ammonium chloride (12.85 g, 240 mmol) were added to the reaction. The resulting slurry was heated to 65° C. and stirred for 4 hours. The reaction was then cooled to rt and quenched with EtOAc and saturated aqueous NaHCO3. The aqueous layer was removed and back extracted with EtOAc (4×). The combined organic layers were washed with 20% brine and dried over Na2SO4, filtered and the solvent removed under vacuum. EtOAc was added and the precipitated product was filtered and washed with methyl tert-butyl ether. The solid was dried at rt under vacuum oven overnight and the material used without further purification. 1H NMR (500 MHz, CH3OH-d4): δ 8.74 (d, J=4.57 Hz, 1H); 8.52 (d, J=8.32 Hz, 1H); 7.51 (dd, J=8.31, 4.44 Hz, 1H); 4.96 (t, J=6.91 Hz, 3H); 3.08-2.97 (m, 2H). m/z=258.3 (M+H).
Reaction SMILES: [NH2:1][C:2](=O)[CH:3]([N:16]([C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])[C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([F:15])=[CH:10][CH:11]=2)[CH2:6]1.CO>C1COCC1>[NH2:1][CH2:2][CH:3]([N:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:25]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH3:26])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([F:15])=[CH:10][CH:11]=2)[CH2:6]1
Reactant: C[C@H](c1ccccc1)N(C(=O)c1ccccc1)C(CC1CCc2ccc(F)cc2C1)C(N)=O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N(Cc1ccccc1)C(CN)CC1CCc2ccc(F)cc2C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
7 ml (7 mmol) of a molar solution of BH3 /THF are added, dropwise and with vigorous stirring, to a solution, maintained under nitrogen, of 1.20 g (2.70 mmol) of the compound obtained in Step 3 (diastereoisomer 1) in 30 ml of anhydrous THF. The mixture is then heated at 70° C. for 1 hour and is then cooled, treated with 8 ml of CH3OH and stirred at 20° C. for 1 hour. After concentrating in vacuo, the residue is chromatographed on silica, eluting with a solution of CH2Cl2 /CH3OH=95/5, to yield the title compound in the form of an oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=[CH:5][CH:4]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29]>O1CCCC1>[F:12][C:2]([F:1])([F:13])[C:3]1[C:8]([C:9]([NH:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29])=[O:11])=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: NC(CO)CO
Reactant: O=C(O)c1cnccc1C(F)(F)F
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: O=C(NC(CO)CO)c1cnccc1C(F)(F)F
Reaction time: 4 h

Procedure:
3.9 g (20 mmol) of 4-trifluoromethylnicotinic acid and 3.2 g (20 mmol) of carbonyl diimidazole in 100 ml of dry tetrahydrofuran were stirred at 40-50° C. for 6 hours. After cooling, 1.8 g (20 mmol) of serinol were added, and stirring was continued at 50-60° C. for another 4 hours. The crude product obtained after removal of the solvent under reduced pressure was purified by silica gel chromatography. This gave 2.9 g of product (55.3% of theory) of melting point 155-156° C.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:3]=1.[K].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][S:33]([NH2:36])(=[O:35])=[O:34].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[Cl:17][C:6]1[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:3]=[C:2]([NH:36][S:33]([CH2:32][CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)(=[O:35])=[O:34])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Reactant: NS(=O)(=O)CCc1ccccn1
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)CCc1ccccn1
Reaction time: 96 h
Yield: 38 %

Procedure:
A solution of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (1.75 g, Referential Example 7) and 2-pyridin-2-yl-ethanesulfonic acid amide potassium salt (1.13 g) in DMSO (30 ml) was stirred at rt for 24 h. Triethylamine (657 mg) was added and stirring was continued for another 96 h before the mixture was diluted with ethyl acetate (150 ml) and washed 4% aq. citric acid and water. The aqueous phase was extracted three more times with EA. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel eluting with EA containing 0–10% methanol to give 2-pyridin-2-yl-ethanesulfonic acid [6-chloro-5-(2-methoxyphenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide (950 mg) as a brown powder. LC-MS: tR=3.63 min, [M+1]+=498.31, [M−1]−=496.10.
Reaction SMILES: [C:1]([CH2:3][C:4](=[S:6])[NH2:5])#[N:2].[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:11][C:10]=1[N+:28]([O-:30])=[O:29])=O>N1CCCCC1.C(O)C>[NH2:5][C:4](=[S:6])[C:3]([C:1]#[N:2])=[CH:7][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:17][CH2:16]2)=[CH:11][C:10]=1[N+:28]([O-:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)c([N+](=O)[O-])c2)CC1
Reactant: N#CCC(N)=S
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=C(C#N)C(N)=S)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
1.5 g (15 mmol) of 2-cyanoethanethioamide, 60 ml of ethanol and one drop of piperidine are added respectively to 5 g (15 mmol) of tert-butyl 4-(4-formyl-3-nitrophenyl)piperazine-1-carboxylate. The reaction mixture is stirred at room temperature for 12 hours. The precipitate obtained is filtered to yield 5.2 g (83%) of tert-butyl 4-(4-(3-amino-2-cyano-3-thioxoprop-1-enyl)-3-nitrophenyl)piperazine-1-carboxylate in the form of a yellow solid.
Reaction SMILES: [CH:1]([O:3][CH:4]=[CH2:5])=[CH2:2].C(OCCCl)=C.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:1]([O:3][CH2:4][CH2:5][C:21]1[CH:20]=[CH:19][CH:18]=[C:14]2[C:15]([NH:16][C:12](=[O:22])[C:13]=12)=[O:17])=[CH2:2]
Reactant: C=COC=C
Reactant: O=C1NC(=O)c2ccccc21
Agent: C=COCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Product: C=COCCc1cccc2c1C(=O)NC2=O

Procedure:
Vinyl ether monomers for incorporation of amine-containing monomers. 2-Vinyloxy Ethyl Phthalimide was prepared via reacting 2-chloroethyl vinyl ether (25 g, 0.24 mol; CAS #110-75-8) and potassium phthalimide (25 g, 0.135 mol; CAS #1074-82-4) in 100° C. N,N-Dimethylformamide (DMF, 75 ml) using tetra n-butyl ammonium bromide (0.5 g; CAS #1643-19-2) as the phase transfer catalyst. This solution was heated for 6 h and then crashed out in water and filtered. This solid was then recrystallized twice from methanol to give white crystals.