Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18](O)=[O:19])=[C:12]([C:21]([F:24])([F:23])[F:22])[C:11]=1[Cl:25].[NH:26]1[CH2:36][CH2:35][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([N:26]2[CH2:27][CH2:28][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:35][CH2:36]2)=[O:19])=[C:12]([C:21]([F:23])([F:22])[F:24])[C:11]=1[Cl:25]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1ccccc1Sc1ccc(/C=C/C(=O)O)c(C(F)(F)F)c1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(C(=O)/C=C/c2ccc(Sc3ccccc3OC)c(Cl)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
To the acyl chloride (37 mg, 0.1 mmol) prepared from the compound of Example 351B, as a solution in CH2Cl2 was added 1.2 eq. of ethyl isonipecotate and 1.2 eq. of Hunig's base. The mixture was stirred at room temperature for 20 min., ˜90% of the solvent was removed in vacuo, and the resultant solution was loaded on a silica column to elute with hexane and EtOAc (3:2) to give 51 mg (98%) of the title compound. 1H-NMR (CDCl3, 300 MHz) δ 1.25 (t, J=7.5 Hz, 3H), 1.65-1.78 (m, 2H), 1.92-2.02 (br, 2H), 2.51-2.60 (m, 1H), 2.93-3.24 (br, 2H), 3.82 (s, 3H), 3.88-3.96 (m, 1H), 4.15 (q, J=7.5 Hz, 2H), 4.40-4.50 (br, 1H), 6.48 (d, J=15 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 7.02 (d, J=7.5 Hz, 2H), 7.12 (d, J=9 Hz, 1H), 7.49 (t, J=9 Hz, 2H), 7.86 (qq, J=4.5 Hz, 1H). MS (DCI/NH3) m/e 528 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:10][S:11]([CH2:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=1[F:23])#[N:2].[CH3:24][Mg+].[Br-]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:10][S:11]([CH2:13][CH:14]([CH3:16])[CH3:15])=[O:12])([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH3:24])=[CH:5][C:4]=1[F:23])#[N:2]
Reactant: CC(C)CS(=O)N=C(c1cccnc1)c1ccc(C#N)c(F)c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)CS(=O)NC(C)(c1cccnc1)c1ccc(C#N)c(F)c1
Reaction time: 0.25 h

Procedure:
N-[(4-cyano-3-fluoro-phenyl)-(3-pyridyl)-methylene]-2-methylpropanesulfinamide (0.315 g, 0.956 mmol) was dissolved in anhydrous THF (10 mL), cooled in a ice bath, and treated with a 3.0 M ethereal solution of MeMgBr (0.96 mL, 2.87 mmol). After 15 min, the reaction was quenched with H2O, diluted with CH2Cl2 and saturated NaHCO3 solution and separated. The aqueous layer was extracted with CH2Cl2 (2×), the organic layers combined, dried (Na2SO4), filtered and concentrated to give the title compound after chromatography on a Waters Prep Pak column eluting with 0.1% TFA/H2O: 0.1% TFA/CH3CN, 95:5 to 5:95.
Reaction SMILES: [OH:1][C:2]1[N:3]([CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([NH:12][CH2:13][CH2:14][OH:15])[N:5]=2.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:24]([O:15][CH2:14][CH2:13][NH:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([OH:1])[N:3]2[CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[C:8]([NH2:11])[N:7]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(Cn2c(O)nc3c(N)nc(NCCO)nc32)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)OCCNc1nc(N)c2nc(O)n(Cc3ccc(C)nc3)c2n1
Reaction time: 3 h
Yield: 12.2 %

Procedure:
To 8-hydroxy-2-(2-hydroxyethylamino)-9-{(6-methyl-3-pyridyl)methyl}adenine (100 mg, 0.32 mmol) prepared by Comparative example 10 in pyridine (1 ml) was added under ice cooling acetic anhydride (0.033 ml, 0.35 mmol), and the mixture was stirred for 3 hours. To the reaction mixture was added sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by preparative thin-layer chromatography to give the captioned compound (14 mg, 0.039 mmol, yield: 12%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([N:24]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=4[O:39][CH3:40])[C:25]4[S:29][N:28]=[CH:27][N:26]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[N:14]([CH3:41])[CH:13]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:40][O:39][C:32]1[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:31]=1[CH2:30][N:24]([C:25]1[S:29][N:28]=[CH:27][N:26]=1)[S:21]([C:17]1[CH:16]=[C:15]2[C:20]([C:12]([C:4]3[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([C:45]4[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=4)[CH:3]=3)=[CH:13][N:14]2[CH3:41])=[CH:19][CH:18]=1)(=[O:23])=[O:22]
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4cc(Br)cc(C(F)(F)F)c4)cn(C)c3c2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4cc(-c5ccncc5)cc(C(F)(F)F)c4)cn(C)c3c2)c(OC)c1

Procedure:
A microwave vial was charged with 3-(3-bromo-5-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.050 g, 0.075 mmol), pyridin-4-ylboronic acid (0.018 g, 0.150 mmol), potassium phosphate (0.056 g, 0.262 mmol), and Pd(AmPhos)2Cl2 (5.30 mg, 7.49 μmol). The vial was flushed with Ar, then dioxane (0.375 ml) and water (0.125 ml) were added in sequence. The vial was sealed and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered and concentrated. The material was purified via column chromatography (silica gel, gradient elution 0 to 100% EtOAc/Heptane) to afford N-(2,4-dimethoxybenzyl)-1-methyl-3-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide as a yellow solid. m/z (ESI) 666.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.[Br:14]Br>CCOCC>[Br:14][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: BrBr
Reactant: COc1ccc2c(c1)C(=O)CCC2
Solvent: CCOCC
Product: COc1ccc2c(c1)C(=O)C(Br)CC2
Yield: 87.2 %

Procedure:
To a 10° C. solution of 25 g (0.142 mol) of 7-methoxy-3,4-dihydro-1(2 H)-naphthalenone in 1 liter ether was added dropwise (maintaining reaction temperature at about 10° C.) 37.9 g (0.237 mol) of bromine. The reaction solution was concentrated on a rotating evaporator and the residue crystallized from ether to give 31.6 g (81%) of present title compound, m.p. 79-80° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[NH:17][C:16](=[O:18])[S:15][N:14]=2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[NH:17][C:16](=[O:18])[S:15][N:14]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2nsc(=O)[nH]2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=c1[nH]c([C@@H]2CCNC2)ns1
Reaction time: 8 h
Yield: 82.6 %

Procedure:
(R)-3-(5-Oxo-4,5-dihydro-[1,2,4]thiadiazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (420 mg, 1.55 mmol) was dissolved in methanol (15 mL). 4M HCl in dioxane (0.70 mL, 2.80 mmol) was then added. The solution was stirred overnight. The reaction was concentrated in vacuo. The residue was purified by reverse phase HPLC to afford (R)-3-pyrrolidin-3-yl-4H-[1,2,4]thiadiazol-5-one (220 mg, 1.28 mmol, 83%) as a white solid.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH2:31])=[NH:30])=[CH:24][CH:23]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:9]2[NH:8][C:7](=[O:18])[CH2:6][C:5]3[CH:4]=[N:30][C:29]([CH2:28][C:25]4[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=4)=[N:31][C:11]=3[C:10]=2[CH:13]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(F)cc2C1=O
Reactant: COc1ccc(CC(=N)N)cc1
Agent: Cl
Product: COc1ccc(Cc2ncc3c(n2)-c2cc(F)ccc2NC(=O)C3)cc1

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepine-2,5-dione and 2-(4-methoxyphenyl)-acetamidine hydrochloride.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:39](#[N:42])[CH:40]=[CH2:41].[OH-].[Na+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH2:23]([O:22][CH2:21][CH:19]([CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:20][CH2:41][CH2:40][C:39]#[N:42])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: C=CC#N
Reactant: CCCCCCCCCCCCCCCCOCC(O)COCCCCCCCCCCCCCCCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCC)OCCC#N
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
A mixture of 1,3-di-O-(n-hexadecyl)-glycerol (80 g., 148 mmoles), acrylonitrile (1.49 kg., 28.1 moles) and aqueous 2 N sodium hydroxide (1.2 1.) was heated to 50° C. Tetrabutylammonium hydroxide (19.2 g. of 40 wt. % aqueous solution, 29.15 mmoles) was slowly added, causing the temperature of the exothermic reaction mixture to rise to about 80° to 90° C. The reaction mixture was then stirred for 20 minutes without any external heating, followed by cooling to 20° C. and addition of water (1.0 l.). A solid material, a mixture of unreacted and cyanoethylated 1,3-di-O-(n-hexadecyl)-glycerol, was isolated and treated again with fresh acrylonitrile (1.49 kg., 28.1 moles), aqueous 2 N sodium hydroxide (1.2 l.) and tetrabutylammonium hydroxide (19.2 g. of 40 wt. % aqueous solution, 29.15 mmoles) for 20 minutes with stirring at 50° C., followed by cooling and addition of water (1.0 l.). The resulting 1,3-di-O-(n-hexadecyl)-2-O-(2-cyanoethyl)-glycerol solids were filtered, washed consecutively with water, methanol and acetonitrile, and dried [82 g., 93% yield, m.p. 45°-46° C., ir (CHCl3) 2250 cm-1, n.m.r. (CDCl3) δ3.92 (t, 2, NCCH2CH2O--), 3.33-3.67 (m, 9, --OCH[CH2OCH2C15H31 ]2), 2.62 (t, 2, NCCH2CH2O--) and 0.75-1.58 (m, 62, aliphatic protons)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2(O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C@H:15]([NH:19][C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:29])[CH3:28])=[CH:4][CH:3]=1.CCN(S(F)(F)[F:37])CC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([F:37])[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C@H:15]([NH:19][C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:29])[CH3:28])=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)[C@@H](NC(=O)C1CCCC1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)C1CCCC1)C(=O)N1CC[C@](F)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: -78 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
N—((R)-1-((S)-4-(4-Chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)cyclopentanecarboxamide (30 mg, 0.069 mmol) was dissolved into methylene chloride (2 mL) then cooled to −78° C. and DAST (13.3 mg, 0.083 mmol) was added. The reaction was stirred overnight at rt. HPLC showed some starting material present and 2 additional drops of DAST was added at rt. Some starting material was still present and 2 additional drops DAST was added and HPLC then showed the reaction was complete. The reaction was concentrated and Example 616 was isolated as a white solid by preparative reverse-phase HPLC (15.3 mg, 51% yield), M+H=437.38.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:38](O)=[O:39])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:41][C:42]1NN=[N:44][N:43]=1.C1CCC(N=C=NC2CCCCC2)CC1>C1(C)C=CC=CC=1>[C:27]([C:24]1[N:23]=[C:22]([NH:31][CH2:32][C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C@H:12]2[CH2:11][C@@H:10]([C:38]3[O:39][C:42]([CH3:41])=[N:43][N:44]=3)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13]2)=[O:20])=[CH:26][N:25]=1)([CH3:29])([CH3:30])[CH3:28]
Reactant: Cc1nnn[nH]1
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1nnc([C@@H]2C[C@H](N(CC(C)C)C(=O)c3cnc(C(C)(C)C)nc3NCc3ccco3)CN(C(=O)OC(C)(C)C)C2)o1
Temperature: 100 °C
Reaction time: 14 h
Yield: 58.3 %

Procedure:
(3R*,5S*)-1-(tert-Butoxycarbonyl)-5-[({2-tert-butyl-4-[(2-furylmethyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-3-carboxylic acid (120 mg) and 5-methyl-1H-tetrazole (22 mg) were suspended in toluene (3 ml), DCC (60 mg) was added and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (5:95-75:25) was concentrated under reduced pressure to give the object compound (74.7 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C([Li])CCC.[NH2:16][C:17]1[N:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:18]=1[C:19](N(OC)C)=[O:20]>O1CCCC1>[NH2:16][C:17]1[C:18]([C:19]([C:6]2[CH:7]=[C:2]([F:1])[C:3]([CH3:10])=[CH:4][C:5]=2[O:8][CH3:9])=[O:20])=[CH:25][CH:26]=[C:27]([Cl:29])[N:28]=1
Reactant: COc1ccc(F)c(C)c1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C)c(F)cc1C(=O)c1ccc(Cl)nc1N
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-fluoro-3-methylanisole (0.75 mL, 802 mg, 5.55 mmol, Aldrich 97%) in anhydrous tetrahydrofuran (5 mL) at −78° C., was added slowly a solution of n-butyllithium in hexanes (2.5 M, 2.22 mL, 5.55 mmol, Aldrich). The reaction was stirred at −78° C. for 10 mins before it was allowed to warm to −25-0° C. and stirred for 1.5 hour. The resulting aryllithium reagent was cooled back to −78° C. and reacted with 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide as described in Example 7 to give (2-Amino-6-chloro-pyridin-3-yl)-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone as an off-white solid. HRMS, observed: 295.0645, Calcd for (M+H)+: 295.0644.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:23][C:24]([CH:26]2[CH2:29][CH2:28][CH2:27]2)=O)[C:16]2[C:17](=[O:22])[NH:18][CH:19]=[N:20][N:21]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O=P(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:23]=[C:24]([CH:26]3[CH2:29][CH2:28][CH2:27]3)[N:21]3[C:16]=2[C:17](=[O:22])[NH:18][CH:19]=[N:20]3)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(c1cccc(OCc2ccccc2)c1)c1nnc[nH]c1=O)C1CCC1
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1[nH]cnn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 0 °C

Procedure:
A solution of cyclobutanecarboxylic acid [(3-benzyloxy-phenyl)-(5-oxo-4,5-dihydro-[1,2,4]triazin-6-yl)-methyl]-amide (216 mg, 0.553 mmol) in POCl3 (5 mL) was heated to 55° C. in an oil bath for 3 h. The reaction mixture was concentrated in vacuo and cooled to 0° C. and charged with 2M NH3 in i-PrOH until slightly basic. The solution was concentrated in vacuo and the reaction mixture was partitioned between EtOAc and H2O and separated. The aqueous layer was re-extracted with EtOAc (3×) and the combined EtOAc fractions were dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound as an off-white foam solid with no further purification. 1H NMR (CDCl3, 400 MHz) δ 1.98-2.07 (m, 1H), 2.08-2.21 (m, 1H), 2.36-2.48 (m, 2H), 2.62-2.77 (m, 2H), 4.09 (quint, J=8.8 Hz, 1H), 5.13 (s, 2H), 6.98 (dd, J=2.0, 7.2 Hz, 1H), 7.27-7.7.40 (m, 4H), 7.42-7.49 (m, 3H), 7.88 (d, J=8.0 Hz, 1H), 7.99 (brs, 1H); MS(ES+): m/z 373.1 (100) [MH+]; HPLC: tR=3.25 min (MicromassZQ, nonpolar—5 min).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:5][N:4]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:5][N:4]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CC(=O)c1ccc(CO)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)c1ccc(COS(C)(=O)=O)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Dissolve 2-hydroxymethyl-5-(3-methyl-butyryl)-pyridine (190 mg, 0.98 mmol) in dichloromethane (10 mL). Cool to 0° C. and add triethylamine (0.151 mL, 1.08 mmol) and methanesulfonyl chloride (0.083 mL, 1.08 mmol). Allow the mixture to warm to room temperature and stir for 2 h. Dilute the reaction mixture with dichloromethane and wash with saturated aqueous NaHCO3. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to provide the title compound as oil (263 mg, 98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=[O:13].[K+].[K+].CS(C)=O.OO>O>[F:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]([NH2:11])=[O:13])[CH:5]=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#CCOc1cncc(F)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)COc1cncc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.1 %

Procedure:
To a mixture of 2-((5-fluoropyridin-3-yl)oxy)acetonitrile (0.55 g, 3.62 mmol), K2CO3 (0.60 g, 4.34 mmol) and DMSO (0.55 mL) in H2O (8 mL) was added H2O2 (0.55 mL, 30%) dropwise in an ice bath and the mixture was stirred at rt for 5 min. It was then concentrated in vacuo and the residue was purified by a silica gel column chromatography (EtOAc) to give the title compound as a white solid (0.37 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15]([C:17]1[C:18](=[O:40])[C:19]2[CH:24]=[N:23][C:22](S(C)(=O)=O)=[N:21][C:20]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1[C:18](=[O:40])[C:19]2[CH:24]=[N:23][C:22]([NH:11][CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:21][C:20]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=[O:16])[CH3:13]
Reactant: COc1ccc(CCN)cc1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCc3ccc(OC)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1 Step F, the title compound was prepared 2-(4-methoxyphenyl)-ethylamine and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1 Step E, 20 mg, 0.04 mmol). 19 mg of 8-Indan-5-yl-2-[2-(4-methoxy-phenyl)-ethylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.23 (s, 1H), 8.47 (s, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.26 (s, 1H), 7.18 (d, J=7.8 Hz, 1H), 6.81 (d, J=8.6 Hz, 2H), 6.77 (d, J=8.6 Hz, 2H), 5.84 (br, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.78 (s, 3H), 3.34 (m, 2H), 3.00 (m, 7H), 2.64 (t, J=7.2 Hz, 2H), 2.18 (m, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: C[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18]C(=O)OC(C)(C)C)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[ClH:26].O1CCOC[CH2:28]1>CO>[ClH:26].[CH3:28][N:12]([C:3]1[CH:2]=[N:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][N:4]=1)[C@H:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[NH2:18]
Reactant: Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-{[3-methyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]carbamate (480 mg, 1.332 mmol) in methanol (5 ml) was added HCl in 1,4-dioxane (4 M, 3.33 ml, 13.32 mmol). The reaction was stirred at room temperature overnight and then concentrated in vacuo, azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:36]=[CH:35][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.[O:37]1[CH2:40][CH:39]([NH2:41])[CH2:38]1>>[CH3:22][NH:21][C:19](=[O:20])[C@:18]([CH3:33])([N:17]([CH3:34])[C:15](=[O:16])[C:14]1[CH:35]=[CH:36][C:11]([C:10]#[C:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][NH:41][CH:39]3[CH2:40][O:37][CH2:38]3)=[CH:4][CH:5]=2)=[CH:12][CH:13]=1)[C:23]([NH:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)=[O:24]
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: NC1COC1
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(CNC3COC3)cc2)cc1

Procedure:
The same procedure as in Example 16-(2) was performed using (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (0.25 g) as obtained in Example 16-(1) and oxetan-3-amine (44 mg), whereby (2S)-N,2-dimethyl-2-{methyl[4-({4-[(oxetan-3-ylamino)methyl]phenyl}ethynyl)benzoyl]amino}-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (light yellow foam) was obtained (0.24 g, 85%).
Reaction SMILES: [I-:1].[Na+].[C:3]([O:24][CH2:25]Cl)(=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(#N)C.[Al]>[C:3]([O:24][CH2:25][I:1])(=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCC(=O)OCCl
Reactant: [I-]
Agent: [Al]
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCCCC(=O)OCI
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
Sodium iodide (8.31 g, 0.0555 mol) was added to a solution of chloromethyl arachidate (6.7 g, 0.0185 mol) in acetonitrile (67 ml) at 25° C. The flask was covered in aluminum foil to protect from light and stirred at 25° C. for 16 hours. The reaction mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with aqueous saturated NaHCO3, aqueous sodium sulfite (10% solution), and brine, then dried with sodium sulphate and concentrated in vacuo to provide the desired product (5.9 g, 71% yield) as a white solid which was not purified any further.