Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[I:14]I.O>CN(C)C=O.C(OCC)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[I:14]
Reactant: COC(=O)c1ccc(N)nc1OC
Reactant: II
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1cc(I)c(N)nc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
A mixture of methyl 6-amino-2-(methyloxy)-3-pyridinecarboxylate (2.1 g, 11.8 mmol) and iodine (15 g, 59 mmol) in N,N-dimethylformamide (50 ml) was stirred overnight at room temperature. The mixture was poured into water (200 ml) and extracted with ethyl acetate (50 ml×2). The combined organic layer was washed with saturated sodium bicarbonate, 20% aqueous thiosulphate and brine, dried over magnesium sulfate, and concentrated in vacuo gave a brown solid. The residue was suspended in diethyl ether and collected by filtration to afford 2.9 g (79%) of the title compound as a pale brown solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:17]([O:21][CH3:22])(=[O:20])[CH2:18][SH:19]>CC#N>[CH3:22][O:21][C:17]([C:18]1[S:19][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[CH:8]=1)=[O:20]
Reactant: O=Cc1cccnc1Cl
Reactant: COC(=O)CS
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cc2cccnc2s1
Yield: 29 %

Procedure:
To 2-chloro-3-pyridine carboxaldehyde, compound 147-A, (5.07 g, 35.8 mmol), dissolved in MeCN (30 mL) was added triethylamine (6.5 mL, 46.5 mmol) followed by methyl thioglycolate (3.49 mL, 38.3 mmol) and the reaction was refluxed for 18 h. The reaction mixture was cooled and the solvent evaporated under reduced pressure. The crude residue was partitioned between H2O and EtOAc, the layers separated and the aqueous phase extracted with EtOAc. The organic layers were combined, washed with H2O, brine, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient to afford compound 147-B as a white solid (2.01 g, 29%). 1H-NMR (DMSO-d6): δ 3.91 (s, 3H), 7.54-7.57 (m, 1H), 8.23 (s, 1H), 8.43-8.46 (m, 1H), 8.72-8.74 (m, 1H); MS: m/z 194.1 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH2:5].[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=4)=[CH:23][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1)#[N:7]>>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([NH:5][CH2:4][CH2:3][CH2:2][OH:1])[N:28]=4)=[CH:23][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1)#[N:7]
Reactant: NCCCO
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCCO)n4)cc3)cc12

Procedure:
Using 3-hydroxy-propylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 1.73 (t, 2H, J=7 Hz); 2.98 (t, 2H, J=7 Hz); 3.40 (m, 2H); 4.48 (bs, 1H); 7.20 (m, 3H); 7.48 (m, 2H); 7.92 (d, 2H, J=8 Hz); 8.18 (m, 3H); 8.37 (bd, 1H, J=5 Hz); 8.68 (bt, 1H); 12.12 (bs, 1H). MS (ion spray) m/z 441 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Br:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>ClCCl>[Br:18][CH2:19][CH2:20][CH2:21][C:22]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:23]
Reactant: COc1ccc(CO)cc1
Reactant: O=C(Cl)CCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COC(=O)CCCBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-methoxybenzyl alcohol and triethylamine in dichloromethane was added 4-bromobutyryl chloride at 0° C. The mixture was stirred at 0° C. for 30 minutes, and the solvent was evaporated. The residue was diluted with ethyl acetate, and the organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The concentrate was chromatographed on a silica gel column to give the object compound.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[N:15]([O-])=O.[Na+].[OH-].[Na+]>O.Cl>[NH:1]([C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)=[CH:4][CH:3]=1)[NH2:15]
Reactant: O=N[O-]
Reactant: Nc1ccc(C[C@H]2COC(=O)N2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NNc1ccc(C[C@H]2COC(=O)N2)cc1

Procedure:
A mixture of (S)-4-(4-aminobenzyl)-1,3-oxazolidin-2-one (100 gms) and concentrated hydrochloric acid (250 ml) in water (500 ml) was treated with an 50% aqueous solution of sodium nitrite (46 gms) at −5 to 10° C. Upon completion of the reaction, as monitored by TLC, the reaction mass was further treated with stannous chloride dihydrate (420 gms) dissolved in concentrated hydrochloric acid (500 ml) and water (544 ml) at −15 to 10° C. When the reaction was complete, as monitored by HPLC, the pH of the reaction mass was adjusted in the range of 2.0 to 6.0 by adding aqueous sodium hydroxide solution. The reaction mass was cooled and filtered to separate the solid. The aqueous layer was extracted with dichloromethane and further made alkaline in the pH range of 6.0 to 10.0 with aqueous sodium hydroxide. The mixture was cooled and filtered to give solid (S)-4-(4-hydrazinobenzyl)-1,3-oxazolidin-2-one (III), which was then suspended in isopropanol (420 ml) and converted to the hydrochloride salt by treatment with hydrogen chloride at reflux temperature to yield the hydrochloride salt of (S)-4-(4-hydrazinobenzyl)-1,3-oxazolidin-2-one (IIIa).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9](=[O:11])[NH:10][C:5]2=[N:4][CH:3]=1.BrC1N=C(N[C@H:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:29])C(N)=NC=1.[C:37](N1C=CN=C1)([N:39]1C=CN=C1)=O.O1CCC[CH2:50]1>CO>[CH3:50][N:10]1[C:5]2=[N:4][CH:3]=[C:2]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:30]=3[CH:28]=[CH:29][CH:37]=[N:39]4)[N:7]=[C:6]2[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:9]1=[O:11].[Br:1][C:2]1[N:7]=[C:6]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9](=[O:11])[NH:10][C:5]2=[N:4][CH:3]=1
Reactant: C[C@H](Nc1nc(Br)cnc1N)c1ccccc1
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C[C@@H](c1ccccc1)n1c(=O)[nH]c2ncc(Br)nc21
Solvent: CO
Product: C[C@@H](c1ccccc1)n1c(=O)n(C)c2ncc(-c3cccc4ncccc34)nc21

Procedure:
(S)-6-Bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. The title compound was prepared using (S)-6-bromo-N2-(1-phenylethyl)pyrazine-2,3-diamine (See Example 3.A) (0.50 g, 1.71 mmol), 1,1′-carbonyldiimidazole (0.35 g, 2.13 mmol), and tetrahydrofuran (7 mL) as described in General Procedure D1. The crude material was dissolved in methanol (5 mL), and the product was triturated with H2O while sonicating. The resulting precipitate was filtered and dried in a vacuum oven overnight to afford 0.34 g (1.07 mmol, 62%) of (S)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. MS (ESI) m/z 319.4 [M+1]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][OH:14])=[CH:7][CH:6]=1)[CH2:2][CH3:3].C1COCC1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(OCC)(=O)C>[CH3:27][S:28]([O:14][CH2:13][CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=1)(=[O:30])=[O:29]
Reactant: CCCOc1ccc(CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCOc1ccc(CCCOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 3-(4-propoxyphenyl)-1-propanol (735 mg) and THF (20 ml) were added at 0° C. triethylamine (1.58 ml) and methanesulfonyl chloride (0.44 ml). The resulting mixture was stirred at 0° C. for 20 minutes and at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 3-(4-propoxyphenyl)propyl methanesulfonate (1.02 g) as a colorless oil.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[C:27]1([S:33]([NH:36][C@H:37]([C:45](O)=[O:46])[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:45](=[O:46])[C@H:37]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[NH:36][S:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:35])=[O:34])(=[O:17])=[O:16])=[CH:19][CH:20]=1.[NH2:5][C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1
Product: CC(C)CN([C@@H](CCCCNC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1)C(=O)O)S(=O)(=O)c1ccc(N)cc1
Product: NCCCC[C@H](N)C(=O)O

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine (385 mg, 1.0 mmol, example 5, step C) as described in general procedure Bc using Nα-benzenesulfonyl-L-phenylalanine (335 mg, 1.1 mmol) which was prepared in step A of example 8. The final product was purified by preparative HPLC to yield 550 mg (85%) of Nα-(4-nitrobenzenesulfonyl)-Nα-isobutyl-Nε-(Nα-benzenesulfonyl)-L-phenylalanyl)-L-lysine. The latter derivative (200 mg) was hydrogenolysed following the indications of general procedure E. Purification by HPLC gave the desired material (129 mg, 65%).
Reaction SMILES: C(OC(C)C)(=O)CCC[CH2:5][C:6](C)([CH3:8])[CH3:7].[C:15](#[N:20])[C:16]([CH3:19])([CH3:18])[CH3:17]>>[CH3:17][C:16]([CH3:19])([CH2:18][C:6]([CH3:8])([CH3:7])[CH3:5])[C:15]#[N:20]
Reactant: CC(C)(C)C#N
Reactant: CC(C)OC(=O)CCCCC(C)(C)C
Product: CC(C)(C)CC(C)(C)C#N

Procedure:
isopropyl neononanoate; pivalonitrile; methyl 2,2,4,4-tetramethyl pentanoate (methyl neononanoate); and methyl 3,5,5 trimethyl hexanoate.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16](=[O:32])[CH2:17][C:18]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)(O)[C:19]([F:22])([F:21])[F:20])=[CH:8][CH:7]=1.Cl>C1(C)C=CC=CC=1>[Br:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16](=[O:32])[CH:17]=[C:18]([C:24]2[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=2)[C:19]([F:21])([F:22])[F:20])=[CH:8][CH:7]=1
Reactant: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(Br)c2ccccc12
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(Br)c2ccccc12
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A solution of thionyl chloride (0.5 g, 4.46 mmol) in toluene (2 mL) was added dropwise to the product of Step A (1.1 g, 2.23 mmol) in toluene (10 mL) at 65° C. The mixture was cooled to ambient temperature and then poured into 1N hydrochloric acid (50 mL). The resulting mixture was extracted with ethyl acetate (2×25 mL). The combined extracts were dried and evaporated to give the title product as an oil (1.0 g, 95% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14](N)[CH:15]=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH:18]S(O)(=O)=O.N([O-])=O.[Na+].C1COCC1>O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccc(N)cc2CC1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2ccc(O)cc2CC1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
Into a 250 ml flask, the product from step (b) (3 g, 12.82 mmol) dissolved in water (15 ml) and concentrated H2SO4 (1.02 ml, 19.23 mmol) was added The reaction mixture was heated to 70° C. and stirred for 15 minutes. A solution of NaNO2 (1.01 g, 14.74 mmol) in water (30 ml) was quickly added, followed by addition of THF (45 ml). The reaction mixture was stirred at 70° C. for 30 minutes and then allowed to cool to room temperature. The reaction mixture was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the sub-title compound as a yellow solid (2.0 g) that was used without further purification. MS: ESI (positive): 236 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.CC(C)=O.Cl.[CH2:24]([NH:26][CH2:27][CH2:28][NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH3:25]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([N:26]([CH2:27][CH2:28][NH:29][S:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH2:24][CH3:25])=[O:12])=[O:7])=[CH:17][CH:18]=1
Reactant: CCNCCNS(=O)(=O)c1ccc(C)cc1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCN(CCNS(=O)(=O)c1ccc(C)cc1)C(=O)c1ccccc1C(=O)c1ccc(Cl)cc1

Procedure:
A solution of 13 grams of ψ-acid chloride of 0-(p-chlorobenzoyl)benzoic acid in 30 ml. of acetone was added dropwise to a stirred solution of 14 grams of N-[2-(ethylamino)ethyl]-p-toluenesulfonamide hydrochloride in 100 ml. of pyridine. The solution was refluxed for 1.75 hours then the solvent was removed in vacuo. The residue dissolved in ethyl acetate and extracted successively with water, and saturated sodium carbonate solution. After drying over magnesium sulfate, the ethyl acetate was removed in vacuo. The solid was slurried with ethyl acetate and separated. On recrystallization from ethyl acetate there was obtained 2-(p-chlorobenzoyl)-N-[2-(p-toluenesulfonamido)ethyl]-N-ethylbenzamide, m.p. 145°-147°C.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:38]1[CH:43]=[CH:42][C:41]([C@@H:44]([NH:57][C:58](=[O:67])[C@H:59]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH3:60])[C@H:45]2[CH2:49][CH2:48][CH2:47][N:46]2[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[CH:40][CH:39]=1>C1COCC1>[CH2:3]([O:4][C:38]1[CH:39]=[CH:40][C:41]([C@@H:44]([NH:57][C:58](=[O:67])[C@H:59]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH3:60])[C@H:45]2[CH2:49][CH2:48][CH2:47][N:46]2[C:50]([O:52][C:53]([CH3:56])([CH3:54])[CH3:55])=[O:51])=[CH:42][CH:43]=1)[CH:2]([CH3:5])[CH3:1]
Reactant: C[C@H](C(=O)N[C@H](c1ccc(O)cc1)[C@H]1CCCN1C(=O)OC(C)(C)C)c1ccccc1
Reactant: CC(C)CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)COc1ccc([C@@H](NC(=O)[C@@H](C)c2ccccc2)[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 140 °C

Procedure:
A solution of 2-methyl-1-propanol (6.52 μL, 0.071 mmol), DEAD (11.19 μL, 0.071 mmol), and triphenylphosphine (18.53 mg, 0.071 mmol) in THF (520 μL) in a microwave vial was stirred at room temperature for 10 min. (R)-tert-Butyl 2-((R)-(4-hydroxyphenyl)((S)-2-phenylpropanamido)methyl)pyrrolidine-1-carboxylate (30 mg, 0.071 mmol) was added and the solution heated at 140° C. in a microwave (Biotage) for 20 min. The crude mixture was filtered through a plug of silica gel eluting with 50% EtOAc in hexanes. The filtrate was concentrated in vacuo and carried directly into the next reaction. LRMS (ESI) m/e 481.50 [(M+H)+, calcd for C29H41N2O4 481.31].
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.C(N(CC)CC)C.Cl[C:40]([O:42][CH3:43])=[O:41]>C(Cl)Cl>[CH3:43][O:42][C:40]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[CH:13][N:12]=2)[CH2:27][CH2:28]1)=[O:41]
Reactant: COC(=O)Cl
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt (80.9 mg, Example 11) in methylene chloride (4 mL) were added triethylamine (0.095 mL, 0.681 mmol, Aldrich) and methyl chloroformate (9.0 mg, 0.0868 mmol, Aldrich) at 0° C. The mixture was stirred for 1 hour at 0° C., the reaction mixture was concentrated in vacuo and crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid methyl ester (27.0 mg). HRMS, observed: 386.1827; Calcd for (M+H)+: 386.1823.
Reaction SMILES: [CH2:1]([C:3]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])=[C:8]([CH3:18])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[F-].[Cs+].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:35]1[O:37][C@H:36]1[CH2:38][OH:39]>C(Cl)Cl.CN(C=O)C>[CH2:1]([C:3]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:35][C@@H:36]([OH:37])[CH2:38][OH:39])=[C:21]([CH3:26])[CH:20]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:17])([CH3:15])[CH3:16])=[C:8]([CH3:18])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(CCC(C)(C)O)c(C)c1
Reactant: OC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(CCC(C)(C)O)c(C)c1)c1ccc(OC[C@@H](O)CO)c(C)c1
Temperature: 80 °C
Yield: 46.7 %

Procedure:
To a solution of 4-{1-ethyl-1-[4-(3-hydroxy-3-methylbutyl)-3-methyl-phenyl]propyl}-2-methylphenol (0.14 g, 0.40 mmol) in anhyd DMF (2 mL) was added CsF (67 mg, 0.44 mmol), Cs2CO3 (26 mg, 80 □ mol) and (S)-glycidol (29 μL, 0.44 mmol). The reaction mixture was heated at 80° C. for 4 h. After cooling, the mixture was diluted with DCM (40 mL), washed with H2O (2×40 mL), 1 N HCl (20 mL) and brine, then dried (Na2SO4) and concentrated under reduced pressure. The crude material was chromatographed (silica, EtOAc/DCM, 0:100 to 75:25) to provide the title compound (80 mg, 47%) as a white powdered solid: 1H-NMR (CD2Cl2) δ 7.01 (1H, d, J=8.1), 6.96 (1H, dd, J=2.3, 8.3), 6.88-6.94 (3H, m), 6.73 (1H, d, J=8.3), 3.97-4.11 (3H, m), 3.77-3.84 (1H, m), 3.69-3.76 (1H, m), 2.62 (2H, m), 2.53 (1H, d, J=5.1), 2.24 (3H, s), 2.16 (3H, s), 2.05 (4H, q, J=7.3), 1.99 (1H, t, J=6.1), 1.67 (2H, m), 1.27 (6H, s), 0.58 (6H, t, J=7.3); 13C-NMR (CD2Cl2) δ 155.0, 147.2, 142.0, 138.4, 135.7, 131.2, 130.4, 128.5, 126.9, 126.3, 126.2, 110.9, 71.4, 71.3, 70.1, 64.6, 49.3, 45.2, 29.8, 29.6, 28.3, 20.0, 17.0, 8.9.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].ClN1C(=[O:19])CCC1=O>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:19])[NH:8]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: O=C1Cc2c(cccc2[N+](=O)[O-])N1
Temperature: 70 °C

Procedure:
A mixture of 4-nitroindole (12.2 g, 75.2 mmol) and N-chlorosuccinimide (6.07 g, 30.1 mmol) in CHCl3 (500 mL) was heated at reflux for 30 h, then concentrated to dryness under reduced pressure. The residue was dissolved in AcOH (200 mL) and the resulting solution was warmed to 70° C., then 85% H3PO4 (80 mL) was added over 2 min. The mixture was heated to reflux for 90 min then cooled on ice. The cooled mixture was adjusted to pH 6 by addition of 10 N NaOH (450 mL), followed by aqueous NaHCO3, keeping the temperature below 30° C. The mixture was extracted with EtOAc (3×1 L) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was partially purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, and then triturated with MeOH to give the title compound. MS: m/z=179 (M+1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][C:14](O)([CH3:17])[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.[OH:19]S(O)(=O)=O.[C:24](#[N:26])[CH3:25]>>[C:24]([NH:26][C:14]1([CH3:17])[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]=3[CH:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1)(=[O:19])[CH3:25]
Reactant: O=S(=O)(O)O
Reactant: CC#N
Reactant: CC1(O)CCN(c2cccc3c2OCCO3)CC1
Product: CC(=O)NC1(C)CCN(c2cccc3c2OCCO3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.03 g (4.1 mmol) of the product of Step 1 are dissolved in 4 ml of acetonitrile. 1 ml of concentrated H2SO4 is added dropwise over a period of 5 minutes while the temperature is maintained below 40° C. The whole is stirred overnight at room temperature and then poured into 50 ml of ice-cold 1N sodium hydroxide solution. The whole is extracted with methylene chloride, washed with water, dried and evaporated to yield 0.85 g of residue, which is purified by flash chromatography (eluants:methylene chloride/ethyl acetate: 50/50, then methylene chloride/methanol: 98/2). 0.54 g of the expected product is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[C:14]([O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O.O>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([O:18][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:27])=[CH:21][CH:22]=3)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Reactant: c1cc(CN2CCNCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(N2CCN(Cc3ccncc3)CC2)cc1
Temperature: 130 °C
Reaction time: 21 h
Yield: 70.2 %

Procedure:
To a solution of 1-[(4-Pyridyl)methyl]piperazine (1.00 g, 5.6 mmol) in DMSO (4.5 mL) in a pressure vessel was added t-butyl-4-fluorobenzoate (1.05 g, 5.4 mmol) followed by potassium carbonate (0.74 g, 5.4 mmol). The pressure vessel was closed and the mixture was stirred at 130° C. for 21 h. The mixture was diluted with EtOAc (300 mL) and water (50 mL). The organic layer was separated, washed with a saturated NaHCO3 solution, brine, dried over MgSO4, and concentrated in vacuo. The residue obtained was purified by flash chromatography using 0-5% MeOH in DCM to afford the title compound 338 as a pink solid (1.34 g, 71% yield).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([S:15]([C:18]2[CH:19]=[CH:20][C:21]([OH:27])=[C:22]([C:24](=[O:26])[CH3:25])[CH:23]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[C:9]1([S:15]([C:18]2[CH:19]=[CH:20][C:21]([O:27][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:22]([C:24](=[O:26])[CH3:25])[CH:23]=2)(=[O:17])=[O:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Benzyl bromide (1.443 g; 0.0087 mol) was added to a suspension of 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone (2.01 g; 0.0073 mol) and potassium carbonate (2.01 g; 0.015 mol) in acetonitrile (5.0 mL). The mixture was heated under reflux for 18 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate, filtered, washed with water and saturated sodium bicarbonate, dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (hexane-ethyl acetate; 7:3) to give 1-(5-benzenesulfonyl-2-benzyloxy-phenyl)-ethanone as a white solid (2.17 g; 81%). A sample was recrystallized from diethyl ether-hexane: M. p. 80.5-82.4° C.