Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[C:38]1([CH2:44][S:45](Cl)(=[O:47])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[CH:27]1([CH2:26][NH:25][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]([OH:24])=[C:14]([C:8]3[NH:7][C:6]4[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:45]([CH2:44][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)(=[O:47])=[O:46])[C:11]=4[S:10](=[O:12])(=[O:13])[N:9]=3)[C:15]2=[O:30])[CH2:28][CH2:29]1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1c(C2=NS(=O)(=O)c3c(CNS(=O)(=O)Cc4ccccc4)csc3N2)c(O)c2ccccc2n1NCC1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of the product of Example 353E (16.5 mg, 0.037 mmol) in N,N-dimethylformamide (0.4 mL) was added triethylamine (0.011 mL, 0.079 mmol). The mixture was cooled to 0° C. and α-toluene sulfonyl chloride was added (0.008 g, 0.041 mmol). The reaction mixture was warmed to 23° C. and stirred for 0.5 hours. The reaction mixture was then heated to 50° C. and stirred for 1.75 hours. Additional triethylamine (0.010 mL, 0.074 mmol) and α-toluene sulfonyl chloride (0.007 g, 0.037 mmol) were added and the reaction mixture was stirred at 23° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with a gradient of 10% acetonitrile/0.1% trifluoroacetic acid in water to 95% acetonitrile/0.1% trifluoracetic acid in water to give the title compound (7.7 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ 0.15 (d, J=4.04 Hz, 2 H) 0.42 (d, J=7.72 Hz, 2 H) 1.00 (m, 1 H) 2.84 (d, J=7.35 Hz, 2 H) 4.23 (d, J=5.52 Hz, 2 H) 4.44 (s, 2 H) 6.37 (bs, 1 H) 7.32 (s, 1 H) 7.42 (m, 6 H) 7.86 (m, 2 H) 8.07 (d, J=8.46 Hz, 1 H) 8.16 (dd, 1 H) 14.50 (bs, 1 H).
Reaction SMILES: [NH:1]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C@H:2]([C:7]([NH:9][C@H:10]([C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:44]([O:46]C)=O)[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].O.[NH2:59][NH2:60]>CO>[NH:1]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C@H:2]([C:7]([NH:9][C@H:10]([C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:44]([NH:59][NH2:60])=[O:46])[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)NN
Reaction time: 20 h

Procedure:
3.97 g of Z-Asn-Lys(BOC)-Phe-His-OMe are dissolved in 20 ml of boiling methanol. 2.5 ml of hydrazine hydrate are added to the solution whilst it is still at about 30° C. and the mixture is allowed to stand for 20 hours at room temperature. The peptide-hydrazide is precipitated by adding water, filtered off and washed with water until free of hydrazine. The product is reprecipitated from dimethylformamide-water.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:25]([C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[N:19]=[C:14]([C:8]4[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:3][CH2:4]4)[C:15]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:33][CH2:32]1)(=[O:36])[CH3:35]
Reactant: Cc1ccc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)nc(C)nc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f57) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[O:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH:9]=2)[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:3]=1.[CH3:25][O:26][CH2:27][CH2:28][NH:29][CH3:30].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1>[O:12]1[CH2:13][CH2:14][CH2:15][O:16][CH:11]1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:3]=[C:2]2[N:29]([CH2:28][CH2:27][O:26][CH3:25])[CH3:30]
Reactant: CNCCOC
Reactant: C[Si](C)(C)CCOCn1nc(Cl)c2cc(C3OCCCO3)ccc21
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCN(C)c1nn(COCC[Si](C)(C)C)c2ccc(C3OCCCO3)cc12
Temperature: 25 °C
Yield: 54 %

Procedure:
To a degassed solution of 400 mg (1.08 mmol) 3-chloro-5-(1,3-dioxan-2-yl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-indazole (Example 45A) and 135 mg (1.52 mmol) 2-methoxy-N-methylethanamine in anhydrous THF (11 ml) were added under inert gas atmosphere 103 mg (0.22 mmol) 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl (XPhos), 50 mg (0.054 mmol) tris(di-benzylideneacetone)dipalladium(0) (Pd2dba3) and 5.42 ml (5.42 mmol) lithium hexamethyldisilazide solution (1 M in THF). The resulting mixture was stirred under reflux for 12 h. After cooling to room temperature and concentration under reduced pressure, the remaining solid was dissolved in ethyl acetate (20 ml). The solution was washed with water and with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (acetonitrile/water gradient, final mixture 90:10 v/v) to yield the title compound as a white solid (246 mg, 42% of th.).
Reaction SMILES: [CH2:1]([C:13]1[CH:14]=[C:15]([C:18]2[C:23]3=[N:24][S:25][N:26]=[C:22]3[C:21](Br)=[C:20]([Cl:28])[C:19]=2[Cl:29])[S:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:30]([C:42]1[CH:43]=[C:44]([Sn](C)(C)C)[S:45][CH:46]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC1C=CC=CC=1>[CH2:1]([C:13]1[CH:14]=[C:15]([C:18]2[C:23]3=[N:24][S:25][N:26]=[C:22]3[C:21]([C:44]3[S:45][CH:46]=[C:42]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:43]=3)=[C:20]([Cl:28])[C:19]=2[Cl:29])[S:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1csc(-c2c(Cl)c(Cl)c(Br)c3nsnc23)c1
Reactant: CCCCCCCCCCCCc1csc([Sn](C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: CCCCCCCCCCCCc1csc(-c2c(Cl)c(Cl)c(-c3cc(CCCCCCCCCCCC)cs3)c3nsnc23)c1
Temperature: 120 °C
Yield: 93 %

Procedure:
4-(4-Dodecyl-thiophen-2-yl)-5,6-dichloro-7-bromo-benzo[1,2,5]thiadiazole (0.530 g, 0.99 mmol), (4-dodecyl-thiophen-2-yl)-trimethyl-stannane (0.577 g, 1.39 mmol), and Pd(PPh3)2Cl2 (34.8 mg) were placed in a 100-mL Schlenk flask. The system was subjected to three quick vacuum-nitrogen cycles and 40 mL of anhydrous chlorobenzene was added. The mixture was heated at 120° C. for 17 hours. After the reaction was cooled down, the solvent was removed by rotary evaporation. The product was purified by silica gel column with chloroform/hexane (v/v, 1/1) as the eluent. The final product (650 mg, 92.8% yield) was obtained as an orange solid after being dried in vacuo. 1H NMR (CDCl3, 500 MHz): δ 7.49 (d, 2H, J=1.0 Hz), 7.22 (d, 2H, J=1.0 Hz), 2.72 (t, 4H, J=8.0 Hz), 1.71 (m, 4H), 1.27 (m, 36H), 0.89 (t, 6H, 7.0 Hz). 13C NMR (CDCl3, 500 MHz): δ 152.71, 143.12, 134.32, 134.23, 132.64, 126.42, 123.09, 31.97, 30.53, 30.46, 29.74, 29.72, 29.70, 29.67, 29.54, 29.42, 22.75, 14.19. Anal. calcd. for (C38H54Cl2N2S3): C, 64.65; H, 7.71; N, 3.97. Found: C, 64.72; H, 7.65; N, 3.98. m.p: 79-80° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]([O:31][C:32]([NH:34][C@@H:35]([CH2:44]O)[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32]([NH:34][C@@H:35]([CH2:44][I:25])[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: II
Reactant: CC(C)(C)OC(=O)C[C@H](CO)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H](CI)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
Triphenylphosphine (1.07 g, 4 mmol), imidazole (277 mg, 4 mmol) and iodine (1.02 g, 4 mmol) were dissolved into methylene chloride (12 mL) under nitrogen atmosphere. (R)-tert-butyl 3-(tert-butoxycarbonylamino)-4-hydroxybutanoate (275 mg, 1 mmol) was dissolved into methylene chloride (4 mL) and added dropwise to the solution. After 1 h, methylene chloride (100 mL) was added and the solution was filtered through celite. The filtrate was washed with 1% sodium bisulfite solution (2×10 mL), brine (20 mL), dried over MgSO4 and concentrated to dryness. The residue was purified by silica gel chromatography (ethyl acetate/hexanes 1:1) to give the title compound (225 mg, 58%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.05-6.95 (m, 1H), 4.04-3.97 (m, 1H), 3.77-3.65 (m, 2H), 2.55-2.50 (m, 1H), 2.38-2.27 (m, 1H), 1.39 (s, 9H), 1.36 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[NH:4][N:3]=1.[C:12]1([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O-:29])=O)=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([C:18]([O-:20])=O)=[CH:14][CH:13]=1>>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[NH:4][N:3]=[C:2]([NH:1][C:27]([C:24]2[CH:23]=[CH:22][C:21]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([NH:1][C:2]4[CH:6]=[C:5]([C:7]5[O:8][CH:9]=[CH:10][CH:11]=5)[NH:4][N:3]=4)=[O:20])=[CH:16][CH:17]=3)=[CH:26][CH:25]=2)=[O:29])[CH:6]=1
Reactant: Nc1cc(-c2ccco2)[nH]n1
Reactant: O=C([O-])c1ccc(-c2ccc(C(=O)[O-])cc2)cc1
Product: O=C(Nc1cc(-c2ccco2)[nH]n1)c1ccc(-c2ccc(C(=O)Nc3cc(-c4ccco4)[nH]n3)cc2)cc1

Procedure:
Compound 468 was prepared from 3-amino-5-(2-furanyl)pyrazole and 4,4′-biphenyldicarboxylate. [M+H]+ calcd for C28H21N6O4: 505.16; found: 504.93.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[Cl:23][C:24]1[C:25]([C:33]([F:36])([F:35])[F:34])=[C:26]([CH2:30][CH2:31][NH2:32])[CH:27]=[CH:28][CH:29]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:24]1[C:25]([C:33]([F:34])([F:35])[F:36])=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:30][CH2:31][NH:32][C:11]1[N:10]=[C:9]([NH:8][C@@H:5]2[CH2:6][CH2:7][C@H:2]([OH:1])[C:3]([CH3:22])([CH3:21])[CH2:4]2)[C:14]([C:15]#[N:16])=[CH:13][N:12]=1
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Reactant: NCCc1cccc(Cl)c1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C[C@H](Nc2nc(NCCc3cccc(Cl)c3C(F)(F)F)ncc2C#N)CC[C@@H]1O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 39.1 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (75 mg, 0.23 mmol), 2-(3-chloro-2-(trifluoromethyl)phenyl)ethanamine (100 mg, crude) and DIEA (85 mg, 0.66 mmol) in THF (2 mL) was stirred at 100° C. in a microwave reactor for 1.5 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by standard methods to afford the title compound (42.2 mg, 0.090 mmol, 39% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.10-8.03 (m, 1H), 7.48-4.41 (m, 2H), 7.30 (m, 1H), 4.31-4.28 (m, 1H), 3.73-3.69 (m, 1H), 3.63-3.56 (m, 1H), 3.39-3.37 (m, 1H), 3.17-3.14 (m, 2H), 1.88-1.44 (m, 6H), 0.97 (s, 3H), 0.96 (s, 3H). MS (ESI) m/z 468.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Cl.C(N1C2C(=CC=C(C(O)=O)C=2)C=C1)C1C=CC=CC=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][N:8]2[CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:13]=2[Cl:12])=[CH:4][CH:3]=1
Reactant: Cc1n[nH]c2cc(Br)ccc12
Reactant: ClCc1cccc(Cl)c1Cl
Agent: O=C(O)c1ccc2ccn(Cc3ccccc3)c2c1
Product: Cc1nn(Cc2cccc(Cl)c2Cl)c2cc(Br)ccc12
Yield: 85.5 %

Procedure:
The titled compound (228 mg) as a white solid was prepared from the 6-bromo-3-methyl-1H-indazole (152 mg) obtained with the method described in the document (JP 2009-528363 W) and 2,3-dichlorobenzyl chloride (215 mg) according to the method of the process (1) of Example 66.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH:16]3[CH2:21][C:20]([CH3:23])([CH3:22])[NH:19][C:18]([CH3:25])([CH3:24])[CH2:17]3)[N:12]=[C:11]([NH:26][CH:27]3[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]3)[N:10]=2)[CH2:5][C:4]([CH3:38])([CH3:37])[NH:3]1.[CH2:40]=[O:41].[OH-].[Na+]>C(O)(=O)C.O>[CH3:33][C:31]1([CH3:34])[CH2:32][CH:27]([NH:26][C:11]2[N:10]=[C:9]([NH:8][CH:6]3[CH2:5][C:4]([CH3:38])([CH3:37])[NH:3][C:2]([CH3:39])([CH3:1])[CH2:7]3)[N:14]=[C:13]([N:15]([CH:16]3[CH2:17][C:18]([CH3:24])([CH3:25])[NH:19][C:20]([CH3:22])([CH3:23])[CH2:21]3)[CH2:40][OH:41])[N:12]=2)[CH2:28][C:29]([CH3:36])([CH3:35])[NH:30]1
Reactant: C=O
Reactant: CC1(C)CC(Nc2nc(NC3CC(C)(C)NC(C)(C)C3)nc(NC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CC(Nc2nc(NC3CC(C)(C)NC(C)(C)C3)nc(N(CO)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
54.3 g of 2,4,6-tris-(2,2,6,6-tetramethyl-4-piperidylamino)-1,3,5-triazine are dissolved in 200 ml of glacial acetic acid. After addition of 20 ml of 36% formaldehyde solution, the reaction mixture is stirred for 18 hours at room temperature, then diluted with water, made strongly alkaline with concentrated sodium hydroxide solution and extracted with toluene. The toluene solution is dried over sodium sulphate and concentrated in vacuo. Crystallisation of the residue yields 2,4-bis-(2,2,6,6-tetramethyl-4-piperidylamino)-6-(2,2,6,6-tetramethyl-4-piperidyl-methylolamino)-1,3,5-triazine in the form of colourless crystals with a melting point of 201°-202° C.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>COCCOC>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[CH:12][CH:13]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(I)cc1
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26 %

Procedure:
tert-Butyl[2-(4-iodophenyl)ethoxy]dimethylsilane (7.1 g, 19.6 mmol), (4-bromophenyl)boronic acid (4.8 g, 23.9 mmol), tripotassium phosphate n-hydrate (10.4 g, 49.0 mmol) and a [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.80 g, 0.98 mmol) were suspended in 1,2-dimethoxyethane (150 mL), followed by stirring at room temperature for 4 hours under a nitrogen atmosphere. After the reaction solution was filtered with celite, the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane), and a fraction corresponding to the Rf value=0.90 (hexane/ethyl acetate=19/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (2.0 g, 5.1 mmol) as a white solid (yield 26%).
Reaction SMILES: FC1C=CC=CC=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[F:61][C:62]1[CH:63]=[C:64](N=C=S)[CH:65]=[CH:66][CH:67]=1>>[F:61][C:62]1[CH:67]=[C:66]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:15][CH:16]=2)[CH:65]=[CH:64][CH:63]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Reactant: Fc1cccc(N=C=S)c1
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(F)c4)cc3)ccc2C1=O

Procedure:
The compound of example 258 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 3-fluorophenyl isothiocyanate. The compound of example 258 was used directly without isolation for the preparation of compound of example 259.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>C1COCC1>[C:24]([O:16][C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1)(=[O:26])[CH3:25]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1oc2cccc(OC(C)=O)c2c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of ethyl-4-hydroxy-3-methylbenzofuran-2-carboxylate (2.2 g, 10 mmol) in dry THF (30 ml) was added triethylamine (2.07 ml, 15 mmol) followed by acetyl chloride (0.85 ml, 12 mmol). The mixture was stirred at 0° C. for 1 hour, and at room temperature for 2 hours, and was then poured into ice water (200 ml). The white precipitate was collected by filtration.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][C@@H:4]1[NH:8][C:7](=[O:9])[CH2:6][C:5]1=[O:10].[H][H]>C(O)C.[Ni]>[OH:10][C@@H:5]1[C@H:4]([CH2:3][CH:2]([CH3:1])[CH3:11])[NH:8][C:7](=[O:9])[CH2:6]1
Reactant: [H][H]
Reactant: CC(C)C[C@@H]1NC(=O)CC1=O
Agent: [Ni]
Solvent: CCO
Product: CC(C)C[C@@H]1NC(=O)C[C@@H]1O
Reaction time: 5 h
Yield: 63.2 %

Procedure:
A solution of 5 g of (S)-5-(2-methylpropyl)-2,4-pyrrolidinedione in 250 ml of ethanol is treated with 2 g of Raney nickel (washed to neutral) and exposed to hydrogen gas at 50 pounds per square inch (psi). After 5 hours, hydrogen uptake ceases, the catalyst is filtered and the filtrate evaporated to a gum. The gum is taken up in chloroform and the chloroform is evaporated. The resulting gum is dissolved in chloroform, filtered through a 250 ml bed of silica gel in chloroform and eluted with chloroform-methanol (96:4) to afford 3.2 g of (4S-cis)-4-hydroxy-5-(2-methylpropyl)-2-pyrrolidinone after crystallization from 12 ml of hot ethyl acetate, 120 ml isopropyl ether and gradual cooling to 10° C.; mp 71°-73° C. [α]D23 =-19° (C=0.7% chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[O:36])[CH:30]=[C:31]([F:33])[CH:32]=1>>[CH3:22][O:21][C:19](=[O:20])[C@@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:35]([NH:34][C:29]4[CH:30]=[C:31]([F:33])[CH:32]=[C:27]([F:26])[CH:28]=4)=[O:36])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[CH:23]([CH3:25])[CH3:24]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C=Nc1cc(F)cc(F)c1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cc(F)cc(F)c4)cc3)cc2C1=O

Procedure:
The compound of example 29 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 3,5-difluorophenyl isocyanate. The compound of example 29 was used directly without isolation for the preparation of compound of example 30.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.CS(C)=O.[Cl-]>C1COCC1>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=3)[CH:5]=[CH:4][N:3]=2)=[CH:18][CH:17]=1
Reactant: Nc1ncc(-c2ccnc(Cl)n2)cn1
Reactant: Nc1ccc(F)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Nc1ncc(-c2ccnc(Nc3ccc(F)cc3)n2)cn1
Temperature: 150 °C
Yield: 12.7 %

Procedure:
To a suspension of 2-chloro-4,5′-bipyrimidin-2′-amine (30) (110 mg, 0.530 mmol) in THF (5298 μl), 4-Fluoroaniline (100 μl, 1.060 mmol) was added. DMSO (1 mL) was added to dissolve the starting chloride, and the suspension was heated to 150° C. in the microwave for 2 hours. The crude reaction mixture was filtered through a syringe filter, then purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] to obtain a reddish purple product. The product was triturated with acetone and acetonitrile, then filtered to obtain a slightly gray solid as the desired product (19 mg, 13% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.15 (t, J=9.09 Hz, 2H) 7.22 (s, 2H) 7.31 (d, J=5.05 Hz, 1H) 7.79 (dd, J=9.09, 5.05 Hz, 2H) 8.44 (d, J=5.05 Hz, 1H) 8.99 (s, 2H) 9.59 (s, 1H). HRMS (ES+) for C14H11FN6.H+ [MH+]: calcd, 283.1107; found, 283.1108. UV-LC: 100/100% UV purity at 214/254 nm; tR=1.07 minutes over 7.75 minutes.
Reaction SMILES: [BrH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.BrBr.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=1>C(O)(=O)C.C(OC)(C)(C)C>[BrH:1].[Br:1][CH:5]1[C:6]([C:15]2[C:16]([O:22][CH3:23])=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[O:13][CH3:12])=[CH:7][CH2:8][N:3]([CH3:2])[CH2:4]1
Reactant: CN1CCC(=O)CC1
Reactant: COc1cc(OC)cc(OC)c1
Agent: Br
Agent: BrBr
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: COc1cc(OC)c(C2=CCN(C)CC2Br)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
75.7 ml (0.44 mol) of 33% strength HBr in glacial acetic acid were added to 200 ml of glacial acetic acid, and 50 g (0.44 mol) of 1-methylpiperidin-4-one (III) were then rapidly added dropwise at 20-25° C. with ice-cooling. 70.4 g (0.44 mol) of bromine were added dropwise at 20-25° C. in the course of 30 min to the suspension of the hydrobromide obtained in this way, a clear, yellowish solution being obtained. This was stirred at 25° C. for a further 15 min and 67.2 g (0.40 mol) of 1,3,5-trimethoxybenzene (V) were then added to the reaction solution. It was then stirred at 25° C. for 1 h. After this, 300 ml of methyl tert-butyl ether were allowed to run in, the product being deposited in oily form. The supernatant was decanted off, the residue was stirred again with 300 ml of methyl tert-butyl ether and the supernatant was decanted off. The residue was then stirred with 150 ml of dichloromethane, the product crystallizing out. The 3(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine hydrobromide (VI) obtained was filtered off with suction, washed with 50 ml of dichloromethane and dried in vacuo.