Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.O.[CH3:17][N:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([N:18]([CH3:19])[CH3:17])=[N:21][CH:22]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CN(C)c1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccc(N(C)C)nc2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 2-(N,N-dimethylamino)pyridine-5-boronic acid hydrate (0.335 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 1.3 h to give 5-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-N,N-dimethylpyridin-2-amine as a yellow solid. Mass Spectrum (ESI) m/e=344.1 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][C:13]=1[O:20][CH3:21])(=[O:3])[CH3:2].[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([N+:22]([O-:24])=[O:23])[C:15]([CH:18]=[O:19])=[CH:14][C:13]=1[O:20][CH3:21])(=[O:3])[CH3:2]
Reactant: COc1cc(C=O)ccc1OCCCCCCOC(C)=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc(C=O)c([N+](=O)[O-])cc1OCCCCCCOC(C)=O
Yield: 92 %

Procedure:
A 250 mL round bottom flask was charged with 3 (10 g, 34 mmol) and was then placed in an ice bath. To this was added a 20% v/v solution of fuming nitric acid in acetic acid (40 mL total volume) at a rate of 1.0 mL/minute with stirring. At the end of addition the bath was removed, the reaction was protected from light, and stirred at room temperature for 4 hours. At this time the solution was poured over crushed ice (200 mg). Water was added and the product was extracted with ethyl acetate (3×200 mL). The combined organics were washed with brine (1×200 mL), saturated sodium bicarbonate (1×200 mL), and water (1×200 mL), dried over magnesium sulfate, and filtered. The solvent was evaporated in vacuo to give 10.6 g of 4 (92%) as an orange-red solid. Rf=0.80 (33% ethyl acetate/hexane). Mp 79.8-81.5° C. 1H NMR (400 MHz, DMSO-d6): δ7.69 (s, 1), 7.37 (s,1), 4.17 (pt, J=6.4, 6.8 Hz, 2), 4.0 (t, J=6.8 Hz, 2), 3.95 (s,3), 1.99 (s, 3), 1.77 (m, 2), 1.59 (m, 2), 1.45-1.37 (m, 4) ppm.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:29])([CH3:28])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:14]([NH:16][C:17]1[CH:22]=[N:21][C:20]([CH3:23])=[CH:19][N:18]=1)=[O:15])[CH3:9])([CH3:4])[CH3:3].[N:30]1([C:34]([C:36]2[CH:41]=[N:40][C:39](Cl)=[CH:38][N:37]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[N:30]1([C:34]([C:36]2[N:37]=[CH:38][C:39]([O:27][C:25]3[CH:24]=[C:13]([CH:12]=[C:11]([O:10][C@@H:8]([CH3:9])[CH2:7][O:6][Si:5]([C:2]([CH3:3])([CH3:4])[CH3:1])([CH3:28])[CH3:29])[CH:26]=3)[C:14]([NH:16][C:17]3[CH:22]=[N:21][C:20]([CH3:23])=[CH:19][N:18]=3)=[O:15])=[N:40][CH:41]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
A mixture of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide (0.12 g, 0.29 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (57 mg, 0.29 mmol) and potassium carbonate (80 mg, 0.57 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 140° C. for 1 hour. The mixture was reduced in vacuo and ethyl acetate (50 mL) added. The mixture was washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo to give a brown oil which was chromatographed on silica, eluting with 50 to 100% ethyl acetate in isohexane, to give the desired compound as a colourless oil (90 mg). 1H NMR δ (CDCl3): −0.03 (s, 3H), 0.00 (s, 3H), 0.81 (s, 9H), 1.26 (d, 3H), 2.32 (quin, 2H), 2.49 (s, 3H), 3.61-3.76 (m, 2H), 4.20 (t, 2H), 4.46 (sextet, 1H), 4.62 (t, 2H), 6.91 (t, 1H), 7.21 (t, 1H), 7.32 (t, 1H), 8.07 (s, 1H), 8.28 (d, 1H), 8.30 (s, 1H), 8.79 (d, 1H), 9.48 (d, 1H). m/z 579 (M+H)+
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([CH3:51])=[C:22]([C:29]([C:31]3[CH:40]=[C:39]4[C:34]([C:35](=[O:50])[N:36]([CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:37](=[O:41])[NH:38]4)=[CH:33][CH:32]=3)=[O:30])[N:23]3[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]3)=[CH:16][CH:15]=1.[NH2:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][OH:58].OS([O-])(=O)=O.[K+]>CN(C=O)C>[OH:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53][NH:52][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([CH3:51])=[C:22]([C:29]([C:31]3[CH:40]=[C:39]4[C:34]([C:35](=[O:50])[N:36]([CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:37](=[O:41])[NH:38]4)=[CH:33][CH:32]=3)=[O:30])[N:23]3[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]3)=[CH:16][CH:15]=1
Reactant: NCCOCCO
Reactant: Cc1c(-c2ccc(OCCCCCI)cc2)c2ccccn2c1C(=O)c1ccc2c(=O)n(CC(=O)OC(C)(C)C)c(=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(OCCCCCNCCOCCO)cc2)c2ccccn2c1C(=O)c1ccc2c(=O)n(CC(=O)OC(C)(C)C)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
Potassium carbonate (0.48 g, 3.46 mmol) and tert-butyl {7-[(1-{4-[(5-iodopentyl)oxy]phenyl}-2-methylindolizin-3-yl)carbonyl]-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}acetate (0.50 g, 0.69 mmol) are added to a solution of 2-(2-aminoethoxy)ethanol (0.73 g, 6.93 mmol) in 7 mL of DMF. The solution is stirred for 24 h at ambient temperature and then run into a molar solution of KHSO4. The precipitate formed is filtered off, washed with water and dried under vacuum to give 380 mg (yield: 79%) of a brown powder.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[CH3:25])[CH2:13][CH2:14][CH3:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[CH2:12]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[C:17]1[CH3:25])[CH2:13][CH2:14][CH3:15]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCn1c(C)cc2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21

Procedure:
To a stirred mixture containing 7.4 g. of phthalic anhydride and 16.0 g. of 1-butyl-2-methylindole at 0°-5° C. was added portionwise 13.3 g. of aluminum chloride. The mixture was diluted with 50 ml. of benzene and stirred overnight at room temperature. The reaction mixture was poured into 200 ml of 5% hydrochloric acid and the product extracted with benzene. The benzene extracts were shaken with dilute aqueous potassium hydroxide. The aqueous alkaline layer was separated, cooled with ice and brought to pH 4 with acetic acid. The precipitated product was collected and dried to give 2-(1-butyl-2-methyl-3-indolylcarbonyl)benzoic acid, m.p. 88°-92° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17]Cl>>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:6]=[O:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: COCCOCCl
Product: COCCOCOc1ccc(C=O)cc1OC
Yield: 36.2 %

Procedure:
The hydroxyl group of 4-hydroxy-3-methoxybenzaldehyde (1.4 g) was protected by use of 2-methoxyethoxymethyl chloride (1.7 g) in accordance with (production process 1), to thereby produce 3-methoxy-4-methoxyethoxymethoxybenzaldehyde (0.8 g, yield: 31%). The thus-produced 3-methoxy-4-methoxyethoxymethoxybenzaldehyde (0.8 g) and 3,4-dimethoxybenzyl cyanide (0.6 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (0.5 g, yield: 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:39])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:39])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
110 mg (0.28 mmol) of the compound from Example 100 were introduced into 20 ml of dichloromethane at 0° C., 68 mg (0.28 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 93 mg (81% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: [Cl-].[CH2:2]([O:4][CH:5]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:3].CN(C)C(=N)N(C)C.[CH:38]([C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][CH:44]=[CH:43]2)=O>ClCCl>[CH2:9]([O:8][C:6](=[O:7])/[C:5](/[O:4][CH2:2][CH3:3])=[CH:38]/[C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][CH:44]=[CH:43]2)[CH3:10]
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)/C(=C/c1ccc2[nH]ccc2c1)OCC
Reaction time: 16 h
Yield: 94.4 %

Procedure:
To a solution of 25.73 g of (1,2-diethoxy-2-oxoethyl)triphenyl phosphonium chloride in 200 ml of dichloromethane was added at 0° C. 8.0 ml of tetramethyl guanidine and the mixture was warmed to 22° C. The mixture was treated with 5.81 g of 5-formyl-indole and stirring was continued at 40° C. for 16 h. The mixture was treated again with 25.73 g of the Wittig salt and 8.0 ml of tetramethyl guanidine and stirring was continued at 40° C. for 24 h after which time the conversion was complete. The mixture was evaporated and the residue partitioned between AcOEt and water. The organic layer was dried, evaporated and the residue chromatographed on silica (n-hexane/AcOEt, 2:1) to give 9.80 g of the title compound as an oil which solidified on storing at 22° C. to give a pale yellow solid. MS: (M)+ 259.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH2:7]1.Cl[C:21]1[N:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][N:22]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][NH:15][C:21]2[N:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:25][N:26]=2)[CH2:8][CH2:7]1
Reactant: NCCNC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: Clc1ncc(-c2ccccc2)cn1
Solvent: Cc1ccccc1
Product: Clc1ccc(CN2CCC(NCCNc3ncc(-c4ccccc4)cn3)CC2)cc1Cl

Procedure:
The title compound (20 mg) was prepared by heating at reflux N1-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-1,2-ethanediamine (100 mg) and 2-chloro-5-phenypyrimidine (100 mg) and Hunigs' base (100 mg) in toluene for 8 hours. The mixture was purified by chromatography on silica, with ethyl acetate methanol (9:1) as eluant to give the title compound as a yellow oil. MS [M+h]+ (ES+) 456/8 1H NMR: (CDCl3) δ 1.51 (2H, m), 1.75 (2H, m), 2.15 (2H, td), 2.9 (2H, m), 3.05 (1H, m), 3.15 (2H, m), 3.44 (2H, m), 3.8 (2H, m), 6.65 (1H, m), 7.0-7.4 (8H, m), 8.5 (2H, m).
Reaction SMILES: [CH3:1][CH:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:11][CH:2]([CH3:1])[CH2:3]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CNc2ccccc2N1
Product: CC(=O)N1CC(C)Nc2ccccc21

Procedure:
Using the method of Example 15, 3-methyl-1,2,3,4-tetrahydroquinoxaline is reacted with acetic anhydride to provide 1-acetyl-3-methyl-1,2,3,4-tetrahydroquinoxaline.
Reaction SMILES: C1(P([N:15]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[Br:25][C:26]1[C:27](C(O)=O)=[N:28][C:29]([Br:32])=[CH:30][N:31]=1>C(O)(C)(C)C>[Br:25][C:26]1[C:27]([NH2:15])=[N:28][C:29]([Br:32])=[CH:30][N:31]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1nc(Br)cnc1Br
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: Nc1nc(Br)cnc1Br
Reaction time: 0.5 h

Procedure:
Diphenylphosphorylazide (2.59 mL, 12 mmol) and triethylamine (1.67 mL, 12 mmol) are added to a solution of 3,6-dibromo-pyrazin-2-carboxylic acid (3.52 g, 12 mmol) in t-butanol (90 mL). The reaction is heated at reflux for 18 hours. The reaction is quenched with water, then concentrated in vacuo and taken up in DCM. The organic solution is washed with water and 1N NaOH, dried over MgSO4 and concentrated in vacuo. The resultant solid is filtered through a pad of silica using EtOAc, then concentrated and TFA:DCM (4:1, 12 mL) is added to the solid and stirred for 30 min. The solution is concentrated in vacuo then neutralised with 1N NaOH and extracted with DCM. The organic layer is dried over anhydrous MgSO4 and concentrated in vacuo to give the product. 1H NMR (250 MHz, DMSO-d6) δ(ppm) 7.25 (br s, 2H), 7.68 (s, 1H); m/z (APCI) 254 (M+H)+; m.p 135-139° C.
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[C:4]2[N:5]([C:9]([C:12]3[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=4)[CH3:22])[N:13]=3)=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[H][H]>C(O)C.O1CCCC1.[C].[Pd]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([C@@H:21]([NH:20][C:14]2[N:13]=[C:12]([C:9]3[N:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH:2]([F:32])[F:1])[C:4]4=[N:11][CH:10]=3)[C:17]([C:18]#[N:19])=[CH:16][N:15]=2)[CH3:22])=[CH:24][CH:25]=1
Reactant: C[C@H](Nc1ncc(C#N)c(-c2cnc3c(C(F)F)cccn23)n1)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@H](Nc1ncc(C#N)c(-c2cnc3c(C(F)F)cccn23)n1)c1ccc(N)cc1
Yield: 18.1 %

Procedure:
83 mg of the 4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]-2-{[(1S)-1-(4-nitrophenyl)ethyl]amino}pyrimidine-5-carbonitrile [103-1] was dissolved in a mixture solvent of 2 mL of ethanol and 3 mL of tetrahydrofuran, then 40 mg of 10% palladiumcarbon catalyst was added, and stirred overnight at room temperature in a hydrogen atmosphere. The insolubles were filtered through celite and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative thin-layer chromatography, and 14 mg of 2-{[(1S)-1-(4-aminophenyl)ethyl]amino}-4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-5-carbonitrile [103-2] was obtained as pale yellow amorphous.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[C@H:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[CH2:24]([C:28]1[CH:33]=[C:32](Cl)[N:31]=[C:30]([N:35]2[CH:39]=[C:38]([C:40]3[CH:45]=[CH:44][C:43]([O:46][C:47]([F:50])([F:49])[F:48])=[CH:42][CH:41]=3)[N:37]=[CH:36]2)[N:29]=1)[CH2:25][CH2:26][CH3:27]>CS(C)=O>[C:2]([O:6][C:7](=[O:14])[CH:8]([NH:9][C:32]1[CH:33]=[C:28]([CH2:24][CH2:25][CH2:26][CH3:27])[N:29]=[C:30]([N:35]2[CH:39]=[C:38]([C:40]3[CH:45]=[CH:44][C:43]([O:46][C:47]([F:48])([F:49])[F:50])=[CH:42][CH:41]=3)[N:37]=[CH:36]2)[N:31]=1)[CH2:10][CH:11]([CH3:12])[CH3:13])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: CCCCc1cc(Cl)nc(-n2cnc(-c3ccc(OC(F)(F)F)cc3)c2)n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1cc(NC(CC(C)C)C(=O)OC(C)(C)C)nc(-n2cnc(-c3ccc(OC(F)(F)F)cc3)c2)n1
Temperature: 80 °C
Yield: 84.9 %

Procedure:
L-Leucine tert-butyl ester hydrochloride (291 mg) was dissolved in DMSO (5 mL) under an argon atmosphere and treated with diisopropylethylamine (450 μL, 2.6 mmol, 4 eq.) followed by 4-Butyl-6-chloro-2-[4-(4-trifluoromethoxy-phenyl)-imidazol-1-yl]-pyrimidine (274 mg). The mixture was heated to 80° C. for 48 h. DMSO and the volatiles were removed in vacuo to give a crude residue from which 2-{6-butyl-2-[4-(4-trifluoromethoxyphenyl) imidazol-1-yl] pyrimidin-4-ylamino}-4-methyl-pentanoic acid tert-butyl ester (321 mg) was isolated by flash chromatography (n-hexanes/ethyl acetate 4/1).
Reaction SMILES: Br.[F:2][C:3]1[C:8]([O:9]C)=[C:7]([CH:11]=[O:12])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20]>C(O)(=O)C>[F:2][C:3]1[C:8]([OH:9])=[C:7]([CH:11]=[O:12])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20]
Reactant: COc1c(C=O)ccc(-c2ccc(F)cc2F)c1F
Agent: Br
Solvent: CC(=O)O
Product: O=Cc1ccc(-c2ccc(F)cc2F)c(F)c1O
Reaction time: 16 h
Yield: 94.5 %

Procedure:
48% hydrobromic acid (22.0 mL) was added at room temperature to an acetic acid (120 mL) solution of 2,2′,4′-trifluoro-3-methoxybiphenyl-4-carbaldehyde (5.14 g), and the mixture was stirred at 120 C for 16 hours in a nitrogen atmosphere. Then, the solvent was distilled off under reduced pressure. The obtained residue was neutralized with a 1 M aqueous sodium hydroxide solution at room temperature, followed by extraction with ethyl acetate. The organic layer was separated, then washed with water and saturated saline in this order, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was passed through a short silica gel column, and the solvent was distilled off under reduced pressure to obtain the title compound (4.60 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)[CH2:9][CH2:10][CH3:11])[CH:3]=1>[Pd].C(O)C>[N:12]1([N:8]([CH2:9][CH2:10][CH3:11])[C:4]2[CH:3]=[CH:2][N:7]=[CH:6][N:5]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1
Reactant: CCCN(c1cc(Cl)ncn1)n1ccc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CCCN(c1ccncn1)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To 100 ml ethanol, was added 10% Pd/C (1.2 g), MgO (1.0 g), and 6-chloro-N-(1H-indol-1-yl)-N-propyl-4-pyrimidinamine (4.2 g). After stirring under H2 at ambient temperature for three hours, the mixture was filtered, and the filtrate evaporated to 4.0 g of an oil. This material was eluted on a silica gel column with 10% ethyl acetate/DCM via HPLC, to give 2.4 g (66%) of an oil, product N-(1H-Indol-1-yl)-N-propyl-4-pyrimidinamine.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.S(Cl)(Cl)=O.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:1][C:2]1[S:3][C:4]([S:13]([Cl:12])(=[O:15])=[O:14])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1csc(Cl)n1
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Product: Cc1nc(Cl)sc1S(=O)(=O)Cl
Temperature: 0 °C
Yield: 89.9 %

Procedure:
At room temperature, 150 g (1.12 mol) of 2-chloro-4-methyl-1,3-thiazole are added dropwise to a solution of 331 g (2.81 mol) of thionyl chloride in 653 g (5.61 mol) of chlorosulphonic acid. The solution is heated at reflux for 48 h. The mixture is then poured into 3 l of ice-water and extracted with 4×400 ml of dichloromethane. The combined organic phases are washed with 2.5 l of water, dried over sodium sulphate and concentrated. Distillation of the crude product gives 233.7 g of product in the form of an oil. (Bp 87-96° C., 0.7 mbar, GC 98.1%, yield 89.6%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.[CH:16]1([CH:21]=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.N1CCCC1>CO>[CH:16]1([CH:21]=[C:11]2[CH2:10][CH2:9][C:8]3[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]=3[C:2]2=[O:1])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=CC1CCCC1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CCC(=CC1CCCC1)C2=O
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (3.4 g, 16.7 mmol) in methanol (30 mL) was added cyclopentanecarboxaldehyde (3.3 g, 33.3 mmol) and pyrrolidine (2.78 mL, 33.3 mmol). The solution was stirred for twenty hours at ambient temperature. The reaction was recharged with 0.5 mL of cyclopentanecarboxaldehyde. The resulting precipitate was collected by vacuum filtration to provide methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate as a solid (2.8 g, 60% yield). LC/MS on 4.6×50 mm C-18 column, tR=6.71 minutes (10 to 90% acetonitrile/water over 8 minutes at 2 mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 285 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24-1.39 (m, 2H), 1.52-1.74 (m, 4H), 1.76-1.89 (m, 2H), 2.77 (t, J=5.77 Hz, 2H), 2.79-2.90 (m, 1H), 2.97 (t, J=6.44 Hz, 2H), 3.85 (s, 3H), 6.71 (d, J=9.94 Hz, 1H), 7.88 (d, J=6.44 Hz, 1H), 7.91 (s, 1H), 7.98 (d, J=8.06 Hz, 1H).
Reaction SMILES: [C:1]([CH:4]1[NH:9][CH2:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[CH2:5]1)([OH:3])=[O:2].Cl.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(C)C>[CH2:14]([O:2][C:1]([CH:4]1[N:9]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[CH2:5]1)=[O:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C1Cc2ccsc2CN1
Reactant: ClCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: O=C(OCc1ccccc1)C1Cc2ccsc2CN1Cc1ccccc1
Yield: 53 %

Procedure:
Obtained according to a procedure analogous to that of Example 7, from 5-carboxy-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine (Example 6) and benzyl chloride. Hydrochloride: pale yellow crystals; M.p. 135°-140° C. (isopropanol); Yield: 53%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].C(OC([NH:15]/[C:16](=[N:46]\C(OC(C)(C)C)=O)/[N:17]([CH3:45])[CH2:18][C:19]([N:21]([CH3:44])[CH2:22][CH2:23][CH2:24][P+:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:20])=O)(C)(C)C>FC(F)(F)C(O)=O>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[NH3+:46][C:16](=[NH:15])[N:17]([CH3:45])[CH2:18][C:19]([N:21]([CH3:44])[CH2:22][CH2:23][CH2:24][P+:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:20]
Reactant: CN(CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)CN(C)/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)N(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=N)[NH3+]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18 %

Procedure:
N2—{(E)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}-N,N2-dimethyl-N-[3-(triphenylphosphonio)propyl]glycinamide trifluoroacetate (330 mg, 0.43 mmol) was dissolved in trifluoroacetic acid (1.6 ml) and stirred at room temperature for 15 minutes, and the crude was isolated upon removal of volatiles. Purification by preparative HPLC to give the title compound as a white solid following lyophilization (18% yield).