Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:15]=3[N:14]=[C:13]2[C:24](=[O:35])[NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[O:10])=[N:6][CH:7]=1.[CH2:36]1[CH2:42][O:41][CH2:40][CH2:39][NH:38][CH2:37]1.Cl>>[CH:32]([N:29]1[CH2:28][CH2:27][CH:26]([NH:25][C:24]([C:13]2[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[C:16]3[CH:17]=[CH:18][C:19]([C:21]([N:38]4[CH2:37][CH2:36][CH2:42][O:41][CH2:40][CH2:39]4)=[O:23])=[CH:20][C:15]=3[N:14]=2)=[O:35])[CH2:31][CH2:30]1)([CH3:34])[CH3:33]
Reactant: CC(C)N1CCC(NC(=O)c2nc3cc(C(=O)O)ccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Reactant: C1CNCCOC1
Agent: Cl
Product: CC(C)N1CCC(NC(=O)c2nc3cc(C(=O)N4CCCOCC4)ccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-5-([1,4]oxazepane-4-carbonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 147.8 mg (0.296 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid and 44.8 mg (0.326 mmol) homomorpholine-hydrochloride. The title compound was obtained as its formiate. Subsequent transformation to the corresponding acetate gave a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[C:13]1([S-:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+]>C(#N)C>[Cl:1][C:2]1[C:8]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4]
Reactant: Nc1c([N+](=O)[O-])ccc(Cl)c1Cl
Reactant: [S-]c1ccccc1
Agent: [Na+]
Solvent: CC#N
Product: Nc1c([N+](=O)[O-])ccc(Sc2ccccc2)c1Cl

Procedure:
A mixture of 103.5 gm of 2,3-dichloro-6-nitroaniline (0.5 mol) and 72.5 gm of sodium thiophenolate (0.55 mol) was dissolved in 800 ml of acetonitrile, and the solution was refluxed for 5 hours. The mixture was then processed according to the procedure set forth in Example 22 (b)(i). The yield was 108 gm of ochre-coloured, crystalline product (77% of theory), m.p. 144°-146° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][C:45]1[C:50]2[O:51][CH2:52][C:53]3([CH2:55][CH2:54]3)[C:49]=2[C:48]([O:56][C:57]2[N:62]=[CH:61][C:60]([NH2:63])=[CH:59][N:58]=2)=[CH:47][CH:46]=1>>[CH3:44][C:45]1[C:50]2[O:51][CH2:52][C:53]3([CH2:55][CH2:54]3)[C:49]=2[C:48]([O:56][C:57]2[N:58]=[CH:59][C:60]([NH:63][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12])=[CH:61][N:62]=2)=[CH:47][CH:46]=1
Reactant: Cc1ccc(Oc2ncc(N)cn2)c2c1OCC21CC1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
To a solution of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (45 mg, 0.222 mmol) in dry DMF (1 ml) DIPEA (870, 0.5 mmol) and then HATU (80 mg, 0.21 mmol) were added and the reaction mixture was stirred for 15 minutes at r.t. 2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-amine (Intermediate 162, 50 mg, 0.185 mmol) was then added and the reaction mixture was stirred for 6 hours at room temperature. The reaction was quenched with water (2 ml) diluted with brine (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 90:10 to cyclohexane/ethyl acetate 60:40 as eluents affording the title compound (45 mg) as a white solid.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([CH3:11])=[N:9][CH:8]=[CH:7][N:6]=1>C(O)C>[NH:2]([C:5]1[C:10]([CH3:11])=[N:9][CH:8]=[CH:7][N:6]=1)[NH2:3]
Reactant: NN
Reactant: Cc1nccnc1Cl
Solvent: CCO
Solvent: O
Product: Cc1nccnc1NN
Temperature: 90 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
Hydrazine hydrate (9.66 mL, 311.14 mmol) was added to 2-chloro-3-methylpyrazine (CAS no. 95-58-9) (8 g, 62.23 mmol) in ethanol (25 mL). The resulting solution was stirred at 90° C. for 16 hours. The resulting solution was evaporated to dryness and the crude product was purified by crystallisation from toluene (125 mL) to afford 2-hydrazinyl-3-methylpyrazine (6.2 g, 80%). 1H NMR (400 MHz, DMSO-d6) δ 2.24 (3H, s), 7.61 (1H, d), 7.61 (1H, d), 7.87 (1H, d).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CO[CH:11](OC)[CH2:12]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:12]=[CH:11][C:4]=2[CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2occc2c1
Temperature: 150 °C
Yield: 30.5 %

Procedure:
A solution of 4-bromophenol (17.3 g, 100 mmol) in dimethylformamide (40 ml) was treated with bromoacetaldehyde dimethyl acetal (16.9 g, 100 mmol) and potassium carbonate (13.8 g, 100 mmol) and heated at 150° C. for 16 h. The mixture was cooled, poured into water (500 ml) and extracted with diethyl ether (3×100 ml). The combined organic extracts were dried (MgSO4), concentrated, and filtered through a plug of silica gel eluting with 10% diethyl ether in hexane. The resulting oil (15 g) was added to a solution of polyphosphoric acid (~12 g) in toluene (100 mL) and heated at 80° C. for 16 h. The mixture was cooled and the toluene layer was decanted off and washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4), concentrated and the residue distilled to give 5-bromobenzofuran (6 g) as a colourless oil, bp. 98° C./1 mmHg; δH (DMSO-d6) 6.96 (1H, m, ArH), 7.45 (1H, m, ArH), 7.59 (1H, m, ArH), 7.91 (1H, m, ArH), and 8.05 (1H, m, ArH).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].[OH-].[Na+]>OS(O)(=O)=O>[N+:12]([C:7]1[C:2]([OH:1])=[CH:3][C:4]([C:8]([F:11])([F:9])[F:10])=[N:5][CH:6]=1)([O-:14])=[O:13]
Reactant: Oc1ccnc(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cnc(C(F)(F)F)cc1O
Temperature: 25 °C

Procedure:
25 mL of fuming H2SO4 under cold conditions (0° C.) is added dropwise to a stirred solution of 4-hydroxy-2-trifluoromethylpyridine [Chemistry of Heterocyclic Compounds 1997, 33, 995-996] (4 g, 24.5 mmol) in concentrated H2SO4 (10 mL). HNO3 (fuming, 90%, 25 mL) is added carefully to the above mixture with caution to keep the offset of any exotherm under control, and the reaction is allowed to warm to room temperature slowly. After heating at 120° C. for 6 h with stirring, the resulting mixture is cooled to room temperature, poured into ice-cold water maintaining the pH around 1 with the addition of 1ON NaOH solution, and then extracted with CHCl3. The combined organic phase is washed successively with saturated aqueous NaHCO3, water, brine, dried over Na2SO4, and concentrated in vacuo to afford 5-nitro-2-trifluoromethyl-pyridin-4-ol as an yellow solid. 1H NMR (300 MHz, CDCl3): δ 9.33 (s, 1H), 7.50 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][N:27]=3)=[O:25])[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:10])[CH3:9].C(Cl)(=O)C(C)(C)C.[S:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[CH2:47][CH2:48][NH2:49]>C(Cl)Cl>[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:19][CH2:20][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([NH:49][CH2:48][CH2:47][C:43]4[S:42][CH:46]=[CH:45][CH:44]=4)=[O:32])=[CH:28][N:27]=3)=[O:25])[CH2:22][CH2:23]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:9])[CH3:10]
Reactant: NCCc1cccs1
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCc3cccs3)cn2)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Triethylamine (0. 8 ml) was added to 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid (2g) in methylene chloride (30 ml) for dissolution and cooled. With the slow addition of pivaloyl chloride (0. 7 ml) at 0° C.˜5° C., the mixture was stirred at 5° C for 1 hour. With the successive addition of triethylamine (0.9 ml) and 2-thiophenethylamine (0.75 g), the mixture was stirred at 5° C.˜10° C. for 2 hours. The solution was washed with an aqueous sodium bicarbonate and water. The separated organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrated residue was treated with ether for crystallization. The solid, so obtained, was recrystallized with ethanol and hexane to give a desired compound of 1.92 g (yield: 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:5][N:6]([C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1)[C@H:7]1[CH2:13][CH2:12][CH2:11][NH:10][C:9]2[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:16]([CH3:18])=[CH:17][C:8]1=2.[Br:36]N1C(=O)CCC1=O>C(O)(=O)C>[Br:36][C:14]1[C:9]2[NH:10][CH2:11][CH2:12][CH2:13][C@H:7]([N:6]([CH2:5][C:4]3[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=[C:2]([Cl:1])[CH:3]=3)[C:23]3[N:24]=[N:25][N:26]([CH3:28])[N:27]=3)[C:8]=2[CH:17]=[C:16]([CH3:18])[C:15]=1[C:19]([F:20])([F:21])[F:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(Cl)cc(C(F)(F)F)c1)c1nnn(C)n1
Solvent: CC(=O)O
Product: Cc1cc2c(c(Br)c1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(Cl)cc(C(F)(F)F)c1)c1nnn(C)n1
Yield: 80.4 %

Procedure:
Stir (S)-(3-chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-yl)-amine (0.53 g, 1.02 mmol) with N-bromosuccinimide (0.22 g, 1.22 mmol) in acetic acid (2 mL) at room temperature for 2 h. Evaporate the solvent under reduced pressure. Dilute the residue with water and neutralize with saturated NaHCO3 and extract with EtOAc (3×25 mL). Combine the organic layers and wash with water and brine, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography, eluting with hexane/ethyl acetate (5-40% EtOAc in hexane), to provide the title compound (0.49 g, 83%). MS (ES+): 599 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:24][C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:30]([C:28]3[S:29][C:25]([F:24])=[CH:26][CH:27]=3)=[O:31])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)c1ccc(F)s1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(F)s3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and 5-fluoro-thiophene-2-carboxylic acid followed by deprotection using procedure H yielded the title compound. MS (ESI): m/z=352.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[C:4]([CH2:11][CH2:12][C:13](OCC)=[O:14])=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[C:4]([CH2:11][CH2:12][CH2:13][OH:14])[C:3]=1[OH:18]
Reactant: CCOC(=O)CCC1=C(C)C(=O)C(C)=C(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1c(C)c(O)c(CCCO)c(C)c1O

Procedure:
A solution of 2,3,5-trimethyl-6-(2'-ethoxycarbonylethyl)-1,4-benzoquinone (formula I-2 wherein R=H3C, n=1, in the form of ethyl ester) (0.39 part) in diethyl ether (50 volume parts) was treated with lithium aluminum hydride in the same manner as Example 53 to give 2,3,5-trimethyl-6-(3'-hydroxypropyl)-hydroquinone (formula III-2 wherein R=H3C, X=Y=OH, n=1 in the free form). The product was treated with ferric chloride in the same manner as Example 53 and then subjected to column chromatography on silica gel and eluted with chloroform. The procedure provided 2,3,5-trimethyl-6-(3'-hydroxypropyl)-1,4-benzoquinone (formula IV-2 wherein R=H3C, n=1, in the free form) (0.25 part) as a yellow oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.CCCCCC.[C:39]1([N:45]=[C:46]=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:39]1([NH:45][C:46]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=4)[N:9]=3)[NH:4][CH:3]=2)=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Reactant: O=C=Nc1ccccc1
Solvent: CCCCCC
Product: COc1cc(-c2cnc3[nH]cc(C(=O)Nc4ccccc4)c3n2)cc(OC)c1OC
Reaction time: 0.01 h

Procedure:
7-Iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine 0.057 gm, 0.1 mM was placed in an oven dried flask and 1 ml anhydrous THF was added. The flask was chilled in an Acetone-dry ice slurry and evacuated and refilled 3 times with nitrogen. Via syringe 0.065 ml of 2.13M Buli in hexane solution (0.14 mM, 1.4 eq) was added and the now yellow mixture was stirred for 30 seconds then phenylisocyanate, 0.027 ml, 0.25 mM, 2.5 eq.) was added. The mixture was stirred for 30 minutes, removed from the dry ice-acetone bath and immediately quenched with saturated aqueous ammonium chloride. Ethyl acetate was added and insoluble material removed by filtration and discarded. The mixture was separated and the aqueous layer was extracted two times with ethyl acetate. The organic layers were rinsed three times with 0.1M HCl and dried over magnesium sulfate. The solution was concentrated and purified on a silica gel column (ethyl acetate/hexane gradient). The product was recrystallized from acetonitrile and dried at 2 torr in a 60° C. vacuum oven overnight to give 2-(3,4,5-Trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid phenylamide. (M+H)+=405.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH3:19][O:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=1N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[CH3:19][O:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=1[NH:13][C:12]1[C:11]2[C:10](=[CH:9][CH:8]=[C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]3=2)[N:14]=[CH:15][N:16]=1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: COc1ccc(N)c(OC)c1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)c(OC)c1
Yield: 59 %

Procedure:
Prepared from VII and 2,4-dimethoxyaniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 59%; orange solid; mp 255-257° C.; IR (KBr) νmax/cm−1 3401, 3081, 2948, 2837, 2233, 1600, 1565, 1540, 1525, 1505, 1443, 1417, 1329, 1278, 1231, 1203, 1159, 1132, 1088, 1030, 959, 915; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 7.98 (s, 1H), 7.83 (d, 1H, J=9.0 Hz), 6.95 (m, 1H), 6.67 (s, 1H), 6.58 (d, 1H, J=9.0 Hz), 3.78 (s, 3H), 3.73 (s, 3H); HRMS calcd for C18H14N5O2S (M+H+): 364.0868, found 364.0856.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:10](=[O:15])[C:11](Br)=[CH:12][N:13]=2)[CH2:3]1.C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:10](=[O:15])[CH:11]=[CH:12][N:13]=2)[CH2:3]1
Reactant: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)ncc(Br)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)nccc1=O
Temperature: 108 °C
Reaction time: 24 h
Yield: 79.7 %

Procedure:
2-[2-(3-(R)-Amino-piperidin-1-yl)-5-bromo-6-oxo-6H-pyrimidin-1-ylmethyl]-benzonitrile (Example 1) (80 mg, 0.21 mmol) and tributyltin hydride (83 μL, 0.31 mmol) were stirred in dry toluene (5 mL) under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.013 mmol) and a catalytic amount of AIBN were added, and the reaction stirred at 108° C. for 24 h. Concentration in vacuo and purification by Prep HPLC gave 51.8 mg (59%) of the title compound as the TFA salt. 1H NMR (400 MHz, CDCl3): δ 8.40 (br s, 3H), 7.71 (d, 1H, J=6.4 Hz), 7.63 (d, 1H, 7.6 Hz), 7.57 (t, 1H, J=7.6 Hz), 7.40 (t, 1H, J=7.6Hz), 7.33 (d, 1H, J=7.6Hz), 6.25 (d, 1H, J=6.4 Hz), 5.36 (AB q, 2H, J=113.2, 15.2 Hz), 3.47-3.59 (m, 3H), 3.21-3.28 (m, 2H), 1.95-2.05 (m, 2H), 1.80-1.91 (m, 1H), 1.60-1.71 (m, 1H). MS (ES) [m+H] calc'd for C17H19N5O, 310; found 310.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[N:3]=1.Cl.[NH2:19][C:20]1[C:25]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])=[CH:24][CH:23]=[C:22]([NH:32][CH:33]2[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]2)[N:21]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:19][C:20]1[N:21]=[C:22]([NH:32][CH:33]2[CH2:38][CH2:37][CH2:36][N:35]([C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=4[Cl:17])[N:3]=3)[CH2:34]2)[CH:23]=[CH:24][C:25]=1[C:26](=[O:31])[C:27]([F:30])([F:29])[F:28]
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2Cl)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2ccc(Cl)cc2Cl)nc1N1CCCC(Nc2ccc(C(=O)C(F)(F)F)c(N)n2)C1
Temperature: 120 °C

Procedure:
29.5 mg (0.1 mmol) of 2-chloro-6-(2,4-dichlorophenyl)pyridine-3-carbonitrile, 30 mg (0.1 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.09 ml (0.52 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated at 120° C. in a microwave for 30 min. The crude product was purified by means of preparative HPLC (method 13). 35 mg (63% of theory) of the product were obtained in solid form.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9](O)=[O:10])=[CH:3][CH:2]=1.Cl.[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32].CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([C:9]([NH:32][CH2:31][CH2:30][C:29]([O:28][CH3:27])=[O:33])=[O:10])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:5][CH:6]=1
Reactant: COC(=O)CCN
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNC(=O)[C@@H](CC(=O)OC(C)(C)C)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 92.4 %

Procedure:
A solution of (R)-2-(biphenyl-4-ylmethyl)-4-tert-butoxy-4-oxobutanoic acid (142 mg, 0.417 mmol), 3-amino-propionic acid methyl ester hydrochloride (76 mg, 0.542 mmol), WSC hydrochloride (120 mg, 0.626 mmol), 1-hydroxy-7-azabenzotriazole (85 mg, 0.626 mmol) and DIPEA (0.219 ml, 1.251 mmol) in DMF (4 mL) is allowed to stir at room temperature under nitrogen for 13 hours. The reaction is quenched with H2O. The products are extracted with ethyl acetate, washed with aqueous 1M HCl and then with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on 12 g of silica gel (heptane/EtOAc=70:30 to 0:100) to give (R)-tert-butyl 3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoate (164 mg, 91%). HPLC retention time=1.59 minutes (condition A); MS (ES+)=425.4 (m); 369.4 (m-tBu+1; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.24-2.44 (m, 2 H) 2.67-2.79 (m, 3 H) 2.89-2.96 (m, 1 μl) 3.28-3.36 (m, 1 H) 3.45-3.53 (m, 1 H) 7.23 (d, J=5.8 Hz, 2 H) 7.33 (t, J=7.35 Hz, 1 H) 7.41-7.44 (m, 2 H) 7.51 (d, J=8.1 Hz, 2 H) 7.58 (d, J=7.4 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]1[C:5]=2[C:6](O)=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=[N:9]1.P(Cl)(Cl)(Cl)(Cl)[Cl:22]>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[S:3][C:4]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]1[C:5]=2[C:6]([Cl:22])=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=[N:9]1
Reactant: CCOC(=O)c1cnc2ccc3nc(Cl)sc3c2c1O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccc3nc(Cl)sc3c2c1Cl

Procedure:
A mixture of 3.09 g of ethyl 2-chloro-9-hydroxythiazolo[5,4-f]quinoline-8-carboxylate, 20 ml of phosphorus oxychloride and 0.2 g of phosphorus pentachloride was refluxed for 1 hour and the reaction mixture was treated in the same manner as described in Example 5 to give ethyl 2,9-dichlorothiazolo[5,4-f]quinoline- 8-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1(=[O:17])[NH:15][C:14](=[O:16])[CH:13]=[CH:12]1>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:13]1[CH2:12][C:11](=[O:17])[NH:15][C:14]1=[O:16]
Reactant: O=C1C=CC(=O)N1
Reactant: Cc1ccc2[nH]ccc2c1
Solvent: CC(=O)O
Product: Cc1ccc2[nH]cc(C3CC(=O)NC3=O)c2c1
Temperature: 25 °C
Yield: 40.4 %

Procedure:
5-Methyl indole (10 g, 76 mmol) and maleimide (7.4 g, 76 mmol) in 77 mL of glacial acetic acid was heated at 90° C. for 24 h. The reaction mixture was cooled to RT, and the acetic acid was evaporated under reduced pressure. The residue was suspended in diethyl ether and filtered to obtain solid product (7 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([SH:26])[CH:23]=[CH:24][CH:25]=1.[H-].[Na+]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([S:26][C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=3)[N:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: COc1cccc(S)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Sc2cc(-c3ccc(C(C)(C)C)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a 25-mL, round-bottomed flask containing 4-(4-tert-butyl-phenyl)-6-chloro-pyrimidine, (Example 1(a)), (0.20 g, 0.82 mmol), 3-methoxybenzenethiol (0.23 g, 1.6 mmol, Aldrich) and DMF (4 mL) under a N2 atmosphere at room temperature was added NaH (0.066 g, 1.6 mmol, 60% disp. in oil, Aldrich). The mixture turned green and gas evolution was observed. The solution was stirred for 20 h at room temperature under a N2 atmosphere. The reaction was quenched with H2O (50 mL), and the resulting solution was extracted with EtOAc (3×25 mL). The combined extracts were washed with H2O (3×25 mL) and brine, dried over Na2SO4, and adsorbed onto silica. The crude material was purified by chromatography (0 to 15% ethyl acetate/hexanes) on silica gel to afford the title compound as a colorless oil. MS (ESI, pos. ion.) m/z: 351.2 (M+1).