Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:5]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:4][N:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:23][S:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:5]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(-c2nc(S)ncc2-c2ccc(Cl)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(-c2nc(SC)ncc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-mercapto-4-(4-methoxyphenyl)-5-(4-chlorophenyl)pyrimidine* (7 g) and potassium carbonate (8 g) in 200 ml acetone was treated with methyl iodide (4.8 ml) and stirred 5 hours at room temperature. The reaction mixture was filtered and concentrated on the rotary evaporator. Chromatography on silica gel and crystallization from ethanol gave the title compound (3.4 g), m.p. 127°-130°. Infrared and H-NMR spectra were consistent with the assigned structure. MS 342 (M+).
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C1C=CC=CC=1.O>[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][C:4]([CH3:9])([CH3:5])[CH:3]=[O:1])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
A mixture of NaOH (0.7 g), and (Bu)4NI (0.15 g) in benzene (2.0 mL) and water (0.7 mL) was heated at 70° C. under argon to obtain a homogeneous mixture. To this mixture was added dropwise a mixture of isobutylaldehyde (1.44 g, Aldrich), and 4-benzyloxybenzyl chloride (3.5 g, Aldrich) in benzene (5.0 mL). After the addition, the resulting mixture was stirred at 70° C. for 3 h under argon. It was cooled, diluted with water, and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water, dried (anhydrous Na2SO4) and concentrated to dryness. This residue was purified by silica gel flash chromatography using 5% EtOAC in hexane. The appropriate fractions (monitored by TLC and ES mass spectrometry) were combined and concentrated to dryness to give the desired product (2.0 g, ˜50%) as a white powder: Rf=0.28 (10% EtOAc/Hexane), 1H -NMR (CDCl3) δ9.56 (s, 1H), 7.4 (m, 5H), 6.99 (d, 2H), 6.83 (d, 2H), 5.02 (s, 2H), 2.71 (s, 2H), 1.02 (6H); ES-MS m/z 286 (M+18); HRMS calcd C18H20O20NH4 (M+NH4) 286.2100, found 286.1833.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]3[O:22]C[O:24][C:18]=3[CH:17]=2)[CH:6]=[CH:7][C:8]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11].B(Br)(Br)Br>CO>[OH:2][C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:24])[CH:17]=2)[CH:6]=[CH:7][C:8]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: COc1cc(NC(=O)c2ccc3c(c2)OCO3)ccc1NS(C)(=O)=O
Agent: BrB(Br)Br
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(NC(=O)c2ccc(O)c(O)c2)cc1O
Reaction time: 20 h
Yield: 33.4 %

Procedure:
To a stirred suspension of N-(3-methoxy-4-methanesulfonylaminophenyl)-3,4-methylenedioxybenzamide (200 mg) in dry CH3Cl2 (20 ml) under nitrogen, was added boron tribromide (0.3 ml) then stirring continued for a further 20 hours. Methanol (50 ml) was added carefully, then the solvent evaporated in vacuo to a volume of 1 ml, this was repeated 2 more times. Purification by column chromatography over silica gel eluting with chloroform containing methanol (10-20%) gave N-(3-hydroxy-4-methanesulfonylaminophenyl)-3,4-dihydroxybenzamide (62 mg, 33%) as pale brown crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1>CO.O1CCCC1.[Pd]>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccc2cc([N+](=O)[O-])c(N)nc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc2cc(N)c(N)nc12
Reaction time: 1 h
Yield: 84.2 %

Procedure:
0.4 g of palladium on active carbon (5% Pd) is added to a solution of 1.1 g of 2-amino-3-nitro-8-methylquinoline (compound B1) in 50 ml of methanol/tetrahydrofurane 1:1 and the resulting suspension is hydrated for 1 h. The catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is chromatographed on silica gel using dichloromethane/methanol 10:1 to give 0.79 g of the title compound as colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([F:19])[CH:11]=2)O)[CH:7]=1.B(F)(F)F.CCOCC>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([F:19])[CH:11]=2)[CH:7]=1
Reactant: CCOc1ccc(C(O)c2cc(Br)ccc2Cl)cc1F
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1F
Reaction time: 3 h
Yield: 82.4 %

Procedure:
(5-bromo-2-chloro-phenyl)-(4-ethoxy-3-fluoro-phenyl)methanol 4d (12.7 g, 35.3 mmol) was dissolved in 100 mL dichloromethane, followed by addition of triethyl silicane (16.9 mL, 106 mmol) and dropwise addition of boron trifluoride etherate (8.95 mL, 70.6 mmol). The reaction mixture was stirred for 3 hours. Thereafter, the reaction mixture was partitioned after 50 mL saturated sodium bicarbonate solution were added. The aqueous phase was extracted with ethyl acetate (100 mL×2) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound 4-[(5-bromo-2-chloro-phenyl)methyl]-1-ethoxy-2-fluoro-benzene 4e (10 g, pale yellow grease), yield: 82.4%. 1H NMR (400 MHz, CDCl3): δ 7.33-7.27 (m, 3H), 6.95-6.90 (m, 3H), 4.14 (q, 2H), 4.01 (s, 2H), 1.49 (t, 3H).
Reaction SMILES: I[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1.[NH:21]1[C:25]2=[N:26][CH:27]=[C:28](B(O)O)[CH:29]=[C:24]2[CH:23]=[CH:22]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH:18]([N:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)[C:2]([C:28]2[CH:29]=[C:24]3[CH:23]=[CH:22][NH:21][C:25]3=[N:26][CH:27]=2)=[N:3]1)([CH3:20])[CH3:19]
Reactant: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
Reactant: OB(O)c1cnc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(-c2cnc3[nH]ccc3c2)n1
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a solution of (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol B-1-3 (0.312 g, 0.8 mmol) in toluene (15 mL) and EtOH (5 mL) were added 1H-pyrrolo[2,3-b]pyridin-5-ylboronic acid (0.40 g, 1.6 mmol) and 2 N aq. Na2CO3 (1.24 mL), and the resulting mixture was degassed under N2 for 2 minutes. Then Pd(PPh3)4 (0.23 g, 0.2 mmol) was added and the mixture was degassed again. The resulting mixture was heated to reflux and stirred overnight. The organic layer was separated and concentrated, the residue was purified via prep HPLC to afford (2S)-1-(4-(1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-1) (0.260 g, 66.19%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]2[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([O:30]C)[CH:25]=3)=[CH:18][N:17]=2)[CH:6]=1)[CH3:3].[ClH:32]>C(O)C>[ClH:32].[ClH:32].[ClH:32].[ClH:32].[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]2[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([OH:30])[CH:25]=3)=[CH:18][N:17]=2)[CH:6]=1)[CH3:3]
Reactant: COc1cc(Cc2cnc(NCCSCc3cc(CN(C)C)ccn3)[nH]c2=O)ccn1
Agent: Cl
Solvent: CCO
Product: CN(C)Cc1ccnc(CSCCNc2ncc(Cc3ccnc(O)c3)c(=O)[nH]2)c1

Procedure:
The product from Example 3, 2-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone was heated under reflux in 2N hydrogen chloride in ethanol to give 2-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamino]-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone tetrahydrochloride.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C@H:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][O:13][C:12]2=[O:22])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:23]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:23]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([O:2][C:1]([C:4]3[CH:5]=[CH:6][C:7]([CH2:10][N:11]4[C@H:15]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH2:14][O:13][C:12]4=[O:22])=[CH:8][CH:9]=3)=[O:3])=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Reactant: O=C(O)c1ccc(CN2C(=O)OC[C@H]2c2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCOc1ccc(-c2ccc(OC(=O)c3ccc(CN4C(=O)OC[C@H]4c4ccccc4)cc3)cc2)cc1

Procedure:
505 mg (1.07 mmol) of (4R)-(-)-3-(4-carboxyphenylmethyl)-4-phenyl-2-oxazolidinone and 555 mg (1.7 mmol) of 4-decyloxy-4'-hydroxybiphenyl and 31 mg of DMAP are dissolved in 17 ml of absolute CH2Cl2, and 390 mg (1.7 mmol) of DCCI are added. The crude product is purified by chromatography.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[CH2:29]O[CH2:27][CH2:26][C:11]=3[N:12]([C:14]([NH:16][C@@H:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:18](NC)=[O:19])=[O:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].N[C@H:31](CO)C(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[CH2:29][CH2:31][CH2:27][CH2:26][C:11]=3[N:12]([C:14]([NH:16][C@@H:17]([C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:18][OH:19])=[O:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(C)(C)C
Reactant: CC(C)(C)[C@H](N)CO
Product: CC(C)(C)[C@@H](CO)NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCCC2

Procedure:
Compound 51 was prepared according to the procedure described for the synthesis of compound 28 by replacing intermediate 16 with intermediate 18, and replacing tert-leucine methylamide with tert-leucinol. 1H NMR (CDCl3) δ 7.54-7.60 (m, 1H), 7.41-7.47 (m, 2H), 7.17-7.23 (m, 1H), 6.95 (dd, J=7.3, 3.4 Hz, 1H), 3.80-3.86 (m, 1H), 3.65-3.70 (m, 1H), 3.04 (m, 2H), 2.64 (m, 2H), 1.74-1.84 (m, 4H), 1.04 (s, 9H). LCMS (+ESI) m/z=378.3 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7]/[C:8](=[N:16]/[NH:17]C(OC)=O)/[S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:22](Cl)(Cl)=O>ClCCl>[C:1]1([C:7]2[S:22][N:17]=[N:16][C:8]=2[S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)N/N=C(/Cc1ccccc1)Sc1ccccc1
Solvent: ClCCl
Product: c1ccc(Sc2nnsc2-c2ccccc2)cc1

Procedure:
A solution of (Z)-[2-phenyl-1-(phenylthio)ethylidene]hydrazinecarboxylic acid, methyl ester in 450 ml of dry dichloromethane was treated with 29.7 g of thionyl chloride. This mixture ws refluxed for one hour, then poured into chipped ice and extracted three times with ether. The extracts were combined, washed with 0.1N sodium hydroxide twice, water and saturated sodium chloride and dried. This material was evaporated onto 100 g of silica gel which was then poured onto a column of silica gel packed in petroleum ether. The column was eluted with a gradient of 20-60% dichloromethane in petroleum ether, giving 35 g of the desired compound as an orange oil. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90 MHz: 7.28 (bs, 5H, C6H5); 7.30-7.65 (m, 5H, C6H5). Infrared absorption spectrum (neat): 1580(m); 1475(s); 1440(s); 1286(w); 1265(m); 1255(m); 1240(w); 1025(w); 1005(w); 985(w); 935(m); 915(m); 805(m); 765(m); 745(s); 695(s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([CH3:23])([CH3:22])[CH2:18][C:19]([OH:21])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C:58]1[S:59][CH:60]=[CH:61][N:62]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([CH3:23])([CH3:22])[CH2:18][C:19]([NH:57][C:58]4[S:59][CH:60]=[CH:61][N:62]=4)=[O:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Nc1nccs1
Reactant: CC(C)(CC(=O)O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)Nc1nccs1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.4 %

Procedure:
To a stirred solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutanoic acid (14 mg, 0.045 mmol) and diisopropylethylamine (0.05 mL) in anhydrous DMF (0.3 mL) was added HATU (30 mg, 0.079 mmol) at 0° C. under argon. After stirring at 0° C. for 5 min, 2-aminothiazole (15 mg, 0.15 mmol) was added. The reaction mixture was stirred at rt for 5 min and 50° C. for 30 min. Purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methyl-N-(thiazol-2-yl)butanamide (Example 114, 9 mg, 0.02 mmol, 44% yield) as a white solid. MS found: (M+H)+=395. 1H-NMR (400 MHz, CDCl3) δ ppm 8.04 (1H, s) 7.67 (1H, s) 7.58 (2H, dd, J=8.90, 4.83 Hz) 7.53 (1H, d, J=9.16 Hz) 7.40-7.46 (1H, m) 7.25 (1H, s) 7.14 (2H, t, J=8.65 Hz) 6.87 (1H, s) 2.81 (2H, s) 1.51 (6H, s).
Reaction SMILES: CO[C:3](=[O:17])[C@H:4]([CH2:13][CH:14]([CH3:16])C)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:18]1(C)C=CC=CC=1>>[C:9]([O:8][C:6]([NH:5][C@@H:4]([CH2:13][CH2:14][CH2:16][CH3:18])[CH:3]=[O:17])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: Cc1ccccc1
Product: CCCC[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Under an argon gas stream, N-(tert-butoxycarbonyl)-(L)-leucine methyl ester (9.8 g, 40 mmol) as dissolved in toluene (70 ml), and cooled to -78° C. To the solution, while keeping the temperature at -60 to -70° C., was added gradually aluminum diisobutyl hydride (toluene 1.0 M solution, 52 ml). After stirring at -78° C. for 40 minutes, the cooling bath was removed, and methanol (2.1 ml) and 20% aqueous citric acid solution (30 ml) were added to the mixture, followed by extraction with ethyl acetate. The organic layer was washed with 20% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution, water and a saturated aqueous sodium chloride solution, successively. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give (S)-2-(tert-butoxycarbonylamino)-5-methylpentanal (8.5 g).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][CH:22]([C:24](O)=[O:25])[CH3:23])[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][CH:22]([C:24]([NH:12][C:10](=[O:11])[C@H:2]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH2:1])=[O:25])[CH3:23])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Product: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)NC(=O)[C@@H](N)Cc1ccccc1

Procedure:
Following General Procedure D and using phenylalanine amide (Bachem) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared as a solid (mp=177-179° C.). This compound was then purified by trituration with chloroform.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)[CH:23]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
1-(3-Bromo-phenyl)-4-methyl-piperazine was prepared from 1-(3-bromo-phenyl)-piperazine (1.33 g, 5.52 mmol) in a manner analogous to Step 32a. The reaction product was isolated as a pale yellow oil (1.4 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.10 (dd, J=8.2, 8.2 Hz, 1H), 7.04 (dd, J=2.1, 2.1 Hz, 1H), 6.95 (ddd, J=7.8, 1.7, 0.7 Hz, 1H), 6.83 (ddd, J=8.3, 2.4, 0.6 Hz, 1H), 3.23-3.18 (m, 4H), 2.58-2.54 (m, 4H), 2.35 (s, 3H). MS=255, 257 (MH)+. 35b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (80.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a yellow solid (0.072 g, 60%). MP=232-234° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=7.2 Hz, 1H), 8.25 (d, J=7.5 Hz, 2H), 8.08 (d, J=7.9 Hz, 2H), 7.65 (d, J=7.7 Hz, 1H), 7.38 (s, 1H), 7.27-7.20 (m, 1H), 7.04-6.95 (m, 2H), 6.84 (s, 1H), 6.60 (d, J=8.0 Hz, 1H), 3.30-3.25 (m, 4H), 3.10 (s, 3H), 2.63-2.58 (m, 4H), 2.38 (s, 3H). MS=463 (MH)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12](Cl)[N:11]=[C:10]([S:18][CH2:19][CH2:20][CH3:21])[N:9]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:7][C:8]1[N:9]=[C:10]([S:18][CH2:19][CH2:20][CH3:21])[N:11]=[C:12]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:13]=1[N+:14]([O-:16])=[O:15]
Reactant: CCCSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: C1COCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCSc1nc(Cl)c([N+](=O)[O-])c(N2CCOCC2)n1

Procedure:
Morpholine (2.6 g) was added dropwise to a stirred solution of 4,6-dichloro-5-nitro-2-propylthiopyrimidine (8 g) and N,N-diisopropylethylamine (3.85 g) in acetonitrile (70 ml ) at 0° C. After 1 h the solvent was evaporated and the residue partitioned between ethyl acetate and water, the organics dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 25% ethyl acetate in isohexane. Yield 7.1 g
Reaction SMILES: [Br-].[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[Zn+].[Cl:8][C:9]1[N:18]=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:8][C:9]1[N:18]=[C:17]([C:3]2[S:2][CH:6]=[CH:5][N:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: [Zn+]c1nccs1
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1nc(-c2nccs2)c2ccccc2n1
Temperature: 110 °C

Procedure:
To a 0.5 M solution of 2-thiazolyl zinc bromide in THF (12.1 mL, 6.03 mmol, 1.2 equiv; commercially available from Aldrich) under Ar was added 2,4-dichloro-quinazoline (1.0 g, 5.02 mmol, 1.0 equiv) and tetrakis(triphenylphosphine) palladium(0) (232.2 mg, 0.20 mmol, 0.04 equiv) and the reaction mixture heated by microwave irradiation to 110° C. After 30 min additional 2-thiazolyl zinc bromide in THF (12.1 mL, 6.03 mmol, 1.2 equiv) was added and the reaction mixture heated to 110° C. for another 30 min. The crude reaction mixture was concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.36 g (29%) of the title compound. MS (ISP): 248.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][CH3:45])[C:10]=3[NH:11][C:12](=[O:39])[CH:13]([NH:15][C:16]([C@H:18]([CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])[C@H:19]([CH2:27][CH2:28][C:29]([F:32])([F:31])[F:30])[C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][CH3:45])[C:10]=3[NH:11][C:12](=[O:39])[CH:13]([NH:15][C:16]([C@H:18]([CH2:33][CH2:34][C:35]([F:37])([F:38])[F:36])[C@H:19]([CH2:27][CH2:28][C:29]([F:32])([F:31])[F:30])[C:20]([OH:22])=[O:21])=[O:17])[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cccc2c1NC(=O)C(NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(=O)OC(C)(C)C)N=C2c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cccc2c1NC(=O)C(NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(=O)O)N=C2c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
A solution of Intermediate 2A (115 mg, 0.174 mmol) in DCM (3 mL) was treated with TFA (0.668 mL, 1.737 mmol). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The crude mixture was diluted with toluene and again concentrated to dryness to afford Intermediate 2B (87 mg, 0.144 mmol, 83% yield). HPLC RT=3.695 (H2O/CH3CN with TFA, Waters Sunfire C18 2.1×30 mm 3.5 um, 4 min gradient, detection at 220 nm). MS(ES): m/z=606.1 [M+H+].
Reaction SMILES: [CH:1]([C:3]1[N:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:5][C:4]=1[C:12]([O:14][CH3:15])=[O:13])=O.[CH3:16][C:17]([S:20]([NH2:22])=[O:21])([CH3:19])[CH3:18].OS([O-])(=O)=O.[K+]>ClCCl>[C:17]([S:20](/[N:22]=[CH:1]/[C:3]1[N:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:5][C:4]=1[C:12]([O:14][CH3:15])=[O:13])=[O:21])([CH3:19])([CH3:18])[CH3:16]
Reactant: COC(=O)c1cc2n(c1C=O)CCCC2
Reactant: CC(C)(C)S(N)=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1cc2n(c1/C=N/S(=O)C(C)(C)C)CCCC2
Temperature: 25 °C
Reaction time: 10 h
Yield: 82.7 %

Procedure:
A 500-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with methyl 3-formyl-5,6,7,8-tetrahydroindolizine-2-carboxylate (10.0 g, 48.3 mmol, 1.0 eq.), 2-methylpropane-2-sulfinamide (11.7 g, 96.6 mmol, 2.0 eq.), KHSO4 (32.8 g, 241.5 mmol, 5 eq.), and dichloromethane (250 mL). The mixture was stirred at room temperature for 10 h. It was then filtered and filtrate was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 1:3 ethyl acetate/petroleum ether to afford 238a (12.4 g, 83%) as a yellow solid. MS: [M+H]+ 311.3.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([CH:16]([NH:18][OH:19])[CH3:17])=[CH:9][CH:10]=3)[S:5][C:4]=2[CH:3]=1.C[Si]([N:24]=[C:25]=[O:26])(C)C.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13]([O:12][C:11]3[CH:10]=[CH:9][C:8]([CH:16]([N:18]([OH:19])[C:25]([NH2:24])=[O:26])[CH3:17])=[CH:7][C:6]=3[S:5]2)=[CH:14][CH:15]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(NO)c1ccc2c(c1)Sc1cc(Cl)ccc1O2
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccc2c(c1)Sc1cc(Cl)ccc1O2)N(O)C(N)=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of the product from Step 1 (320 mg, 1.09 mmol) in THF (15 mL) there was added 85% trimethylsilyl isocyanate (295 mg, 2.18 mmol) and the mixture was stirred at room temperature for 45 minutes. After addition of water (5 mL) the mixture was stirred a further 10 minutes, then the THF was evaporated, the residual aqueous suspension diluted with water and filtered to afford the title compound as a white solid, m.p.: dec 173° C. (gassing).