Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([CH2:5]Br)=[O:4].[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:36]=1[OH:42].[I-].[K+].C(OCC)(=O)C.CN([CH:54]=[O:55])C>>[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:36]=1[O:42][CH2:2][C:3]([CH2:5][O:55][C:54]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:7])=[O:4].[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30])=[O:27])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)C=O
Reactant: Cc1cccc(C)c1O
Reactant: O=C(CBr)CBr
Agent: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1OCC(=O)COc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Benzyloxycarbonyl-L-phenylalanyl-L-alanine bromomethyl ketone (50 mg, 0.11 mmol) and 2,6-dimethylphenol (14 mg) were dissolved in dry DMF (5 mL) and blanketed with argon gas. The solution was treated with potassium iodide on alumina (80 mg, KF-alumina, 2:3) and stirred overnight at room temperature. Ethyl acetate was added and the inorganic salts were removed by filtration. The organic filtrate was washed with saturated NaCl solution (4×25 mL), then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was applied to a silica gel column. Then N-benzyloxycarbonyl-L-phenylalanyl-L-alanine 2,6-dimethylphenoxymethyl ketone was eluted with EtOAc/hexane (1:1) under pressure. Evaporation gave a white solid (30 mg, 49%), m.p. 167°-168° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([NH:27][CH2:28][CH2:29][O:30][CH3:31])[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:40](C(OC(C)(C)C)=O)[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([N:27]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:40])[CH2:28][CH2:29][O:30][CH3:31])[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCNC(CO[Si](C)(C)C(C)(C)C)c1cccc(NC(=O)OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(C(=O)OC(C)(C)C)C(CO[Si](C)(C)C(C)(C)C)c1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 0 °C
Yield: 32.8 %

Procedure:
{3-[2-(tert-Butyl-dimethyl-silanyloxy)-1-(2-methoxy-ethylamino)-ethyl]-phenyl}-carbamic acid benzyl ester (1 g) was dissolved in dry DCM (10 mL) and stirred under argon at 0° C. Triethylamine (0.4 g) and (BOC)2O (0.52 g) were added and the reaction mixture was stirred at room temperature for 2 days. The reaction was quenched by addition of water and the mixture extracted with DCM. The organic phase was separated, dried over Na2SO4 and concentrated to give a crude product which was purified by column chromatography to give the title compound (400 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=3[N:17]=2)=[CH:12][CH:11]=1.[Cl:28][C:29]1C=CC(C=O)=[CH:31][CH:30]=1.[C:37]1(C)[CH:42]=CC(C=O)=C[CH:38]=1>>[Cl:28][C:29]1[CH:30]=[CH:31][C:5]([CH2:6][N:1]2[CH2:42][CH2:37][CH2:38][CH:7]([CH2:8][O:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]4[NH:20][C:19]5[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=5[N:17]=4)=[CH:14][CH:15]=3)[CH2:2]2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCCCN4)cc3)nc2c1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1ccc(C=O)cc1
Product: NC(=O)c1ccc2[nH]c(-c3ccc(OCC4CCCN(Cc5ccc(Cl)cc5)C4)cc3)nc2c1

Procedure:
This compound was prepared using the methods outlined in Example 27, substituting 2-[4-(piperidin-3-ylmethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide for 2-[4-(2-piperidin-2-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide and p-chlorobenzaldehyde for p-tolualdehyde. HPLC (Method C): Rt=4.57. MS (ESI+): mass calcd. for C27H27ClN4O2, 474.18; m/z found, 475.3 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.13 (s, 1H), 8.00 (d, J=8.8 Hz, 2H), 7.85 (dd, J=1.5, 8.7 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.43 (s, 4H), 7.10 (d, J=8.8 Hz, 2H), 4.28-4.27 (m, 2H), 4.08-4.04 (m, 1H), 3.95-3.91 (m, 1H), 3.62-3.57 (m, 1H), 3:45-3.40 (m, 1H), 2.91-2.85 (m, 2H), 2.32-2.24(m, 1H), 2.01-1.89 (m, 2H), 1.80-1.69 (m, 1H), 1.46-1.36 (m, 1H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:10][C:11]([Cl:15])=[N:12]2)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[N+:23]([C:26]1[CH:43]=[CH:42][C:29]([C:30]([O:32][C:33]([CH2:40][CH3:41])([C:36]([F:39])([F:38])[F:37])[C:34]#[CH:35])=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24].C(N(C(C)C)CC)(C)C>C1COCC1.[Cu](I)I>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][C@@:33]([C:34]2[N:3]=[N:2][N:1]([CH2:4][C:5]3[CH:14]=[C:13]4[C:8]([C:9]([C:16]5[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=5)=[CH:10][C:11]([Cl:15])=[N:12]4)=[CH:7][CH:6]=3)[CH:35]=2)([C:36]([F:37])([F:38])[F:39])[CH2:40][CH3:41])=[O:31])=[CH:42][CH:43]=1)([O-:25])=[O:24]
Reactant: C#CC(CC)(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: [N-]=[N+]=NCc1ccc2c(-c3ccc(F)cc3)cc(Cl)nc2c1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 7-(azidomethyl)-2-chloro-4-(4-fluorophenyl)quinoline (500 mg, 1.60 mmol), 1-ethyl-1-(trifluoromethyl)prop-2-yn-1-yl 4-nitrobenzoate (529 mg, 1.76 mmol), copper iodide (456 mg, 2.4 mmol) and diisopropylethylamine (1.4 mL, 8.04 mmol) in THF (10 mL) was stirred at rt for 16 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification on silica gel (eluting with EtOAc/hexanes, 4:6) gave the title compound. MS (+ESI): 614 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:11].ClC1C=CC(C(C2C=CC(F)=CC=2)O)=CC=1F>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)([OH:11])[CH3:9])=[CH:13][CH:14]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: OC(c1ccc(F)cc1)c1ccc(Cl)c(F)c1
Product: CC(O)(c1ccc(F)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared starting from 5.00 g (28.57 mmol) of 4-bromofluorobenzene and 4.86 g (31.43 mmol) of 4-chloroacetophenone in analogy to the synthesis of the compound from Example 176A. A difference was that a preliminary separation by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9/1) was carried out before the purification of the crude product by preparative HPLC. 5.23 g (73% of theory) of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[C:11]([C:12](=[O:23])[C:13](=[CH:19][N:20](C)[CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:25])=[C:7]([F:24])[CH:8]=2)[N:3]=1.[F:26][C:27]1[CH:33]=[C:32]([F:34])C=[CH:30][C:28]=1N.C(O)C.N12CCCN=C1CCCCC2>ClC(Cl)Cl>[F:34][C:32]1[CH:33]=[C:27]([F:26])[CH:28]=[CH:30][C:21]=1[N:20]1[C:2]2[N:3]=[C:4]3[CH:5]=[C:6]([F:25])[C:7]([F:24])=[CH:8][C:9]3=[CH:10][C:11]=2[C:12](=[O:23])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19]1
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)cc2nc1Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc3cc(F)c(F)cc3cc2c1=O
Temperature: 80 °C
Yield: 79.4 %

Procedure:
Ethyl 1-(2,4-difluorophenyl)-7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate was obtained under the conditions of Example 13, but from 3.68 g of ethyl 3-(2-chloro-6,7-difluoro-3-quinolyl)-2-dimethylaminomethylene-3-oxopropionate and 3.87 g of 2,4-difluoroaniline in 40 cm3 of trichloromethane. 50 cm3 of ethanol and 1.5 cm3 of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to the mixture, which was heated at a temperature around 80° C. for approximately 1 hour. After cooling to a temperature around 10° C., the product was filtered off and washed 2 times with 50 cm3 of ethanol and 2 times with 50 cm3 of isopropyl ether. 3.3 g of ethyl 1-(2,4-difluorophenyl)-7,8-difluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylate were obtained in the form of a yellow solid melting at approximately 300° C., which solid was used without additional purification in the subsequent stages.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[CH:10][CH:9]=[C:8]([CH:13]2[CH2:15]C2)[N:7]=1)=[O:5])[CH3:2].[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[N:21][CH:22]=1>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[CH:10][CH:9]=[C:8]([CH2:13][CH3:15])[N:7]=1)=[O:5])[CH3:2]
Reactant: Nc1cncnc1
Reactant: CCOC(=O)c1nc(C2CC2)ccc1Br
Agent: [Pd]
Product: CCOC(=O)c1nc(CC)ccc1Nc1cncnc1

Procedure:
Palladium catalysed arylation of 3-Bromo-6-cyclopropyl-pyridine-2-carboxylic acid ethyl ester with 5-Aminopyrimidine according to the general procedure described in example 78 step 3 yielded the title compound as a white solid, MS (ISP): m/e=273.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(O)c1c(F)cccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1c(F)cccc1Br
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.3 %

Procedure:
To a solution 2-bromo-6-fluorobenzoic acid (50 g, 0.229 mol) and potassium carbonate (31.6 g, 0.229 mol) in N,N-dimethylformamide (250 mL) was added dropwise methyl iodide (51.83 g, 0.365 mol) over a 30 minute period. The reaction mixture was stirred at RT for 3.5 hours. The resulting mixture was diluted with water (500 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with 1M aqueous HCl (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (53 g, 99.7%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10](S(C2SC(Cl)=CC=2)(=O)=O)[C:11]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#N)[CH:25]=3)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.S1C=CC=C1S(N)(=O)=O.[OH-:50].[Na+].Cl.C[OH:54]>>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:23][C:24]3[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=3)[C:30]([OH:54])=[O:50])[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COc1cc(F)cc2c1c(N(S(=O)(=O)c1ccc(Cl)s1)S(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(C#N)c1
Reactant: CO
Reactant: [OH-]
Agent: Cl
Agent: NS(=O)(=O)c1cccs1
Agent: [Na+]
Product: COc1cc(F)cc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(C(=O)O)c1
Temperature: 60 °C
Yield: 65 %

Procedure:
A solution of 5-chloro-N-[(5-chloro-2-thienyl)sulfonyl]-N-[1-[(3-cyanophenyl)methyl]-6-fluoro-4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide (for a preparation see Intermediate 53) (53 mg, 0.08 mmol) in methanol (10 mL) was treated with 2M NaOH solution (1 mL) was heated to 60° C. under nitrogen overnight. More 2M NaOH solution (0.5 mL) was added and the mixture was heated to 71° C. over the weekend. The mixture was allowed to cool to RT and then treated with 2M HCl solution to pH 0. The mixture was extracted with ethyl acetate and the organic solution was washed with 2M HCl, brine, dried (MgSO4) and evaporated to a gum 54 mg. The residue was dissolved in 1:1 MeOH-DMSO 1 mL and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier (Method A) collecting fractions with RT=7.77 min 19% and 8.73 min, 81%). The solvent was evaporated in vacuo from the major fraction (RT=8.73 min) to give 3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-6-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}benzoic acid (26 mg, 65%), as a white solid: LCMS (System A) RT=1.04 min, ES+ve m/z 496/498 (M+H)+ for carboxylic acid product. The minor component (RT=7.77 min) was evaporated under reduced pressure to give the title compound (6.2 mg, 15%) as a white solid: LCMS (System A) RT=0.97 min, ES+ve m/z 495/497 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])=[CH:15][CH:14]=1)=[CH:9][C:8]([Br:24])=[CH:7][CH:6]=2.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:24][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[NH:1][C:33](=[O:35])[N:12]([C:13]4[CH:14]=[CH:15][C:16]([C:19]([CH3:22])([CH3:23])[C:20]#[N:21])=[CH:17][CH:18]=4)[C:11]=3[C:10]=2[CH:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C#N)c1ccc(Nc2c(N)cnc3ccc(Br)cc23)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reaction time: 0.33 h

Procedure:
A solution of 2-(4-(3-amino-6-bromoquinolin-4-ylamino)phenyl)-2-methylpropanenitrile (Compound of Preparation D, 5 g, 13.1 mmol) and triethylamine (1.59 g, 15.7 mmol) in CH2Cl2 (120 mL) was added over 40 minutes to a solution of triphosgene (4.3 g, 14.4 mmol) in CH2Cl2 (80 mL) at 0° C. using ice-bath. The reaction mixture was stirred for 20 minutes at this temperature then was quenched with saturated aqueous NaHCO3, stirred for 5 minutes and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and solvent was evaporated to obtain the title compound. Yield: 3.2 g (60%); 1H NMR (DMSO-d6, 300 MHz): δ 11.835 (s, 1H), 8.783 (s, 1H), 7.908-7.938 (d, 1H, J=9 Hz), 7.810-7.838 (d, 2H, J=8.4 Hz), 7.665-7.694 (d, 2H, J=8.7 Hz), 7.613-7.650 (dd, 1H, J=9 Hz, 1.8 Hz), 6.949-6.955 (d, 1H, J=1.8 Hz), 1.609 (s, 6H); MS: m/z 406 (M+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:26]1([CH:32]=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:52]CCl>>[ClH:52].[CH:26]1([CH2:32][N:23]2[CH2:22][CH2:21][N:20]([C:17]3[N:16]=[CH:15][C:14]([NH:13][S:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)(=[O:11])=[O:12])=[CH:19][CH:18]=3)[CH2:25][CH2:24]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2ccc(N3CCNCC3)nc2)cc1
Reactant: ClCCl
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1ccc(S(=O)(=O)Nc2ccc(N3CCN(CC4CCCCC4)CC3)nc2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
150 mg (0.42 mmol) of 4-isopropyl-N-(6-piperazin-1-yl-pyridin-3-yl)-benzenesulfonamide from Example 7 and 51 mg (0.46 mmol) of cyclohexanealdehyde were dissolved in 5 ml of dichloromethane and 40 μl (0.62 mmol) of glacial acetic acid under a nitrogen atmosphere. 133 mg (0.63 mmol) of sodium trisacetoxyborohydride were then added. The mixture was stirred at room temperature for 90 minutes and, after that, the solvent was evaporated down to dryness. The resulting residue was taken up in water and this mixture was made to pH>11 with a 1N aqueous solution of sodium hydroxide. After that, the aqueous reaction mixture was extracted with diethyl ether. After the organic phase had been dried over sodium sulfate and the solvent had been filtered and evaporated down to dryness, the resulting residue was converted into the hydrochloride with ethereal hydrochloric acid, resulting in 156 mg (76% of theory) of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C([O:17][CH2:18][CH3:19])(=O)C>S(=O)(=O)(O)O.O.C(O)CCCCCCC.C1(C)C=CC=CC=1>[C:18]([O:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C@@H:2]([C:11]([OH:13])=[O:12])[NH2:1])=[CH:9][CH:8]=1)(=[O:17])[CH2:19][CH2:11][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCOC(C)=O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCCCCO
Product: CCCCCCCC(=O)Oc1ccc(C[C@H](N)C(=O)O)cc1
Temperature: 25 °C

Procedure:
9.06 g of tyrosine was dissolved in a solution of 10 g of concentrated sulfuric acid, 20 mL water, 10 mL of octanol, and 200 mL of toluene in a 500 mL round bottom flask equipped with a condenser and a Dean-Stark apparatus. The resulting solution was heated at reflux temperature until no more water could be distilled. The resulting solution was then cooled to room temperature and washed with saturated aqueous sodium bicarbonate to neutralize acidic impurities to provide an emulsion. About 150 mL of ethyl acetate was added to the emulsion to provide two phases. The aqueous phase was discarded and the organic phase washed with saturated Brine and dried over anhydrous sodium sulfate. The solvent was the removed under reduced pressure to provide tyrosine octanoate as a white solid that was purified using a silica gel column eluted with a 1:9 methanol:dichloromethane mixture.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16]C(C)(C)C)=[O:15])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(F)c2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2cccc(F)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 5-(3-fluorophenyl)picolinate 33-5 (414 mg, 1.51 mmol) in dichloromethane (3 mL) was added TFA (1.5 mL) dropwise at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (100 mL) and H2O (100 mL), adjusted with Na2CO3 to pH around 4, and separated. The organic layer was washed with H2O and brine, dried over Na2SO4, concentrated to dryness to afford 5-(3-fluorophenyl)picolinic acid 6-7 as an off-white solid. MS m/z 218.1 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH:27]=4)[N:20]=3)=[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.N([C@@H]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)C)=C=O.[CH2:49]1[CH2:53][O:52][CH2:51][CH2:50]1>>[CH3:37][N:35]([CH3:36])[CH2:34][CH2:33][O:32][C:28]1[CH:27]=[C:26]([NH:25][C:21]2[N:20]=[C:19]([C:18]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:51]([C:50]5([C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=6)[CH2:49][CH2:53]5)=[O:52])[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=34)[CH:24]=[CH:23][N:22]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: C[C@@H](N=C=O)c1ccccc1
Reactant: C1CCOC1
Reactant: COc1ccc2c(-c3ccnc(Nc4cccc(OCCN(C)C)c4)n3)c(-c3cccc(N)c3)nn2c1
Product: COc1ccc2c(-c3ccnc(Nc4cccc(OCCN(C)C)c4)n3)c(-c3cccc(NC(=O)C4(c5ccccc5)CC4)c3)nn2c1
Reaction time: 2 h
Yield: 44 %

Procedure:
4-[2-(3-Aminophenyl)-6-(methyloxy)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)-2-pyrimidinamine (61 mg, 0.12 mmol) and [(1R)-1-isocyanatoethyl]benzene (34 mg, 0.23 mmol) were combined in THF (2 mL) and stirred for 2 h, after which time additional [(1R)-1-isocyanatoethyl]benzene (10 mg, 0.068 mmol) was added in portions until the reaction was complete by LC/MS. The mixture was absorbed onto silica get and purified by silica gel chromatography to afford the title compound as a yellow solid (34 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.53 (d, J=5.9 Hz, 2H), 8.45 (d, J=9.9 Hz, 1H), 8.20 (d, J=5.5 Hz, 1H), 7.64 (s, 1H), 7.51 (s, 1H), 7.44 (d, J=7.4 Hz, 1H), 7.32-7.19 (m, 7H), 7.15-7.04 (m, 3H), 6.61 (d, J=8.5 Hz, 1H), 6.51 (d, J=8.1 Hz, 1H), 6.44 (d, J=5.2 Hz, 1H), 4.78 (t, J=7.4 Hz, 1H), 3.96 (t, J=5.5 Hz, 2H), 3.85 (s, 3H), 2.56 (t, J=5.7 Hz, 2H), 2.16 (s, 6H), 1.36 (d, J=7.1 Hz, 3H). ES-LC/MS m/z 643 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>C1C=CC=CC=1>[ClH:1].[CH2:20]([NH:24][CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH2:21][CH2:22][CH3:23]
Reactant: ClCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CCCCN
Solvent: c1ccccc1
Product: CCCCNCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Product: Cl
Yield: 72 %

Procedure:
A solution of 8 g. 2-chloromethyl-4,5-diphenyl-oxazole (prepared as described in Example 1 a) and 6.6 g. n-butylamine in 100 ml. anhydrous benzene was refluxed for 4 hours. The reaction mixture was washed with water and the separated benzene phase was distilled at 20 mm. pressure. The oily residue was dissolved in 100 ml. anhydrous ether and a flow of gas hydrogen chloride was bubbled through the resulting solution. The 2-n-butylaminomethyl-4,5-diphenyloxazole hydrochloride was recrystallized from absolute ethanol/anhydrous diethyl ether: 7.4 g., m.p. 120°-123° C (yield 72%).
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([CH3:16])[CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:16][N:11]1[CH2:10][CH:9]2[CH:13]([CH2:14][CH2:15][NH:8]2)[CH2:12]1
Reactant: CN1CC2CCN(Cc3ccccc3)C2C1
Agent: [Pd]
Solvent: CCO
Product: CN1CC2CCNC2C1

Procedure:
10.3 g (47.6 mmol) of 2-benzyl-7-methyl-2,7 -diazabicyclo[3.3.0]octane in 200 ml of ethanol are hydrogenated at 100° C. and 100 bar on 2.5 g of palladium-active carbon (10% Pd). The catalyst is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([NH2:11])=[CH:5][N:4]=1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[S:13].CCCCCC.C(OCC)(=O)C>O1CCCC1>[N:11]([C:6]1[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=1)=[C:12]=[S:13]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1ncc(N)c(OC)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ncc(N=C=S)c(OC)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
To a solution of 2,4-dimethoxypyrimidin-5-amine (prepared by the method described in U.S. Pat. No. 6,342,503B1) (4.68 g, 30.0 mmol) in tetrahydrofuran (60 mL) was added 1,1′-thiocarbonyldiimidazole (6.41 g, 36.0 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 20 hr. The mixture was concentrated in vacuo to give a residue which was passed through a pad of silica gel eluting with n-hexane/ethyl acetate. The filtrate was concentrated in vacuo to give the title compound (5.0 g, 84%) as a colorless solid.