Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[C:8]([NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]3[C:36]([CH3:38])([CH3:37])[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:39](O)=[O:40])[CH:33]=4)[NH:28]3)[CH:22]=2)=[CH:17][CH:16]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[C:8]([NH:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]3[C:36]([CH3:38])([CH3:37])[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:39]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:40])[CH:33]=4)[NH:28]3)[CH:22]=2)=[CH:19][CH:20]=1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)NC(=O)c1ccc(-c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1ccc(-c2cccc(C3Nc4ccc(C(=O)NS(C)(=O)=O)cc4CC3(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.6 %

Procedure:
To a suspension of 60% sodium hydride (87 mg, 2.1 mmol) in N,N-dimethylformamide (1.5 mL) was added methanesulfonamide (210 mg, 2.2 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(4′-tert-butylcarbamoyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.22 mmol) and 1,1′-carbonyldiimidazole (72 mg, 0.44 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3′-(6-methanesulfonylaminocarbonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-biphenyl-4-carboxylic acid tert-butylamide (23 mg, 20%) as a white solid: LC/MS m/e calcd for C30H35N3O4S (M+H)+: 534.70, observed: 534.1.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:15][CH:14]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([NH:28][C:29]1[C:30]([NH2:35])=[CH:31][CH:32]=[CH:33][CH:34]=1)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[F:36][C:37]([F:42])([CH3:41])[C:38](O)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:36][C:37]([C:41]1[N:28]([C:5]2[N:4]=[C:3]3[C:8]([N:9]=[C:10]([CH2:11][N:12]4[CH2:13][CH:14]([CH:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)[CH2:15]4)[N:2]3[CH3:1])=[C:7]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:6]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]=1)([F:42])[CH3:38]
Reactant: CC(F)(F)C(=O)O
Reactant: Cn1c(CN2CC(C3CCOCC3)C2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
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: Cn1c(CN2CC(C3CCOCC3)C2)nc2c(N3CCOCC3)nc(-n3c(C(C)(F)F)nc4ccccc43)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.3 %

Procedure:
To a mixture of N-{9-methyl-6-morpholin-4-yl-8-[3-(tetrahydropyran-4-yl)azetidin-1-ylmethyl]-9H-purin-2-yl}benzene-1,2-diamine (0.234 g, 0.49 mmol) and 2,2-difluoropropionic acid (0.057 g, 0.51 mmol) and DIPEA (0.185 mL, 1.08 mL) in DMF (14 mL) was added HATU (0.223 g, 0.59 mmol) and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 7.5:92.5). The solution was concentrated in vacuo, the residue was diluted in acetic acid (30 mL) and the reaction mixture was stirred at 90° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (Si—PPC, MeOH:DCM, 0:100 to 7.5:92.5) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 468 as a white solid (0.063 g, 24%). LCMS (Method I): RT=3.34 min, [M+H]+ 553.3. 1H NMR (400 MHz, DMSO-d6): δ 7.84-7.82 (m, 1 H); 7.75-7.72 (m, 1 H); 7.42-7.36 (m, 2 H); 4.58 (dd, J=7.85, 6.0 Hz, 2 H); 4.40-4.00 (m, 4 H); 4.32 (t, J=6.0 Hz, 2 H); 3.78 (s, 3 H); 3.77 (s, 2 H); 3.77-3.73 (m, 4 H); 2.85 (d, J=11.1 Hz, 2 H); 2.68-2.66 (m, 1 H); 2.26 (t, J=19.02 Hz, 3H); 2.09 (t, J=11.1 Hz, 2 H); 1.57 (d, J=12.5 Hz, 3 H); 1.03 (d, J=12.5 Hz, 2 H)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=3)([I:11])[CH2:8][C:6]=2[N:7]=1.[C:28](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([C:12]3[CH:13]=[C:14]([N:18]([CH3:28])[C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=3)([I:11])[CH2:8][C:6]=2[N:7]=1
Reactant: CC(=O)Nc1cccc(C2(I)Cc3nc(Cl)nc(N4CCOCC4)c3S2)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CC(=O)N(C)c1cccc(C2(I)Cc3nc(Cl)nc(N4CCOCC4)c3S2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 60 mg of N-(3-(2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine-6-yl)phenyl)acetamide and 78 mg of cesium carbonate in DMF was added 12 μL of iodomethane. The reaction mixture was stirred for 2 h at room temperature. The mixture was diluted with ethyl acetate, washed with H2O. The organic layer was dried over (MgSO4) and evaporated to yield N-(3-(2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine-6-yl)phenyl)-N-methylacetamide.
Reaction SMILES: [CH2:1]([N:8]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:9]1[CH2:13][CH:12]([C:14](=O)[CH2:15][NH:16][C:17]2[N:18]=[C:19]3[CH:25]=[CH:24][N:23]([S:26]([C:29]4[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:20]3=[N:21][CH:22]=2)[CH:11]([CH3:37])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>O1CCOCC1>[CH2:1]([N:8]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:9]1[CH2:13][CH:12]([C:14]2[N:18]3[C:19]4[CH:25]=[CH:24][N:23]([S:26]([C:29]5[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=5)(=[O:28])=[O:27])[C:20]=4[N:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]([CH3:37])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NCC(=O)C4CC(N(Cc5ccccc5)Cc5ccccc5)CC4C)cnc32)cc1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ncc(C4CC(N(Cc5ccccc5)Cc5ccccc5)CC4C)n23)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A mixture of 1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone (5.32 g, 8.75 mmol, Preparation #50) and Lawesson's reagent (1.88 g, 4.64 mmol) in 1,4-dioxane (60 mL) was heated at about 60° C. for about 2 h. Lawesson's reagent (1.88 g, 4.64 mmol) was added and stirring at about 60° C. was continued for about 1 h. The solvent was removed and the residue subjected to silica gel flash chromatography eluting with a gradient of 0-8% MeOH in DCM to yield N,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (4.47 g, 87%) as a brown amorphous solid: LC/MS (Table 1, Method a) Rt=2.99 min; MS m/z 590 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[C:22]#[N:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>N.CCO.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[CH2:22][NH2:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C#N)c1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(CN)c1
Reaction time: 2.5 h
Yield: 94.5 %

Procedure:
To a solution of 4-(2-cyano-4-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (680 mg, 2.14 mmol) in NH3/EtOH (2M, 15 mL) was added Raney Nickel (5 mL slurry in water). The atmosphere was exchanged with hydrogen via balloon and the mixture was allowed to stir for 2.5 h. After this time the mixture was filtered through celite and concentrated to yield the title compound (650 mg). m/z (M+1) 321.57.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](C)=[C:5]([C:18]([O:20][CH3:21])=[O:19])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH2:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.B(F)(F)F.CCOCC>C(Cl)(Cl)Cl>[CH3:1][C:2]12[CH2:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:5]([C:18]([O:20][CH3:21])=[O:19])([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]1[C:8]([O:10][CH3:11])=[O:9])[CH:4]=[N:3]2
Reactant: C=Cc1ccccc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1C(c2ccccc2)C2(C(=O)OC)C=NC1(C)CC2c1ccccc1
Reaction time: 3 h

Procedure:
To 0.45 g (1.5 mmol) dimethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (1) in 25 ml CHCl3 under N2 and cooled to 0°-10° in an ice bath there was added 3.12 g (30.0 mmol) of commercially obtained styrene (4) followed by 0.64 g (4.5 mmol) boron trifluoride etherate added dropwise via syringe. The resulting solution was stirred at 0°-10° for 3 hours and then at room temperature for 16 hours.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.C(N(CC)CC)C.[NH2:18][C@H:19]([CH3:22])[CH2:20][OH:21]>C(O)(C)C>[NH2:8][C:7]1[C:2]([NH:18][C@H:19]([CH3:22])[CH2:20][OH:21])=[N:3][C:4]([CH3:10])=[N:5][C:6]=1[Cl:9]
Reactant: C[C@@H](N)CO
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c(N)c(N[C@H](C)CO)n1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Charge 4,6-dichloro-2-methyl-pyrimidin-5-ylamine (307 g, 1.72 moles) into a 10 L flange flask mounted on an isomantle equipped with an overhead stirrer, reflux coil condenser, thermometer, and addition funnel. Then add isopropyl alcohol (3.45 L) to the flask and stir to give a clear pale yellow solution. Add triethylamine (456.7 mL, 3.28 mol) to the flask in one portion while stirring and warm to 50° C. Slowly add (R)-(−)-2-amino-1-propanol (194.30 g, 202.10 mL, 2.59 mol) from the addition funnel over 30 min. After the final addition heat the reaction mixture at reflux for 36 h. Allow the reaction mixture to cool. Add additional (R)-(−)-2-amino-1-propanol (64.77 g, 67.37 mL, 862.26 mmol, 0.5 eq) and triethylamine (174.51 g, 240.37 mL, 1.72 moles, 1.0 eq) to the reaction mixture and reflux for 18 h. Allow the reaction mixture to cool. Add additional (R)-(−)-2-amino-1-propanol (32.38 g, 33.68 mL, 431.13 mmol, 0.25 eq) and triethylamine (87.25 g, 120.18 mL, 862.26 mmol, 0.5 eq) to the reaction mixture and heat to reflux for 6 h. Allow to cool while stirring at ambient temperature for 48 h.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29]([OH:31])=O)[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.[NH:36]1[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]1>>[C:40]([CH:38]1[CH2:39][N:36]([C:29](=[O:31])[CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:34])([F:33])[F:1])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH3:32])[CH2:37]1)#[N:41]
Reactant: N#CC1CNC1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Agent: Cl
Product: CC(C(=O)N1CC(C#N)C1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and azetidine-3-carbonitrile hydrochloride (Asta Tech, Inc. and Cat. No. 52028). LCMS (M+H)+: m/z=538.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([NH:19][NH:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1>P(Cl)(Cl)(Cl)=O>[F:28][C:24]1[CH:23]=[C:22]([C:21]2[O:18][C:17](/[CH:16]=[CH:15]/[C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:19][N:20]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cc(/C=C/C(=O)NNC(=O)c2cccc(F)c2)ccc1-n1cnc(C)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(/C=C/c2nnc(-c3cccc(F)c3)o2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A solution of 3-fluorobenzoic acid N′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (86 mg) in phosphorus oxychloride (2 mL) was stirred at 120° C. for one hour. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Methylene chloride and a 1 N sodium hydroxide solution were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane:ethyl acetate=1:1→ethyl acetate) to obtain 65 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[N:14](C3CCCCO3)[N:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:21][O-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][C:11]=2[Cl:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(-c2ccnn2C2CCCCO2)cc1Cl
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc(-c2[nH]ncc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (12.0 g, 41.7 mmol) was dissolved in acetic acid (20 ml) and sodium hypochlorite solution (29.0 ml, 416 mmol) was added. The reaction mixture was stirred at RT overnight. Further again, acetic acid (120 ml) and sodium hypochlorite solution (14 ml) were added and the mixture was stirred at RT overnight. The precipitate was filtrated and washed with water and DCM. The precipitate was dried in vacuum 40° C. overnight to yield 5.8 grams of 2-chloro-4-(4-chloro-1H-pyrazol-5-yl)benzonitrile. The mixture of 2-chloro-4-(4-chloro-1H-pyrazol-5-yl)benzonitrile (5.8 g, 24.36 mmol) and 10% HCl/ethanol solution (167 ml, 365 mmol) was stirred for 2 h at RT and the precipitate was filtrated and washed with water. The precipitate was silted up with ethanol to yield 4.0 g of the raw material. The product was purified with Flash-chromatography to yield total 18% of the title compound. 1H NMR (400 MHz; d6-DMSO): δ 8.05 (m, 2H), 8.16 (m, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[NH:32][CH:31]=[C:30]4[CH:34]=O)[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18].[OH-].[Na+]>CO>[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[NH:32][CH:31]=[C:30]4[CH2:34][NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:8])[CH3:7])[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:18])[CH3:19]
Reactant: COC(=O)[C@H](C)N
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)c[nH]c34)no2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@H](C)NCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
L-alanine methyl ester hydrochloride (420 mg) and 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbaldehyde (D71) (382 mg) was added to a solution of NaOH (120 mg) in methanol (20 mL). After stirring for 0.5 hour, methanol was evaporated off and then after addition of AcOH (0.5 mL) in dichloromethane (40 mL), NaBH(OAc)3 (847 mg) was added. The reaction mixture was stirred at room temperature overnight and quenched by saturated NaHCO3 solution. The organic layer was separated and washed with water and brine. After the solvent was evaporated off the residue was purified by Mass Directed AutoPrep to afford methyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-D-alaninate (D76) (223 mg) as a white solid. MS (ES): C24H25ClN4O4 requires 468; found 491.1 (M+Na+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C(O)c1ccc(Br)cc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)cc1Br
Temperature: 25 °C

Procedure:
A solution of 2,4-dibromobenzoic acid (52.0 g, 176 mmol, 1.00 equiv, 95%) and sulfuric acid (20 mL) in methanol (400 mL) was stirred at 90° C. overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with 500 mL of ethyl acetate and washed with 3×100 mL of H2O followed by 1×100 mL of NaHCO3 (aq., sat. Note: gas evolution occurs). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 45.0 g (78%) of methyl 2,4-dibromobenzoate as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=[O:17].N1(CC(O)=O)CCCCC1>C1C=CC=CC=1>[CH2:21]([O:20][C:14](=[O:19])[C:15]([C:16](=[O:17])[CH3:18])=[CH:6][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([OH:11])=[C:9]([O:12][CH3:13])[CH:8]=1)[CH3:22]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: CCOC(=O)CC(C)=O
Agent: O=C(O)CN1CCCCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1cc(OC)c(O)c(OC)c1)C(C)=O

Procedure:
Condensation of 3,5-Dimethoxy-4-hydroxy benzaldehyde (syringaldehyde) with ethyl acetoacetate in the presence of piperidine-acetic acid and benzene as the reaction medium at reflux temperature yields the title product. The reaction takes about 3.5 hours for completion.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:23](=[O:25])[CH3:24])[CH:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:10]=1[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[C:26]([C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1)([OH:28])=[O:27]>>[C:1]([C:5]1[CH:6]=[C:7]([C:23](=[O:25])/[CH:24]=[CH:33]/[C:32]2[CH:35]=[CH:36][C:29]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=2)[CH:8]=[C:9]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:10]=1[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)c1cc(-c2ccc(C)cc2)c(OCC(C)C)c(C(C)(C)C)c1
Reactant: O=Cc1ccc(C(=O)O)cc1
Product: Cc1ccc(-c2cc(C(=O)/C=C/c3ccc(C(=O)O)cc3)cc(C(C)(C)C)c2OCC(C)C)cc1
Yield: 50 %

Procedure:
In a similar manner to that of Example 2 b, by reacting 1 g (2.9 mmol) of 1-(5-tert-Butyl-6-isobutoxy-4′-methyl-3-biphenylyl)ethanone with 400 mg (2.6 mmol) of 4-carboxybenzaldehyde. A yellow solid is obtained (m=700 mg; yield=50%; m.p.=243° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([N:16]([C:18]2[C:19]([Cl:38])=[C:20]([C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[N:31]=[C:30]([CH3:33])[CH:29]=[CH:28]3)[CH3:17])=[O:15])=[O:11])=[CH:4][CH:3]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>ClCCl>[C:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([N:16]([C:18]2[C:19]([Cl:38])=[C:20]([C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[N:31]=[C:30]([CH3:33])[CH:29]=[CH:28]3)[CH3:17])=[O:15])=[O:11])=[CH:4][CH:3]=1)(=[O:41])[CH3:40]
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CSc4ccc(N)cc4)c3Cl)c2n1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(SCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
A mixture of 8-[3-[N-[2-(4-aminophenylthio)-acetylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (56 mg) triethylamine (15 mg), and acetic anhydride (15 mg) in dichloromethane (2 ml) was stirred for 4 hours at ambient temperature. The resulting precipitates were collected by filtration to give 8-[3-[N-[2-(4-acetamidophenylthio)acetylglycyl]-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (30 mg) as a colorless crystal.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]2=[C:9]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=[C:11]([C:12]([CH:14]3[CH2:18][CH2:17][NH:16][CH2:15]3)=[O:13])[N:7]2[N:6]=[CH:5][N:4]=1.C([O-])([O-])=O.[Na+].[Na+].[C:41](Cl)(=[O:43])[CH3:42]>CC#N.CO>[NH2:2][C:3]1[C:8]2=[C:9]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:23]=4)[CH:10]=[C:11]([C:12]([CH:14]3[CH2:18][CH2:17][N:16]([C:41](=[O:43])[CH3:42])[CH2:15]3)=[O:13])[N:7]2[N:6]=[CH:5][N:4]=1
Reactant: Nc1ncnn2c(C(=O)C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(=O)N1CCC(C(=O)c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.8 %

Procedure:
[4-Amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-pyrrolidin-3-yl-methanone hydrochloride salt (80 mg, 0.17 mmol) was dissolved in CH3CN/MeOH (1:1, 2 mL) and 2N Na2CO3 (0.84 mL, 1.68 mmol) was added, followed by acetyl chloride (0.013 mL, 0.19 mmol). The resulting mixture was stirred at rt for 12 h. The mixture was concentrated, diluted with EtOAc and layers were separated. The organic layer was washed with brine and concentrated. The residue was purified by short silica-gel column eluting with EtOAc, then 10% MeOH in EtOAc to give 39 mg (48%) of the desired product. 1H-NMR (CD3OD-d4) 8.39-8.35 (m, 1H), 8.03 (d, 1H), 7.81 (dt, 1H), 7.69-7.67 (m, 1 H), 7.47 (d, 1H), 7.37-7.27, (m, 5 H), 7.19 (fit, 1 H), 5.64 (s, 1 H), 4.53-4.38 (m, 1 H), 3.92-3.72 (m, 2 H), 3.62 (t, 1H), 3.52 (t, 1 H), 2.38-2.07 (m, 2 H), 2.10 (d, 3 H); LC-MS [M+H]+=480.1, RT=2.64 min.
Reaction SMILES: [NH3:1].Cl[S:3]([C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].ClCCl>C(#N)C>[NH2:1][S:3]([C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: COC(=O)Cc1cccc(S(=O)(=O)Cl)c1
Reactant: N
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)Cc1cccc(S(N)(=O)=O)c1
Temperature: 22 °C
Reaction time: 2 h

Procedure:
0.880 Ammonia (0.027 ml) was added to a stirred solution of methyl [3-(chlorosulfonyl)phenyl]acetate (0.35 g) in a 1:1 mixture of dichloromethane and acetonitrile (1.75 ml), and the mixture was stirred at 22° C. for 2 h. The mixture was allowed to stand for a further 18 h, and the solvent was evaporated in vacuo. The residue was re-dissolved in dichloromethane and applied to a silica gel cartridge (10 g Varian Bond Elut, pre-conditioned with dichloromethane). The cartridge was eluted with dichloromethane, chloroform, ether, ethyl acetate, acetone, acetonitrile and methanol (1 column volume each), the fractions containing the product evaporated in vacuo, and the residue passed down a 5 g silica gel cartridge which was prepared and eluted in an identical manner. The product containing fractions were evaporated in vacuo to give a residue which was further purified using mass-directed preparative HPLC, to give the title compound as a colourless gum (0.018 g).