Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc2cc[nH]c2c1
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc2cc[nH]c2c1
Yield: 51.6 %

Procedure:
To a solution of 4-chloro-3-nitrophenylsulfonamide (12 g, 51 mmol) dissolved in 50 ml of anhydrous dimethylformamide, was added 13.1 g (116 mmol) of ethylcyanoacetate and 10.5 g (76 mmol) of anhydrous potassium carbonate. This mixture was heated at 110° C. for 3 hours, cooled to room temperature, and added to ice water containing 8 ml of concentrated sulfuric acid. The mixture was extracted with ethyl acetate (3×200 ml), and the combined organic layer was back extracted with 200 ml of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by a preparative high pressure liquid chromatogram (Waters Prep 500 A) with 55% ethyl acetate in hexanes on a silica gel cartridge. The product was added to 45 ml of 50% aqueous acetic acid containing 3 ml of concentrated sulfuric acid and refluxed for 12 hours. The reaction was cooled to room temperature and added to 400 ml water. This mixture was extracted with ethyl acetate (3×100 ml). The combined organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was crystallized from 40 ml of ethyl acetate, 3 ml of ethanol and 1 ml of hexanes to obtain 6.9 g of 3-nitro-4-(2-acetonitrile)phenyl sulfonamide. This material was dissolved in 40 ml of ethanol containing 3 g of 5% palladium on activated carbon. This mixture was placed in a Parr Hydrogenation apparatus with 60 p.s.i. of hydrogen at 40° C. for 3 hours. This mixture was filtered, the filtrate concentrated under vacuum, and the residue recrystallized from 20 ml of ethyl acetate and 10 ml of ethanol to obtain 2.4 g of 6-indolesulfonamide. The sulfonamide (6.1 mmol) was reacted with 4-chlorophenylisocyanate (6.1 mmol) as described in Preparation 2 supra to obtain 1.1 g of the title product as a solid.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH:8]([C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][CH3:19])[CH:11]=1)=[O:9]>C1COCC1.CS(C)=O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([CH:8]2[CH2:4][O:9]2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: COc1cc(C=O)ccc1C#N
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1cc(C2CO2)ccc1C#N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cool solution of NaH (0.16 g, 3.9 mmol) in THF (40 ml) was added dropwise a solution of trimethylsulfonium iodide (0.91 g, 4.5 mmol) in DMSO (20 ml). The resulting mixture was stirred at 0° C. under N2 for 20 min. The solution of 4-formyl-2-methoxybenzonitrile (0.60 g, 3.7 mmol) in THF (20 ml) was added. The resulting reaction mixture was stirred at 0° C. under N2 for 1 hr, and then it was warmed gradually to room temperature and stirred at that temperature for 12 hr. The starting material was consumed as indicated by TLC (25% ethyl acetate/hexanes). The reaction mixture was cooled to 0° C. and quenched by drop-wise addition of water. The mixture was extracted with ethyl acetate (2×70 mL). The combined organic layers were washed with water, brine, then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes) to afford 2-methoxy-4-(oxiran-2-yl)benzonitrile. 1H NMR (CDCl3, 500 MHz) δ 7.57 (d, J=8 Hz, 1H), 6.99 (dd, J=1.1 Hz, J=1.2 Hz, 1H), 6.89 (s, 1H), 3.97 (s, 3H), 3.94-3.92 (m, 1H), 3.22 (dd, J=5.2, Hz, J=4.1 Hz, 1H), 2.77 (J=2.5 Hz, 1H); LC/MS (IE, m/z) 176.33 [M+1]+; tR=2.55 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@H:28]([CH3:33])[C:29](OC)=[O:30])[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[CH3:34][NH2:35]>>[CH3:34][NH:35][C:29](=[O:30])[C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Reactant: CN
Product: CNC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Yield: 86 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (210 mg, 0.46 mmol) was reacted with methylamine to give the title compound as a white solid (181 mg, 86%); NMR Spectrum 1.66 (d, 3H), 2.68 (d, 3H), 5.16 (q, 1H), 6.04 (s, 2H), 7.01 (d, 1H), 7.37 (d, 1H), 7.66 (s, 1H), 7.72-7.80 (m, 4H), 8.21 (s, 1H), 8.39 (m, 1H), 8.54 (s, 1H), 8.56 (s, 1H), 10.70 (br s, 1H); Mass spectrum MH+ 460.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:18]=[CH:17][C:12]3[NH:13][C:14](=[O:16])[O:15][C:11]=3[CH:10]=2)[CH2:5][CH2:4]1.[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]=O)=[CH:25][CH:24]=1)[CH:20]([CH3:22])[CH3:21].Cl>>[CH2:19]([C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][CH2:31][N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]3[CH:18]=[CH:17][C:12]4[NH:13][C:14](=[O:16])[O:15][C:11]=4[CH:10]=3)[CH2:7][CH2:8]2)=[CH:27][CH:28]=1)[CH:20]([CH3:21])[CH3:22]
Reactant: CN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: CC(C)Cc1ccc(CCC=O)cc1
Agent: Cl
Product: CC(C)Cc1ccc(CCCN(C)[C@H]2CC[C@H](c3ccc4[nH]c(=O)oc4c3)CC2)cc1

Procedure:
Condensation of 15 (1.0 g, 3.6 mmol) and 3-(4-isobutylphenyl)-propionaldehyde (700 mg, 3.6 mmol), following the procedure described in Example 45, Step 2, followed by conversion to the HCl salt, gave 6-(trans-4-{[3-(4-isobutylphenyl)propyl]methylamino}cyclohexyl)-3H-benzoxazol-2-one (977 mg, 61%), as an off-white solid: mp 162-165° C.; IR (KBr): 2953, 1773, 1498, 1451 cm−1; 1H NMR (300 MHz, DMSO-d6): δ 11.55 (s, 1H), 10.00 (s, 1H), 7.17-7.08 (m, 5H), 7.00 (s, 2H), 3.32-3.28 (m, 1H), 3.21-3.08 (m, 1H), 3.08-2.95 (m, 1H), 2.70 (d, J=5 Hz, 3H), 2.65-2.52 (m, 3H), 2.41 (d, J=7 Hz, 2H), 2.14-1.73 (m, 7H), 1.68-1.49 (m, 4H), 0.85 (d, J=7 Hz, 6H); HRMS-API (m/z): [M+H]+ calcd for C27H36N2O2, 421.2855; found, 421.2858; HPLC: method A, 7.49 minutes (>99%); method B, 13.59 minutes (>99%); Anal. Calcd for C27H36N2O2.HCl.0.5H2O: C, 69.58; H, 8.22; N, 6.01. Found: C, 69.23; H, 8.20; N, 5.87.
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[S:10][CH2:11][CH2:12][N:13]=1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].Cl>C(Cl)Cl>[CH2:18]([O:17][C:15]([N:13]1[CH2:12][CH2:11][S:10][C:9]1=[S:8])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: SC1=NCCS1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCSC1=S
Temperature: 25 °C
Reaction time: 3 h

Procedure:
12.9 ml of triethylamine cooled to 0° to 5° C. were added to 10 g of mercapto-thiazoline in solution in 200 ml of methylene chloride, then 12 ml of benzyl chloroformate in solution in 60 ml of methylene chloride were added dropwise. After stirring for 3 hours at ambient temperature, the mixture was poured into an iced solution of N hydrochloric acid and the aqueous phase was extracted with methylene chloride. The organic phase was dried and concentrated to dryness and the residue was chromatographed on silica (eluant: hexane-ethyl acetate 7-3) to obtain 17.9 g of the expected product melting at 72° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][NH2:6])=[O:4].[C:7]1([CH:13]=[C:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH3:1][O:2][C:3]([NH:5][N:6]=[C:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:14]1=[CH:13][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: COC(=O)NN
Reactant: O=C1CCCCCC1=Cc1ccccc1
Solvent: CCO
Product: COC(=O)NN=C1CCCCCC1=Cc1ccccc1
Yield: 91 %

Procedure:
9.0 g (0.1 mole) of N-methoxycarbonyl hydrazine are dissolved in 250 ml of anhydrous ethanol, under stirring, and 20.0 g (0.1 mole) of 2-phenylmethylenecycloheptan-1-one are added to the solution. The reaction mixture is kept at the boiling point under stirring, thereafter clarified with activated carbon, filtered and the filtrate is crystallized. 24.78 g of the named compound are obtained. Yield: 91%.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[N:8]1.[C:13]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O1CCCC1>[CH3:12][C:11]1[N:7]([CH2:6][C:13]2([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[CH:9][CH:10]=1
Reactant: Cc1ccnn1C
Reactant: O=C1CCCCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccnn1CC1(O)CCCCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of n-butyllithium (10 mL, 2.5M) in tetrahydrofuran (20 mL) was added 1,5-dimethyl-1H-pyrazole (2.0 g) in tetrahydrofuran (10 mL) dropwise via syringe. After 1 hour, cyclooctanone (2.63 g) in tetrahydrofuran (5 mL) was added dropwise and the reaction mixture was allowed to warm to room temperature. The mixture was quenched by the addition of saturated ammonium chloride solution and ethyl acetate. The layers were separated and the aqueous layer was extracted twice with additional ethyl acetate. The combined organics were dried over Na2SO4, filtered, and concentrated to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:9]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: Clc1cccc(C2CNc3ccccc32)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CC(c2cccc(Cl)c2)c2ccccc21
Reaction time: 1.5 h

Procedure:
To a solution of 3-(3-chlorophenyl)indoline (3.88 g, 16.9 mmol) and DIEA (2.40 g, 18.6 mmol) in DCM (40 mL) was added dropwise methanesulfonyl chloride (2.13 g, 18.6 mmol) at about 0° C. The mixture was stirred for about 1.5 hours. The solution was diluted with DCM and washed with saturated NaHCO3 solution (2 times), 1N HCl aqueous solution (2 times) and brine (2 times) and dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluting with EtOAc/hexane 1:4. The title compound was obtained as an oil Yield: 4.40 9, 85%. Rf=0.41, silica, EtOAc/hexane 1:2. 1H NMR (300 MHz, CDCl3) δ:7.52 (d, 1H), 7.24-7.34 (m, 3H), 7.20 (s, 1H), 7.02-7.14 (m, 3H), 4.59 (t, 1H), 4.38 (t, 1H), 3.87 (dd, 1H), 2.92 (s, 3H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1CN(C(=O)[C@H](NC(C2C3C(=NC=C([C:47]4[C:51]5=[N:52][CH:53]=[CH:54][CH:55]=[C:50]5[N:49]([CH3:56])[N:48]=4)N=3)NC=2)=O)C)C1)#N>CN(C=O)C.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.[Cu]I>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:47]3[C:51]4=[N:52][CH:53]=[CH:54][CH:55]=[C:50]4[N:49]([CH3:56])[N:48]=3)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cccnc34)nc12)C(=O)N1CC(C#N)C1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2ncccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (110 mg, 0.26 mmol) and 1-methyl-3-tributylstannyl-1H-pyrazolo[4,3-b]pyridine (see Example 98, 340 mg, 0.40 mmol) were dissolved in DMF (2.4 ml). The reaction mixture was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (15 mg, 0.013 mmol) and copper (I) iodide (10 mg, 0.053 mmol) were added. The reaction mixture was stirred at 80° C. overnight then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 12 g silica gel with EtOAc/hexanes (gradient: 0-70% EtOAc) to afford 51 mg (41%) of 2-(1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][CH:12]=1)C(OC)=O)=[O:4].[I-].[Na+]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:20]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:10][CH2:5][C:3]([O:2][CH3:1])=[O:4])#[N:21]
Reactant: COC(=O)C(Cc1c[nH]c2ccc(C#N)cc12)C(=O)OC
Agent: [I-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)CCc1c[nH]c2ccc(C#N)cc12
Yield: 80.8 %

Procedure:
To a solution of 1.14 g (3.98 mmol, 1.0 equiv.) of methyl 2-methoxycarbonyl-3-(5-cyano-1H-indol-3-yl)propanoate in 20 mL of pyridine was added 1.19 g (7.96 mmol, 2.0 equiv.) of sodium iodide. The mixture was heated to reflux for sixteen hours. The solution was cooled and diluted with 150 mL of chloroform. The organic layer was washed once with 25 mL of saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was filtered through a plug of silica gel with 1:1 ethyl acetate:hexane to remove colored impurities to provide 0.734 g (81%) of methyl 3-(5-cyano-1H-indol-3-yl)propanoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)=[O:33]>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([CH:32]=[O:33])[CH:39]=2)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:31]
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: O=Cc1cccc(B(O)O)c1
Product: COC(=O)c1cc(-c2cccc(C=O)c2)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 99.9 %

Procedure:
In the same manner as described in Example 241, 505.4 mg (1.0 mmol) of the product of Example 89 and 165 mg (1.1 mmol) of 3-formylbenzeneboronic acid provided 530 mg (100%) of the desired product as a pale yellow crystal. Electrospray Mass Spec 531 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][O:26][CH2:27][C:28](Cl)=[O:29]>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:28](=[O:29])[CH2:27][O:26][CH3:25])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COCC(=O)OC1CCN(C)C(=O)N1c1nnc(C2CC2)s1

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone 0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Methoxyacetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-methoxyacetyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [CH:1]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>C(O)C.[Pd]>[CH2:1]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC=Cc1cc2ccccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCc1cc2ccccc2[nH]1

Procedure:
2-Hex-1-enyl-1H-indole was dissolved in ethanol and 10% palladium on carbon was added to the solution. The reaction flask was sealed and exposed to hydrogen gas under pressure and was stirred until the hydrogen gas consumption was completely stopped. The reaction mixture was filtered through Celite. The solvent was evaporated to afford the product.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]([CH3:26])[CH3:25])=[CH:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1>C1COCC1.C([O-])(O)=O.[Na+]>[CH:24]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]([S:12]([C:9]2[CH:8]=[CH:7][C:6]([C:5]([OH:27])=[O:4])=[CH:11][CH:10]=2)(=[O:13])=[O:14])[CH:16]=1)([CH3:26])[CH3:25]
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C(C)C)c3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1cn(S(=O)(=O)c2ccc(C(=O)O)cc2)c2ccccc12
Reaction time: 8 h
Yield: 89.3 %

Procedure:
Add five molar NaOH (1.5 mL 0.0075 mol) to a stirring solution of 4-(3-isopropyl-indole-1-sulfonyl)-benzoic acid methyl ester (0.230 g, 0.00061 mol) in THF (10.0 mL) at ambient temperature under N2. Stir the resulting mixture overnight Dilute with 5% NaHCO3 (75 mL) and extract with Et2O. Separate the aqueous layer and acidify with 37% HCl. Extract the resulting precipitate into EtOAc, wash with brine, dry (MgSO4), filter and evaporate giving 0.187 g of the title compound as an off white solid: Mass spectrum (m/e) (M−H) 342.0800; Found (M−H) 342.0802.
Reaction SMILES: [NH2:1][C:2]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([Cl:17])[N:3]=1.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25](OC)(OC)[CH2:26]Br)[CH:20]=1.CCOCC>ClC1C=CC=CC=1>[Br:18][C:19]1[CH:20]=[C:21]([C:25]2[N:1]=[C:2]3[C:14]([CH3:15])=[C:13]([CH3:16])[C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])=[C:4]([Cl:17])[N:3]3[CH:26]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1c(N)nc(Cl)c(C(=O)OC(C)(C)C)c1C
Reactant: COC(CBr)(OC)c1cccc(Br)c1
Solvent: CCOCC
Solvent: Clc1ccccc1
Product: Cc1c(C(=O)OC(C)(C)C)c(Cl)n2cc(-c3cccc(Br)c3)nc2c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
A slurry of tert-butyl 6-amino-2-chloro-4,5-dimethylnicotinate (1.2 g, 4.7 mmol, 1 equiv) and 1-bromo-3-(2-bromo-1,1-dimethoxyethyl)benzene (2.3 g, 7.0 mmol, 1.5 equiv) in chlorobenzene (23 mL) was heated at reflux for 1.5 h. Upon cooling to ambient temperature, the reaction was added slowly to ether. The slurry was stirred for 15 min and the filtered to provide the product as a HBr salt (1.86 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.32 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.47-7.40 (m, 1H), 2.56 (s, 3H), 2.30 (s, 3H), 1.60 (s, 9H); LCMS (ESI, M+1): 435.05.
Reaction SMILES: C1(N[C:5](=[O:37])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([O:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[CH:19]=[C:20]([NH:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:36])CC1.Br.[OH2:39]>>[F:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[O:28][C:18]1[CH:19]=[C:20]([NH:21][CH2:22][CH2:23][C:24]([F:27])([F:25])[F:26])[C:15]2[N:16]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([C:5]([OH:37])=[O:39])=[C:7]([CH3:36])[CH:8]=3)=[CH:13][N:14]=2)[N:17]=1
Reactant: O
Reactant: Cc1cc(-c2cnc3c(NCCC(F)(F)F)cc(Oc4cccc(F)c4)nn23)ccc1C(=O)NC1CC1
Agent: Br
Product: Cc1cc(-c2cnc3c(NCCC(F)(F)F)cc(Oc4cccc(F)c4)nn23)ccc1C(=O)O
Yield: 9 %

Procedure:
A mixture comprising 50 mg (97 μmol) N-cyclopropyl-4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide and 0.5 mL hydrobromic acid was heated at 120° C. for 10 minutes under microwave irradiation. Water was added, the precipitate filtered off and purified by chromatography to give 30.0 mg (62%) of title compound A and 4.1 mg (9%) of title compound B.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([NH2:19])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[O:25][CH:24]=[N:23][C:22]=1[C:26](O)=[O:27]>>[CH:1]1([C:7]2[CH:8]=[C:9]([NH:19][C:26]([C:22]3[N:23]=[CH:24][O:25][C:21]=3[CH3:20])=[O:27])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ocnc1C(=O)O
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: Cc1ocnc1C(=O)Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Yield: 48.5 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 8b) (100 mg, 0.36 mmol) and 5-methyl-4-oxazolecarboxylic acid (71 mg, 0.55 mmol) as starting materials. The title compound (67 mg, 47.2%) was isolated as off white solid; MS (ESI): 384 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[N:20]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:28][CH2:27][CH2:26][N:20]2[CH2:25][CH2:24][S:23][CH2:22][CH2:21]2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Reactant: NCCN1CCSCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCN3CCSCC3)cc2F)cn1
Reaction time: 8 h
Yield: 81.1 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 2-thiomorpholin-4-ylethylamine (0.402 g, 2.75 mmol) and 3 Å molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 30% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.792 g, 81%): TOF MS ES+ 391.2 (M+H)+, HRMS calcd for C19H24N4O2FS 391.1604 (M+H)+, found 391.1594, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=6.7 min, 100% purity.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:27])([C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1)[CH3:27]
Reactant: Cc1csc(C(C)(C)N)n1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: Cc1csc(C(C)(C)NC(=O)c2cnc(C3CC3)c(OCC3CC3)n2)n1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g; 100 mg, 0.42 mmol) and α,α,4-trimethyl-2-thiazolemethanamine (CAN 859466-62-9, 78.2 mg, 0.64 mmol) as starting materials, and isolated (12 mg, 9.22%) as colorless sticky solid, LC-MS (UV peak area, ESI) 99.24%, 373.4 (M+H).