Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:25]([C:28]2[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:6]2[NH:10][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])=[N:8][C:7]=2[CH:24]=1.C(=O)(O)[O-:40].[Na+:43]>C(COC)OC.O>[Na+:43].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:25]([C:28]2[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)(=[O:26])=[O:27])[C:6]2[NH:10][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)(=[O:40])=[O:12])=[N:8][C:7]=2[CH:24]=1
Reactant: COc1cc(S(=O)(=O)c2ccc(OCC(=O)O)cc2)c2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(S(=O)(=O)c2ccc(OCC(=O)[O-])cc2)c2[nH]c(S(=O)(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 85.8 %

Procedure:
To a suspension of the sulfoxide acid (4.47 g, 0.008 mol) in glyme (75 mL) was added a solution of sodium bicarbonate (0.672 g, 0.008 mol) in water (50 mL). The reaction mixture was extracted with ethyl acetate (4×50 mL). The combined organic layers were back extracted with water (2×25 mL). The combined aqueous layers were lyophilized to give 4.1 g (88%) of the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([I:29])=[N:23][C:24]=3Cl)[O:7]1)(=[O:3])[CH3:2].[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:12]([O:11][C@H:10]1[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([I:29])=[N:23][C:24]=3[NH:35][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[O:7][C@@H:6]1[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:14])[CH3:13]
Reactant: NC1CCCC1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1.15 g of [(2R,3R,4R,5R)-3,4-diacetyloxy-5-(6-chloro-2-iodopurin-9-yl)oxolan-2-yl]methyl acetate (Toronto Research Chemicals) was placed in 20 mL of DMF (dimethylformamide) and stirred. To this solution was added 0.42 mL of cyclopentyl amine and 10 mL of DIPEA (diisopropylethylamine). The resulting mixture was stirred overnight at room temperature. The next morning, the solvent was removed and the residue purified using a dichloromethane/methanol 20:1 column to provide (2R,3R,4R,5R)-4-acetyloxy-2-(acetyloxymethyl)-5-[6-(cyclopentylamino)-2-iodopurin-9-yl]oxolan-3-yl acetate, a compound of formula (10).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH:12]=C)[C:9]#[N:10])=[CH:4][CH:3]=1.CC(C)=[O:16].O>O.O=[Os](=O)(=O)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH:12]=[O:16])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: C=CCC(C#N)c1ccc(I)cc1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: N#CC(CC=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(4-iodo-phenyl)-pent-4-enenitrile (2.8 g, 9.9 mmol, intermediate for preparing EXAMPLE 2), OsO4 (0.7 mL, 4% in water, 0.10 mmol), and NaIO4 (4.44 g, 20.8 mmol) in 2:1 acetone/H2O (100 mL) was stirred at room temperature for 16 h. TLC (1:1 hexanes/EtOAc) showed no starting material left. The mixture was diluted with H2O (50 mL) and extracted with CH2Cl2 (50 mL×4). The organic layer was washed with brine, dried (Na2SO4) and concentrated by rotary evaporation. Purification by silica gel chromatography (1:1 hexanes/EtOAc) gave 2-(4-iodo-phenyl)-4-oxo-butyronitrile as a yellowish oil, 1.9 g (68%). 1H NMR (300 MHz, CDCl3): δ 9.85 (s, 1H), 7.84 (d, 2H), 7.24 (d, 2H), 4.44 (t, 1H), 3.33 (dd, 1H), 3.14 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[NH2:19][CH2:20][C:21]1[C:22](=[O:31])[NH:23][C:24]([CH3:30])=[CH:25][C:26]=1[CH2:27][CH2:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][CH2:20][C:21]2[C:22](=[O:31])[NH:23][C:24]([CH3:30])=[CH:25][C:26]=2[CH2:27][CH2:28][CH3:29])=[O:18])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)[C:9]=2[CH:10]=1
Reactant: O=C(O)c1cc(Cl)cc2c1cnn2C1CCCC1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Cl)cc2c1cnn2C1CCCC1

Procedure:
The title compound was prepared in the same manner as described for example 3 (step c) from 6-chloro-1-cyclopentyl-1H-indazole-4-carboxylic acid (0.12 g, 0.453 mmol) and 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (0.128 g, 0.680 mmol). The final product was collected as 0.170 g (86%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.33 Hz, 3H), 1.45-1.57 (m, 2H), 1.61-1.74 (m, 2H), 1.80-1.92 (m, 2H), 1.92-2.03 (m, 2H), 2.05-2.19 (m, 5H), 4.36 (d, J=5.05 Hz, 2H), 5.21 (t, J=7.07 Hz, 1H), 5.91 (s, 1H), 7.59 (d, J=1.52 Hz, 1H), 8.06 (s, 1H), 8.37 (s, 1H), 8.62 (t, J=4.80 Hz, 1H), 11.55 (s, 1H); LC-MS (ES) m/z=426.7 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:10]([C:11]3[NH:15][C:14](=[O:16])[O:13][N:12]=3)=[C:4]2[CH:3]=1.Br[CH2:26][CH2:27][Cl:28].N12CCCN=C1CCCCC2>CN(C)C(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:10]([C:11]3[N:15]([CH2:26][CH2:27][Cl:28])[C:14](=[O:16])[O:13][N:12]=3)=[C:4]2[CH:3]=1
Reactant: ClCCBr
Reactant: COc1ccc(-c2nn3ccc(Br)cc3c2-c2noc(=O)[nH]2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2nn3ccc(Br)cc3c2-c2noc(=O)n2CCCl)cc1
Yield: 18.7 %

Procedure:
A mixture of Example 19H (0.64 g, 1.653 mmol), 1-bromo-2-chloroethane (0.206 mL, 2.479 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.374 mL, 2.479 mmol) in N,N-dimethylacetamide (8 mL) was heated at 100° C. for 20 hours, cooled and partitioned with ethyl acetate and 1 M aqueous HCl. The organic layer was washed with brine twice, dried with sodium sulfate, filtered and concentrated. Purification on a 40 g silica cartridge eluting with 1-2% methanol in dichloromethane provided the title compound as a solid (0.139 g, 19%). MS (ESI+) m/z 449/451 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([NH:13]N)[CH:6]=[C:7]([CH3:12])[C:8]=1[O:9][CH2:10][CH3:11].[CH3:15][CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=O.[OH-].[Na+]>C(O)(=O)C.O>[CH2:10]([O:9][C:8]1[C:3]([CH3:2])=[CH:4][C:5]2[N:13]=[C:17]3[C:18]4[C:23]([CH2:24][C:16]3([CH3:15])[C:6]=2[C:7]=1[CH3:12])=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:11]
Reactant: CC1Cc2ccccc2C1=O
Reactant: CCOc1c(C)cc(NN)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCOc1c(C)cc2c(c1C)C1(C)Cc3ccccc3C1=N2
Yield: 96.1 %

Procedure:
A solution of 2.16 g (0.01 mol) of 3,5-dimethyl-4-ethoxyphenylhydrazine hydrochloride and 1.46 g (0.01 mol) of 2-methyl-1-indanone in 20 ml of acetic acid was stirred overnight at room temperature and then refluxed for 3 hours. The mixture was diluted with water, alkalinized with 10N sodium hydroxide solution and extracted three times with methylene chloride. The combined organic phase was washed with water, dried (Na2SO4) and evaporated giving 2.8 g of crude product which was recrystallized from light petroleum/ethyl acetate (5/1). Yield 2.1 g (72%). M.p. 164° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([CH2:22][C:23]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=O)[C:13]([C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)=O)=[CH:11][C:6]=2[N:5]([CH2:31][CH3:32])[C:4]1=[O:33])[CH3:2].C([O-])(=O)C.[NH4+:38].[NH4+].[OH-]>C(O)(=O)C>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:22]=[C:23]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[NH:38][C:13]=3[C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)=[CH:11][C:6]=2[N:5]([CH2:31][CH3:32])[C:4]1=[O:33])[CH3:2]
Reactant: CCn1c(=O)n(CC)c2cc(C(CC(=O)c3cccnc3)C(=O)c3cccc(C)c3)ccc21
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCn1c(=O)n(CC)c2cc(-c3cc(-c4cccnc4)[nH]c3-c3cccc(C)c3)ccc21
Reaction time: 0.08 h
Yield: 6.3 %

Procedure:
A solution of 2-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-4-pyridin-3-yl-1-m-tolyl-butane-1,4-dione (600 mg, 1.13 mmol) and ammonium acetate (871 mg, 11.3 mmol) in acetic acid (3.77 mL) was heated at 110° C. for 4 hours. The reaction was then poured over a mixture of ice and NH4OH and stirred for 5 minutes. The aqueous mixture was extracted with EtOAc (3×10 mL). The organics were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a orange oil. The oil was purified by flash chromatography using a gradient of Et2O to 50% EtOAc/Et2O, affording 30 mg of the title compound. MS (M+1)=423.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[H-].[Na+].[CH3:30][C:31]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)([CH3:34])[CH2:32][CH3:33].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:41]([C:38]1[CH:39]=[CH:40][C:35]([C:31]([CH3:30])([CH3:34])[CH2:32][CH3:33])=[CH:36][CH:37]=1)(=[O:43])=[O:42])[C:6](=[O:11])[C:5]2([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[NH:12][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1Nc2ccc(Cl)cc2C1(NCCN1CCOCC1)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)(C)c1ccc(S(=O)(=O)N2C(=O)C(NCCN3CCOCC3)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
A solution of 1 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-[[2-(morpholin-4-yl)ethyl]amino]indol-2-one in 10 ml of DMF is cooled to 0° C. under an argon atmosphere and 0.108 g of sodium hydride as a 60% dispersion in oil is added. After stirring for 30 minutes, 0.607 g of 4-(1,1-dimethylpropyl)benzenesulfonyl chloride is added and the reaction mixture is stirred for 2 hours, the temperature being allowed to rise to RT. It is poured into water and extracted with AcOEt, the organic phase is washed with water and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (80/20; v/v) as the eluent to give 0.45 g of the expected product after crystallization from a DCM/iso ether mixture. M.p.=147° C.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:19](=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[CH2:18][C@:8]1([C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]1=[O:17])[CH2:7]2.C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N:39]([CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:19](=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[CH2:18][C@:8]1([C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]1=[O:17])[CH2:7]2)=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc(CCO)c([N+](=O)[O-])cc1C2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)Nc2ncccc21
Temperature: 100 °C

Procedure:
To a stirred solution of (2S)-5-(2-hydroxyethyl)-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′-one from Step E (174 mg, 0.54 mmol) in DMF (4 mL) were added diphenyl phosphoryl azide (177 mg, 0.64 mmol) and DBU (0.096 mL, 0.64 mmol). The mixture was heated at 100° C. for 6 h, then quenched with H2O (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 80:20, to give the title compound. MS: m/z=351 (M−1).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C(=O)(O)[O-].[Na+].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(OC)(C)C.O>[CH3:6][N:5]([CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])[C:21](=[O:22])[CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CNCC(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: COC(CN(C)C(=O)Cc1ccccc1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a 20 L Morton flask was added MTBE (5.52 L, 7 volumes) and (N-methyl-amino)-acetaldehyde dimethyl acetal (614 g, 5 mol) to form a solution at room temperature. A solution of sodium bicarbonate prepared by the addition of sodium bicarbonate (546 g, 6.5 mol) and water (6.31 L, 8 volume) was added to the Morton reaction flask. The mixture was cooled to less than 10° C and a MTBE (789 mL) solution of phenylacetyl chloride (789 g, 5 mol) was added dropwise to the cooled reaction mixture over a 1 h period. After addition, the reaction mixture was stirred at room temperature for 1 h. At this stage an HPLC analysis indicated that the reaction was completed. Extractive workup with MTBE (4 volumes), anhydrous magnesium sulfate drying followed by concentration on the rotary evaporator provided 1.187 kg (98%) of N-methyl-N-(2,2-dimethoxyethyl)phenylacetamide as a liquid, (M+H)+=237.9.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([NH:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][CH2:24][CH3:25])[C:20]([C:26]([F:29])([F:28])[F:27])=[CH:19][N:18]=1>CC(O)(C)C>[CH2:24]([NH:23][C:21]1[C:20]([C:26]([F:28])([F:29])[F:27])=[CH:19][N:18]=[C:17]([NH:1][C:2]2[C:7]3[O:8][CH2:9][CH2:10][O:11][C:6]=3[C:5]([C:12]([NH:14][CH3:15])=[O:13])=[CH:4][CH:3]=2)[N:22]=1)[CH3:25]
Reactant: CCNc1nc(Cl)ncc1C(F)(F)F
Reactant: CNC(=O)c1ccc(N)c2c1OCCO2
Solvent: CC(C)(C)O
Product: CCNc1nc(Nc2ccc(C(=O)NC)c3c2OCCO3)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 21.5 %

Procedure:
A microwave vial equipped with a magnetic stirrer was charged with 8-amino-N-methyl-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide (50 mg, 0.18 mmol), 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (40 mg, 0.18 mmol), and t-BuOH (1.0 mL). The mixture was heated at 100° C. for 2 h under microwave irradiation. It was then concentrated and the residue was purified by reverse-phase prep-HPLC to afford the title compound as white solid (15.4 mg, 32%). LCMS: ESI (10 minute run), m/z=398.1 Retention time: 5.471 minute. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=9.0 Hz, 1H), 8.17 (s, 1H), 7.82 (d, J=4.5 Hz, 1H), 7.67˜7.62 (m, 1H), 7.50˜7.47 (m, 1H), 5.20 (s, 1H), 4.46˜4.44 (m, 2H), 4.41˜4.40 (m, 2H), 3.63˜3.56 (m, 2H), 3.01 (d, J=5.0 Hz, 3H), 1.31 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[CH:7]=2)([CH3:3])[CH3:2].Cl[CH2:18][C:19]1[O:20][CH:21]=[CH:22][N:23]=1>>[CH:1]([C:4]1[N:5]([CH2:18][C:19]2[O:20][CH:21]=[CH:22][N:23]=2)[C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[CH:7]=2)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(C=O)c(C(C)C)[nH]c2c1
Reactant: ClCc1ncco1
Product: COc1ccc2c(C=O)c(C(C)C)n(Cc3ncco3)c2c1

Procedure:
2-Isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 137, 0.54 g, 2.49 mmol) and 2-(chloromethyl)oxazole (0.58 g, 4.4 mmol) were reacted as described in General Procedure J to give the title compound as an oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[OH:12][C:13]1[N:17]=[C:16]([S:18][CH2:19][CH:20]=[CH2:21])[S:15][N:14]=1>O1CCCC1>[CH3:8][NH:9][C:10]([N:14]1[C:13](=[O:12])[N:17]=[C:16]([S:18][CH2:19][CH:20]=[CH2:21])[S:15]1)=[O:11]
Reactant: CN=C=O
Reactant: C=CCSc1nc(O)ns1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCSc1nc(=O)n(C(=O)NC)s1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
0.5 ml of triethylamine and 5 ml of methyl isocyanate were added to a solution of 13.9 g of 3-hydroxy-5-allylthio-1,2,4-thiadiazole in 150 ml of tetrahydrofuran and the mixture was stirred at 20° C for 2 hours and was concentrated to dryness under reduced pressure. The residue was empasted with ethyl ether and was vacuum filtered and dried to obtain 15.9 g of 2-(N-methylcarbamoyl)-5-allylthio-1,2,4-thiadiazole-3-one melting at 110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[CH:12](O)=O>>[O:11]1[C:3]2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]=2[N:1]=[CH:12]1
Reactant: O=CO
Reactant: Nc1ccc(C(=O)O)cc1O
Product: O=C(O)c1ccc2ncoc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Amino-3-hydroxybenzoic acid (2.200 g) and formic acid (20 ml) were heated at 117° C. for 4 h. The reaction mixture was cooled to ambient temperature and the precipitated solid collected by filtration, washed with diethyl ether and dried at reduced pressure. The solid (0.580 g) was heated at reflux with zinc chloride (2.00 g) and c.H2SO4 (2 drops) in xylene (150 ml) under a Dean and Stark for 16 h. On cooling, water was added and the brown solid collected by filtration and washed with water. The resulting solid was washed with methanol and the solvent removed from the filtrate under reduced pressure to give the title compound as a dark brown solid (0.349 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:25]([O:31]COC)[C:24]=2[O:35][CH3:36])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].Cl>CO.O1CCOCC1>[CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:25]([OH:31])[C:24]=2[O:35][CH3:36])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: COCOc1ccc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)c1OC
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)ccc(O)c2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2,6-dimethoxy-3methoxymethoxyphenyl)-L-phenylalanine methyl ester (165 mg) was dissolved in MeOH (5 mL) and HCl in dioxane (4 M, 1 mL) was added to the mixture. The mixture was stirred at room temperature for 3 h. The mixture was evaporated and the residue was taken up with water (40 mL) and extracted with CH2Cl2. The extract was dried (MgSO4), filtered and evaporated. The residue was purified by preparative TLC (silica gel; eluent: hexane and AcOEt 3:1 to 1:1) to give N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxy-3-hydroxyphenyl)-L-phenylalanine methyl ester (145 mg ).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[OH:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1ccc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 110 °C
Yield: 90.8 %

Procedure:
In a microwave vial, 2-chloro-5-nitropyridine (80 mg, 0.505 mmol) was dissolved in 2 mL of dry dimethylformamide. 2,5-dimethylphenol (80 mg, 0.505 mmol, 1 equiv) and potassium carbonate (418 mg, 3.03 mmol, 6 equiv) were added. The reaction mixture was heated under microwave irradiation for 1 hour at 110° C. (Biotage Initiator). The reaction mixture was filtered. The filtrated solid was washed with dichloromethane (5 mL). The volatiles were evaporated. The residue was dissolved in dichloromethane (10 mL) and brine was added (10 mL). The organic layer was extracted 2 times with dichloromethane (2×15 mL) and 2 times with ethylacetate (2×15 mL). The organic phase was dried over sodium sulphate. The solvent was removed to afford the title compound (112 mg)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=[O:13])#[N:2].[Cl-].[NH4+].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.C(OCC)(=O)C>[NH:16]1[C:1]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][NH:7][C:6]3=[O:13])=[N:2][N:18]=[N:17]1
Reactant: N#Cc1ccc2nc[nH]c(=O)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1[nH]cnc2ccc(-c3nnn[nH]3)cc12
Temperature: 100 °C
Yield: 89.5 %

Procedure:
6-Cyanoquinazolin-4-one (0.5 g) in dimethylformamide (5 ml) was treated with ammonium chloride (0.33 g) and sodium azide (0.38 g) and heated at 100° C. under nitrogen for 45 minutes. The resulting mixture was cooled, diluted with ethyl acetate and filtered. The filter cake was washed with dimethylformamide and ethyl acetate to give the title compound (0.56 g) as a cream solid; δH [2H6]DMSO 13.00(1H,bs), 8.70(1H,d), 8.40(1H,dd), 8.38(1H,bs), 8.05(1H,s), 7.68(1H,d); m/z (M−1+) 213.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].Cl[CH2:13][CH2:14][CH2:15][C:16](Cl)=O.C(N(CC)CC)C>O1CCCC1.[OH-].[Na+]>[O:10]=[S:8]1(=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]2[CH2:13][CH2:14][CH2:15][C:16]2=[N:11]1
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccccc1S(N)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S1(=O)N=C2CCCN2c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.8 mmol of 2-aminobenzenesulfonamide are dissolved in tetrahydrofuran (THF) at room temperature. This solution is cooled on an ice bath, and 6 mmol of 4-chlorobutanoyl chloride and 6 mmol of triethylamine are successively added. The mixture is stirred for 16 hours at room temperature, filtered and evaporated. The yellow solid obtained is taken up in 40 ml of 1N sodium hydroxide and stirred at room temperature. After complete dissolution, a white precipitate appears; it is filtered off and gives the expected product after crystallization from an ethanol/water (4/1) mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.Br[CH2:25][CH2:26][O:27][CH3:28]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][N:19]([CH2:25][CH2:26][O:27][CH3:28])[C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1cc[nH]c(=O)c1
Reactant: COCCBr
Product: COCCn1ccc(-n2c(C)nc(C#Cc3ccnc(Cl)c3)c2C)cc1=O

Procedure:
The title compound, light brown solid, MS: m/e=382.3, 384.1 (M+H+), was prepared in accordance with the general method of example 3 from 4-[4-(2-chloro-pyridin-4-ylethynyl)-2,5-dimethyl-imidazol-1-yl]-1H-pyridin-2-one and 2-bromoethyl-methylether.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([CH2:16][NH:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]4[C:31]([NH:43][CH:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)=[C:32]5[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]5=[N:34][C:35]=4[CH2:36][CH3:37])=[O:27])[CH:21]=3)=[O:19])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:50]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)[CH3:51]>C1COCC1>[CH2:41]([N:38]1[C:33]2=[N:34][C:35]([CH2:36][CH3:37])=[C:30]([CH2:29][NH:28][C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([C:18]([NH:17][CH2:16][C:11]4[CH:10]=[C:9]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][N:55]6[CH2:56][CH2:57][N:52]([CH2:50][CH3:51])[CH2:53][CH2:54]6)[CH:4]=5)[C:14]([F:15])=[CH:13][CH:12]=4)=[O:19])[CH:21]=3)=[O:27])[C:31]([NH:43][CH:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[C:32]2[CH:40]=[N:39]1)[CH3:42]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CCl)c3)c2)c1
Reactant: CCN1CCNCC1
Solvent: C1CCOC1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(CC)CC4)c3)c2)c1

Procedure:
N-{[3′-(Chloromethyl)-6-fluoro-3-biphenylyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (0.034 g, 0.05 mmol) and 1-ethylpiperazine (0.0285 g, 0.25 mmol) were combined in THF (1 mL) and microwaved at 150° C. for 1 h. The mixture was purified using a Gilson HPLC with a TFA system followed by passing the product though a quaternary ammonium hydroxide cartridge to give the free base, the title compound, as a tan solid. LC-MS m/z 760.8 (M+H)+, 1.55 min (ret time); mp 155-158° C. Analytical HPLC shows 95.7% purity, (ret time 10.098 min).