Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:25]=[CH:26][C:27]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[O:30])=[CH:28][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[CH2:38]([P:40](C#N)([CH2:42][CH3:43])=[O:41])[CH3:39]>CN(C)C=O>[CH2:38]([P:40]([NH:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:25]=[CH:26][C:27]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[O:30])=[CH:28][C:12]=3[N:11]=2)=[CH:8][CH:9]=1)=[NH:2])([CH2:42][CH3:43])=[O:41])[CH3:39]
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C(=N)N)cc1)n2CCCCc1ccccc1
Reactant: CCP(=O)(C#N)CC
Solvent: CN(C)C=O
Product: CCP(=O)(CC)NC(=N)c1ccc(-c2nc3cc(C(=O)NCCC(=O)OC)ccc3n2CCCCc2ccccc2)cc1

Procedure:
Prepared by reacting 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-1-(4-phenyl-butyl)-benzimidazole with diethylphosphorylcyanide in dimethylformamide.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[ClH:12]>>[ClH:12].[CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cccnc1C
Agent: Cl
Product: Cc1ncccc1C(=O)O

Procedure:
A solution of methyl 2-methylnicotinate (13.0 g, 86.1 mmol) in conc. HCl (65 mL) was heated to reflux overnight. The mixture was concentration under reduced pressure to give a solid which was washed twice with chloroform and dried to afford 2-methyl-nicotinic acid hydrochloride. The salt was dissolved in a minimum amount of methanol and the pH was adjusted with triethylamine to pH 3-4. The precipitated solid was filtered, washed with acetone and dried under high vacuum to afford 2-methyl-nicotinic acid (10.2 g, 87%) as an off-white-solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:33])=[CH:13]\[CH:14]=[CH:15]\[C:16](\[CH3:32])=[CH:17]/[CH2:18][O:19][C@@H:20]1[O:25][C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H:21]1O.CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/CO>>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:33])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:32])=[CH:17]/[CH2:18][O:19][C:20]([CH3:21])=[O:25]
Reactant: CC1=C(/C=C/C(C)=C\C=C\C(C)=C/CO[C@@H]2O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]2O)C(C)(C)CCC1
Agent: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Product: CC(=O)OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C

Procedure:
The starting materials for the preparation of retinyl β-glucuronide include retinol that can be obtained as an oil by saponification of commercially available retinyl acetate, and methyl (2,3,4-tri-O-acetyl glucopyranosyl bromide)-uronate that can be synthesized from commercially available 6,3-glucuronolactone by known procedures (Bollenback et al. J. Amer. Chem. Soc. 77: 3310-3315, 1955). The reaction is carried out in the presence of silver carbonate by stirring at room temperature for 20-24 hours. The resulting product is a mixture of unconverted retinol and the fully protected glucuronide of retinol. To obtain the free glucuronide, the crude mixture is saponified without separating the other products and then the products are separated by a combination of column chromatography and HPLC.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:16])=[CH:10][CH:9]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>O1CCCC1>[O-:42][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2[CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:16])=[CH:12][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Cc4ccccn4)cc2)CO3)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Cc4cccc[n+]4[O-])cc2)CO3)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.7 %

Procedure:
To a solution of N-[4—(2-pyridylmethyl)phenyl]-6—(4-methylphenyl)-2H-1-benzopyran-3-carboxamide (250 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.21 g) at 0° C., and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added sodiumithiosulfate solution, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:3) concentrated to give crystals, which were recrystallized from chloroform-ethanol to give N-[4—(1-oxidopyridin-2-ylmethyl)phenyl]-6—(4-methylphenyl)-2H-1-benzopyran-3-carboxamide (Compound 200) (191 mg) as pale yellow crystals.
Reaction SMILES: [B-](F)(F)(F)F.CN(C(O[N:14]1[C:19](=O)[CH2:18][CH2:17]C1=O)=[N+](C)C)C.[F:21][C:22]1[CH:23]=[C:24]([NH:29][CH:30]([C:32]2[CH:33]=[C:34]([C:49]([OH:51])=O)[CH:35]=[C:36]3[C:41]=2[O:40][C:39]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:38][C:37]3=[O:48])[CH3:31])[CH:25]=[C:26]([F:28])[CH:27]=1.C(N(C(C)C)C(C)C)C.N1CCC1>C(Cl)Cl.CN(C=O)C>[N:14]1([C:49]([C:34]2[CH:35]=[C:36]3[C:41](=[C:32]([CH:30]([NH:29][C:24]4[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=4)[CH3:31])[CH:33]=2)[O:40][C:39]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:38][C:37]3=[O:48])=[O:51])[CH2:17][CH2:18][CH2:19]1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Agent: C1CNC1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)N2CCC2)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.9 %

Procedure:
2-(2,5-dioxopyrrolidin-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (409 mg, 1.36 mmol) was added portionwise to a suspension of the enantiomer 2 of 8-(1-(3,5-difluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid ([α]D20°: −102°, enantiomer 2, see Example 7.0a) (450 mg, 1.05 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.310 mL, 1.78 mmol) in DCM (5 mL) at RT under nitrogen. The resulting mixture was stirred at RT for 4 hrs. Azetidine (0.211 mL, 3.14 mmol) was then added to the mixture and stirring was maintained overnight. The mixture was diluted with DMF and concentrated to remove DCM. The reaction mixture was purified by preparative HPLC on a Waters X-Bridge system. The fractions were evaporated to dryness afford a white solid 6-(azetidine-1-carbonyl)-8-(1-(3,5-difluorophenylamino)ethyl)-2-morpholino-4H-chromen-4-one (300 mg, 61%). Mass Spectrum: M+H+ 470. [α]D20°: −113° in MeCN. NMR Spectrum (DMSOd6): 1.50 (d, 3H), 2.18-2.28 (m, 2H), 3.50-3.63 (m, 4H), 3.69-3.78 (m, 4H), 3.98-4.07 (m, 2H), 4.09-4.19 (m, 2H), 4.97-5.05 (m, 1H), 5.61 (s, 1H), 6.15 (d, 2H), 6.21 (t, 1H), 7.03 (d, 1H), 7.79 (d, 1H), 8.02 (d, 1H).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([NH2:16])[CH:6]=[C:7]([CH2:11][P:12]([OH:15])([OH:14])=[O:13])[CH2:8][CH2:9][F:10])C>O>[NH2:16][CH:5]([CH:6]=[C:7]([CH2:11][P:12]([OH:14])([OH:15])=[O:13])[CH2:8][CH2:9][F:10])[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C(N)C=C(CCF)CP(=O)(O)O
Solvent: O
Product: NC(C=C(CCF)CP(=O)(O)O)C(=O)O

Procedure:
0.5 g (1.86 mmol) of 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester are heated under reflux in 4 ml of water for 17 hours. The reaction mixture is concentrated by evaporation and separated with water on a strongly acidic ion-exchanger (Dowex 50Wx8; H⊕ form). 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid having a melting point of 160°-162° C. (decomp.) is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:31])=[C:11]([CH2:13][CH2:14][O:15][C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH2:18][CH2:19][CH:20]=[C:21]4[CH2:26][CH2:27][C:28](O)=[O:29])[N:12]=2)=[CH:4][CH:3]=1.[NH2:32][O:33][C:34]([O:37][CH3:38])([CH3:36])[CH3:35].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(N(CC)CC)C.CN(C)C=O>[CH3:35][C:34]([O:37][CH3:38])([O:33][NH:32][C:28](=[O:29])[CH2:27][CH2:26][C:21]1[C:22]2[C:17](=[C:16]([O:15][CH2:14][CH2:13][C:11]3[N:12]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=4)[O:9][C:10]=3[CH3:31])[CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:19][CH:20]=1)[CH3:36]
Reactant: COC(C)(C)ON
Reactant: Cc1ccc(-c2nc(CCOc3cccc4c3CCC=C4CCC(=O)O)c(C)o2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(C)(C)ONC(=O)CCC1=CCCc2c(OCCc3nc(-c4ccc(C)cc4)oc3C)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a dimethylformamide (5 ml) solution of the compound (208 mg) prepared in Example 2 and 2-aminooxy-2-methoxypropane (57.7 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), 1-hydroxybenzotriazole (81 mg) and triethylamine (83 μl ) were added, followed by stirring at room temperature overnight. The reaction mixture was concentrated. The residue was diluted with methylene chloride. The diluted solution was washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and saturated saline in this order, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to thereby obtain the title compound (239 mg) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.[ClH:27].[N:28]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:27].[CH3:17][C:14]1([CH3:16])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]2[C:2]([NH:1][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:3][C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:5][C:6]=2[O:15]1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: CCCCCC(C)C(C)c1cc(N)c2c(c1)OC(C)(C)c1ccncc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(NC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
A mixture of 0.87 g. (2.47 mmole) of 10-amino-5,5-dimethyl-8-(1,2-dimethylheptyl)-5H-[1]benzopyrano[4,3-c]-pyridine, 0.51 g. (2.47 mmole) of 4-piperidinobutyric acid hydrochloride, 0.56 g. (2.72 mmole) of dicyclohexylcarbodiimide, and 50 ml. of dry methylene chloride was stirred at room temperature for 72 hours. The mixture was cooled and filtered and the filtrate concentrated to a residue which was recrystallized from methylene chloride-ether, m.p. 185-186°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C[N:9]([CH2:11][C:12]1[CH:13]=[C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:34][CH2:33]2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH3:10].[CH3:43][C:44](C)([CH3:47])[CH2:45]N.CNC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:43][C:44]([CH3:47])([CH3:45])[CH2:10][NH:9][CH2:11][C:12]1[CH:13]=[C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:39])=[O:40])[CH2:34][CH2:33]2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: CC(C)(C)CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(OC)c(CN(C)C)c4)cc23)CC1
Agent: CNC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(OC)c(CNCC(C)(C)C)c4)cc23)CC1
Yield: 16 %

Procedure:
The title compound was prepared according to the general procedure of 5-[3-[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 2,2-dimethyl-1-propanamine (20 μL, 0.214 mmol) for the dimethylamine to afford 11 mg of the title compound (16%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)=[N:7][C:8]([S:13][CH3:14])=[N:9][C:10]=1[CH2:11][CH3:12])=[O:4].O.[OH-].[Li+]>C1COCC1.O.C(OCC)(=O)C>[Cl:22][C:17]1[CH:16]=[C:15]([C:6]2[C:5]([C:3]([OH:4])=[O:2])=[C:10]([CH2:11][CH3:12])[N:9]=[C:8]([S:13][CH3:14])[N:7]=2)[CH:20]=[C:19]([Cl:21])[CH:18]=1
Reactant: CCc1nc(SC)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(SC)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)O
Temperature: 80 °C
Reaction time: 12 h

Procedure:
274 mg (0.768 mmol) of 4-(3,5-dichlorophenyl)-6-ethyl-2-(methylthio)-pyrimidine-5-carboxylic acid methylester was dissolved in 5 ml of THF and 5 ml of water. 38.7 mg (0.922 mmol) of lithium hydroxide monohydrate was added and stirred at 80° C. for 12 hours. 10 ml of water was added thereto and the organic layer was batched off. The obtained aqueous layer was diluted with ethyl acetate and washed with 5 ml of 3 N hydrochloric acid and then with 5 ml of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:42][S:43][CH2:44][C@H:45]([O:61][C:62](=[O:74])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:46][O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:20](=[O:41])[NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.C1(C)C=CC=CC=1>C(#N)C>[CH2:35]([O:34][P:33]([CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][NH:21][C:20](=[O:41])[C@@H:19]([NH2:18])[CH2:42][S:43][CH2:44][C@H:45]([O:61][C:62](=[O:74])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:46][O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])(=[O:40])[O:37][CH2:38][CH3:39])[CH3:36]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: C1CCNCC1
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Temperature: 25 °C

Procedure:
To a solution of diethyl (14R,18R)-14-(((9H-fluoren-9-yl)methoxy)carbonylamino)-18-(dodecanoyloxy)-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12-azadotriacontylphosphonate (1 eq) was added 20% piperidine (50 eq) in acetonitrile. The resulting mixture was stirred at 25° C. until the deprotection completed. To the mixture was added toluene and then concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 100% EtOAc then 0-10% MeOH/DCM to give the product as colorless oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[N:5][N:4]=1.Cl[C:17]1[N:26]=[C:25]([NH2:27])[C:24]2[C:19](=[CH:20][C:21]([O:30][CH3:31])=[C:22]([O:28][CH3:29])[CH:23]=2)[N:18]=1>C(O)CC(C)C>[NH2:27][C:25]1[C:24]2[C:19](=[CH:20][C:21]([O:30][CH3:31])=[C:22]([O:28][CH3:29])[CH:23]=2)[N:18]=[C:17]([N:13]2[CH2:14][CH2:15][CH:10]([C:8]([C:6]3[O:7][C:3]([S:2][CH3:1])=[N:4][N:5]=3)=[O:9])[CH2:11][CH2:12]2)[N:26]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: CSc1nnc(C(=O)C2CCNCC2)o1
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCC(C(=O)c4nnc(SC)o4)CC3)nc(N)c2cc1OC

Procedure:
2.13 g of 4-(5-methylthio-1,3,4-oxadiazole-2-carbonyl)-piperidine and 2.4 g of 2-chloro-4-amino-6,7-dimethoxy-quinazoline in 50 cm3 of isoamyl alcohol are heated under reflux for 8 hours with stirring. After cooling and concentration, 3.9 g of product are isolated, which are purified by recrystallisation from ethanol.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl[C:22]1[S:26][N:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[N:23]=1.O>CN(C)C=O>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[N:23]=[C:22]([N:18]2[CH2:19][CH2:20][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:14])[CH2:16][CH2:17]2)[S:26][N:25]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccccc1-c1nsc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3F)ns2)CC1
Yield: 65.5 %

Procedure:
Triethylamine (14.7 ml, 105 mmol) was added to a solution of 1-(tert-butoxycarbonyl)piperazine (5.64 g, 26.3 mmol) and 5-chloro-3-(2-fluorophenyl)-1,2,4-thiadiazole (4.89 g, 26.3 mmol) in N,N-dimethylformamide (100 ml), the mixture was stirred was stirred at room temperature for 30 minutes, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 6.28 g (65.6%) of the desired product as a crystal.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[C:9]([CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>O>[C:9]([CH:13]1[CH2:17][CH2:16][N:15]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=2)[CH2:14]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)C1CCNC1
Reactant: Nc1cccc(F)n1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)C1CCN(c2cccc(N)n2)C1
Temperature: 150 °C
Yield: 55.2 %

Procedure:
A suspension of 6-fluoropyridin-2-amine (500 mg, 4.46 mmol), 3-tert-butylpyrrolidine (730 mg, 4.46 mmol) in water (0.5 mL) and triethylamine (0.9 g, 8.92 mmol) was heated to 150° C. in a microwave oven for 30 minutes. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH=20:1) to give 6-(3-tert-butylpyrrolidin-1-yl)pyridin-2-amine (540 mg, 55%) as a brown oil. LC-MS: [M+H]+, 220, tR=1.228 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:17][C:16]([NH:21][CH2:22][CH3:23])([C:18]([NH2:20])=[O:19])[CH2:15]3)[N:11]3[C:24](=[O:27])[NH:25][N:26]=[C:10]3[C:9]=2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:42][CH3:43].O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:17][C:16]([NH:21][CH2:22][CH3:23])([C:18]([NH2:20])=[O:19])[CH2:15]3)[N:11]3[C:24](=[O:27])[N:25]([CH2:42][CH3:43])[N:26]=[C:10]3[C:9]=2[C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[CH:6][CH:7]=1
Reactant: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3n[nH]c(=O)n23)C1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(CC)c(=O)n23)C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
To a solution of 1-(7,8-bis(4-chlorophenyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide (25 mg, 0.05 mmol) in DMF (0.5 mL) at room temperature under argon was added K2CO3 (10 mg, 0.07 mmol), followed by iodoethane (10 mg, 0.064 mmol). The reaction mixture was stirred at 60° C. in a pre-heated oil bath for 30 min. After the reaction mixture was cooled to room temperature, water (5 mL) and EtOAc (5 mL) were added. The layers were separated. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product thus obtained was purified by preparative reverse phase HPLC (without TFA) to obtain 21.5 mg of the title compound as a white solid. HPLC/MS: retention time=3.465 min, [M+H]30 =526.
Reaction SMILES: [CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.Br[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].CC([O-])=O.[Na+]>CC(N(C)C)=O>[CH:12]1[C:7]2[CH2:6][CH2:5][C:4]3[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=3[C:2](=[CH:1][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: C=C1c2ccccc2CCc2ccccc21
Reactant: N#Cc1ccccc1Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccccc1C=C1c2ccccc2CCc2ccccc21

Procedure:
Sparge a mixture of 5-methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (2.0 g, 9.7 mmol) (prepared as described in Journal of Organic Chemistry, 53 (8) 1768-1774 (1988)), 2-bromobenzonitrile ((1.77 g, 9.7 mmol), NaOAc (1 g, 12 mmol) and dimethylacetamide (100 mL) with nitrogen for 15 minutes. Add Hermann catalyst (320 mg, 0.46 mmol)(Chem. Eur. J. 1357-1364 (1997)) and heat at 150° C. for 6 days. Cool the reaction and partition between water (1 L) and EtOAc (500 mL). Wash the organic layer with water (3×1L). Dry (MgSO4) and concentrate under reduced pressure to give 3.3 g brown oil. Purify on silica gel using EtOAc/hexane 500 mg nitrile that is 81% pure by glc. Recrystallize (EtOH) to give 213 mg (7%) pale yellow plates, mp 185.4° C. 1H NMR (CDCl3) δ 3.04 (br d, 2H), 3.47 (br s, 2H), 6.82-7.34 (m, 11H), 7.62 (m, 2H); MS (ES) 308 (M+1). HPLC shows 98% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C@H:13]2[C:17](=[O:18])[N:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][C@H:14]2[C:24]([O:26]C(C)(C)C)=[O:25])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C@H:13]2[C:17](=[O:18])[N:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][C@H:14]2[C:24]([OH:26])=[O:25])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCCCN1C[C@@H](C(=O)OC(C)(C)C)[C@@H](NC(=O)Nc2ccc(Cl)c(Cl)c2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN1C[C@@H](C(=O)O)[C@@H](NC(=O)Nc2ccc(Cl)c(Cl)c2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
The tert-butyl ester of Example 10 (160 mg, 0.35 mmol) was dissolved in 5ml of trifluoroacetic acid and stirred for 16 h at room temperature after which time the reaction was concentrated in vacuo. The resulting material was radially chromatographed on silica gel eluting with EtOH/CH2Cl2 /HOAc (5/95/1) to give the title compound (119 mg, 85%) as a colorless solid. DSC=139.0°-143° C. @5.7 J/g and 191.7°- 203.5° C.@99.6 J/g. MS M+1 calcd for C17H21N3O4Cl2 403, found 403.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:33][N:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[CH2:43]O)[CH:36]=[C:35]1[CH3:45].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:33][N:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[CH2:43][N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]2=[O:13])[CH:36]=[C:35]1[CH3:45]
Reactant: Cc1cc2cccc(CO)c2n1C
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C)n1c(=O)n(Cc2cccc3cc(C)n(C)c23)c2ccccc21
Reaction time: 16 h
Yield: 46.4 %

Procedure:
To a solution of 1-isopropenylbenzimidazolone (220 mg, 1.3 mmol) in dry THF (10 mL) are added triphenylphosphine (397 mg, 1.5 mmol) and (1,2-Dimethyl-1H-indol-7-yl)-methanol (220 mg, 1.3 mmol). Then diisopropyl azodicarboxylate (0.31 mL, 1.5 mmol) is added drop wise into the above solution at room temperature. The mixture is stirred for 16 hrs and then the solvent is removed under vacuum. The residue is purified by flash column chromatography using 10-30% EtOAc in hexanes to give 200 mg (48%) of 1-(1,2-dimethyl-1H-indol-7-ylmethyl)-3-isopropenyl-1,3-dihydro-benzimidazol-2-one.