Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[O:24]=[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([S:35]([Cl:38])(=[O:37])=[O:36])[CH:33]=2)[N:28]=[CH:27][NH:26]1.Cl>C(Cl)(Cl)Cl.C(O)C.O>[ClH:38].[O:24]=[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([S:35]([N:9]3[CH2:8][CH2:7][N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:11][CH2:10]3)(=[O:37])=[O:36])[CH:33]=2)[N:28]=[CH:27][NH:26]1
Reactant: CCOC(CN1CCNCC1)c1ccccc1
Reactant: O=c1[nH]cnc2ccc(S(=O)(=O)Cl)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(CN1CCN(S(=O)(=O)c2ccc3nc[nH]c(=O)c3c2)CC1)c1ccccc1
Reaction time: 15 h
Yield: 76.2 %

Procedure:
In 200 ml of chloroform was dissolved 11.7 g of 1-(2-ethoxy-2-phenylethyl)piperazine, and then 6.9 g of anhydrous potassium carbonate was added thereto. To the solution thus obtained was added dropwise 100 ml of a chloroform solution containing 12.2 g of 3,4-dihydro-4-oxo-6-quinazolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 20° C. to 25° C. for 15 hours, and then added with 50 ml of water. After the pH of the reaction solution was adjusted to 7, the chloroform layer was separated therefrom and the aqueous layer was further extracted with chloroform and the chloroform layer obtained was combined with the one previously separated. Then the chloroform layer was washed with water, dried with Glauber's salt and condensed under reduced pressure to give an oily substance. To this oily substance were added 50 ml of ethanol and 10 ml of conc. hydrochloric acid to form a solution, and the solution was condensed to dryness and the residue was recrystallized from ethanol and then from ether to give 18.2 g of 1-(3,4-dihydro-4-oxo-6-quinazolinesulfonyl)-4-(2-ethoxy-2-phenylethyl)piperazine hydrochloride having a melting point (decomposition) of 249° C. to 250° C. in a yield of 76%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13](=[O:24])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)[CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]=O>[NH2:21][C:17]1[CH:16]=[C:15]([CH2:14][C:13]([NH:12][C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])=[O:24])[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1cccc(N)c1
Yield: 101.1 %

Procedure:
A suspension of platinum oxide (0.35 g) in ethyl acetate (100 ml) containing methyl 4-chloro-2-(3-nitrophenyl)acetamidobenzoate (9.96 g, 28.6 mmol) was shaken under an atmosphere of hydrogen at 40 psi until hydrogen uptake had ceased. The suspension was filtered and the filtrate evaporated to leave methyl 2-(3-aminophenyl)acetamido-4-chlorobenzoate as a pale green solid (9.22 g); δ(CDCl3) 3.65 (2H, s, CH2), 3.66 (3H, s, OCH3), 6.61 (1H, dd, J 7.9 and 2.1 Hz, ArH), 6.70 (1H, s, ArH), 6.74 (1H, d, J 7.6 Hz, ArH), 7.01 (1H, dd, J 8.6 and 2.0 Hz, 5-H), 7.14 (1H, d, J 7.7 Hz, ArH), 7.89 (1H, d, J 8.6 Hz, 6-H), 8.81 (1H, d, J 2.0 Hz, 3-H) and 11.03 (1H, br s, CONH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:54][O:55][C:56]1[CH:61]=[CH:60][C:59]([S:62](Cl)(=[O:64])=[O:63])=[C:58]([N+:66]([O-:68])=[O:67])[CH:57]=1>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:62]([C:59]1[CH:60]=[CH:61][C:56]([O:55][CH3:54])=[CH:57][C:58]=1[N+:66]([O-:68])=[O:67])(=[O:63])=[O:64])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: COc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(OC)cc1[N+](=O)[O-])O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (20 mg) was reacted with 4-methoxy-2-nitro-benzenesulfonyl chloride to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(4-methoxy-2-nitro-benzenesulfonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester according to General Procedure E. This product (5 mg) was hydrolyzed according to General Procedure B to give the title compound (4 mg). LCMS (m/z): 951.
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:8]=3[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:5]=[CH:4][CH:3]=1.[OH:25][C@H:26]1[CH2:30][CH2:29][N:28](O)[CH2:27]1>CN(C)C(=O)C.C(OCC)(=O)C>[OH:25][C@H:26]1[CH2:30][CH2:29][N:28]([C:2]2[C:10]3[C:9]4[CH:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:8]=4[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=3[N:5]=[CH:4][CH:3]=2)[CH2:27]1
Reactant: O[C@H]1CCN(O)C1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](O)C3)ccnc21
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (130 mg, 0.36 mmol) and (S)-3-hydroxypyrrolidinol (91 mg, 1.04 mmol) in N,N-dimethylacetamide (1.6 mL) was heated at 100° C. for 2 hours. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-100% ethyl acetate in heptane) to afford the title compound as a white waxy solid, which was used in the next step without further purification (140 mg, 94%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:14][C:15]([C:19]([NH2:21])=[O:20])=[N:16]2)=[CH:11][CH:10]=1.[N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[NH:31][CH:30]=1>CN(C=O)C>[N:29]1([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[CH:14][C:15]([C:19]([NH2:21])=[O:20])=[N:16]3)=[CH:11][CH:10]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[CH:30]1
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2n1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(Cn3cnc4ccccc43)cc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
Cs2CO3 (91 mg, 0.278 mmol, 2.0 equiv.) was added to a solution of 7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carboxamide (3-1, 50 mg, 0.139 mmol, 1.0 equiv.) and benzimidazole (18.09 mg, 0.153 mmol, 1.1 equiv.) in DMF (696 μl) and the reaction stirred at rt for 2 hours. The crude residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier). A Waters Porapak® Rxn CX (6 cc) was conditioned with MeOH (5 mL). Fractions containing the desired product were loaded onto the cartridge and the cartridge was washed with MeOH (10 mL). The desired product was eluted with 2M NH3 in MeOH (5 mL) and the solvent removed in vacuo to afford 7-((1H-Benzo[d]imidazol-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide (3-2, 23.6 mg, 43%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.40 (s, 1H); 8.09 (s, 1H); 8.00-7.91 (m, 2H); 7.73-7.70 (m, 1H); 7.61-7.55 (m, 3H); 7.47 (dd, J=7.2, 2.0 Hz, 1H); 7.33-7.23 (m, 4H); 5.80 (s, 2H). LRMS m/z (M+H)+ 397.17 found, 397.42 required.
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[C:10]([O:14][C:15]([C@H:17]([CH2:21][S:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[C:41]4[O:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=5[C:40]=4[CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[C:18]([OH:20])=[O:19])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(O)(=O)C.C(OCC)(=O)C>[C:10]([O:14][C:15]([C@H:17]([CH2:21][S:22]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[C:41]4[O:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=5[C:40]=4[CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:28][CH:29]=1)(=[O:6])=[O:5])[C:18]([OH:20])=[O:19])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)[C@H](CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](CS(=O)(=O)Cc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
Sodium perborate tetrahydrate (105 mg, 0.68 mmol) was added as a solid to a stirred solution of (2R)-2-tert-Butoxycarbonyl-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethyl-sulfanyl)-propionic acid (150 mg, 0.27 mmol), in acetic acid (10 mL) at 50° C. This solution was stirred at 40° C. for 2 hours (HPLC control) and then diluted with ethyl acetate (50 mL), washed with water, brine (2×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by trituration of the product with diethyl ether afforded the title compound as a white solid (138 mg, 87%): Rf 0.5 (20% methanol in dichloromethane). 1H NMR (MeOH-d4, 300 MHz): δ 7.90 (4H, m, Ar—H), 7.70 (4H, m, Ar—H), 7.53 (2H, m, Ar—H), 7.29-7.49 (5H, m, Ar—H), 4.62 (1H, m, CHN) 4.41 (2H, s, PhCH2S), 3.42 (2H, m, CH2CHN), 1.46 (9H, s, CMe3); ESI-LCMS e/z calcd for C33H31NO7S 585.674, found 586 (M+H)+, 608 (M+Na)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=[N:13][C:8]2=[N:7][N:6]=1)=[N+]=[N-].C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>>[C:14]1([C:11]2[CH:12]=[N:13][C:8]3[N:9]([C:5]([CH2:4][NH2:1])=[N:6][N:7]=3)[N:10]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [N-]=[N+]=NCc1nnc2ncc(-c3ccccc3)nn12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1nnc2ncc(-c3ccccc3)nn12

Procedure:
A 50 mL RB flask was charged with 3-(azidomethyl)-6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazine (0.3492 g, 1.38 mmol) and THF (14.0 ml, 171 mmol), resulting in a dark brown solution. Triphenylphosphine (0.545 g, 2.08 mmol) and water (0.0998 ml, 5.54 mmol) were added, and the flask was placed in a 65° C. oil bath for 2 hours. The reaction mixture was concentrated to give a thick brown oil, which was purified by column chromatography using an 80 g ISCO column, eluting with a gradient of 5% MeOH (containing NH4OH)/DCM to 10% MeOH (containing NH4OH)/DCM over 40 minutes. (6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methanamine was isolated as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Cl[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)nc1
Reactant: ClC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncc(OC2CCCC2)cn1
Temperature: 65 °C
Yield: 54.6 %

Procedure:
A mixture of 2-chloropyrimidin-5-ol (1 g, 7.66 mmol), chlorocyclopentane (2.39 mL, 22.98 mmol) and potassium carbonate (3.18 g, 22.98 mmol) in N,N-dimethylformamide were heated at 65° C. for 16 h at ambient temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (0-25% ethyl acetate/hexanes) to afford 2-chloro-5-(cyclopentyloxy)pyrimidine (831 mg, 4.18 mmol, 54.6% yield) as a white solid. MS (LC/MS) R.T.=2.32; [M+H]+=199.23.
Reaction SMILES: [C:1]([O:5]CCO)(=[O:4])[CH:2]=[CH2:3].CC1C(N=C=O)=CC([N:16]=[C:17]=[O:18])=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.COC1C=CC(O)=CC=1.C([C:52]1C=C(C)C=C(C(C)(C)C)[C:53]=1[OH:63])(C)(C)C>>[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[NH2:16][C:17]([O:63][CH2:53][CH3:52])=[O:18]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: C=CC(=O)OCCO
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: COc1ccc(O)cc1
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 70 °C
Reaction time: 7 h

Procedure:
232 g (2 mol) of 2-hydroxyethyl acrylate (molecular weight 116) was placed in a flask equipped with a stirring blade, and with constant stirring, 174 g (1 mol) of TDI (2,4-tolylene diisocyanate) was added dropwise, with care taken over the generated heat, and the temperature was raised to 70° C. 1 g of dibutyl tin diacetate, 0.2 g of hydroquinone monomethyl ether and 1 g of 2,6-di-t-butyl-4-methylphenol were then added. Reaction was allowed to proceed at this temperature for 7 hours, and once the disappearance of NCO absorption had been confirmed via an infrared absorption spectrum, the reaction mixture was removed, yielding a urethane acrylate (A-Y) as the radical polymerizable oligomer (A). The number average molecular weight of the synthesized urethane acrylate (A-X) was 406.
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.C([O-])([O-])=O.[Na+].[Na+].CC1(C)C(C)(C)OB([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])O1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:50]([O:49][C:48]([NH:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[C:2]1[N:3]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)=[O:54])([CH3:51])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)CCn1c(Br)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)CCn1c(-c2ccccc2NC(=O)OC(C)(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Yield: 60 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1-(3-methoxy-3-oxopropyl)-1H-indole-6-carboxylate in dioxane (0.15 M) was added Na2CO3 (4 eq, 2 M aqueous solution), tert-butyl [2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (1.5 eq) and bis(triphenylphosphine)palladium(II) dichloride (0.2 eq). The mixture was heated at reflux for 45 mins. The reaction mixture was filtered and then the filtrate was diluted with EtOAc. The organic phase was washed with H2O, brine and dried over Na2SO4 before being filtered and concentrated in vacuo. The crude was purified by flash chromatography (Biotage cartridge Si65i, 1:9 EtOAc/PE) to give the title compound as a white solid (60%); MS (ES+) m/z 535 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([N:35]=[CH:36][N:37]=2)[N:34]=1>O1CCCC1>[ClH:28].[ClH:28].[C:22]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][C:29]3[CH:30]=[CH:31][C:32]4[N:33]([N:35]=[CH:36][N:37]=4)[N:34]=3)[CH2:14][CH2:15]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1ccc2ncnn2n1
Reactant: OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cl
Product: c1ccc(C(c2ccccc2)N2CCN(CCOCCOc3ccc4ncnn4n3)CC2)cc1
Temperature: 0 °C
Yield: 157 %

Procedure:
100 mg of 60% sodium hydride in oil was suspended in 20 ml of tetrahydrofuran; 470 mg of 4-(diphenylmethyl)-1-[2-(2-hydroxyethoxy)ethyl]piperazine was added, followed by heating and refluxing for 1 hour. After cooling, 200 mg of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added, followed by heating and refluxing for 4.5 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. After the dry product was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with dichloromethane-ethyl acetate-methanol (10:10:1). The desired fraction was collected and dissolved in 5 ml of ethyl acetate; 0.83 ml of a 4 N hydrogen chloride solution in ethyl acetate was added; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 0.54 g of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([CH3:25])[CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][OH:20])=[C:17]([CH3:25])[CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2)ccc1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A suspension of 0.11 g (2.93 mmol) of lithium aluminum hydride in 20 ml of tetrahydrofuran was cooled to 0° C. A solution of 0.75 g (2.93 mol) of methyl 4-benzyloxy-2-methylbenzoate in 20 ml of tetrahydrofuran was added dropwise to the suspension at DOC. After stirring at 0° C. for 2 hours, the reaction mixture was treated in a conventional manner to give 0.66 g of 4-benzyloxy-2-methylbenzyl alcohol.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:44][N:45]1[C:54]2[C:49](=[CH:50][N:51]=[C:52]([CH3:55])[CH:53]=2)[CH:48]=[C:47]([C:56]2[CH:57]=[C:58]([NH:63]/[C:64](/[NH2:67])=[N:65]/O)[CH:59]=[CH:60][C:61]=2[CH3:62])[C:46]1=[O:68]>CN(C=O)C>[CH3:44][N:45]1[C:54]2[C:49](=[CH:50][N:51]=[C:52]([CH3:55])[CH:53]=2)[CH:48]=[C:47]([C:56]2[CH:57]=[C:58]([NH:63][C:64]3[N:65]=[C:6]([C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[CH:10][CH:9]=4)[O:8][N:67]=3)[CH:59]=[CH:60][C:61]=2[CH3:62])[C:46]1=[O:68]
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Reactant: Cc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nc(Nc3ccc(C)c(-c4cc5cnc(C)cc5n(C)c4=O)c3)no2)cn1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
6-Methylnicotinic acid (0.67 g, 4.89 mmol), HATU (1.86 g, 4.89 mmol), and DIPEA (0.85 mL, 4.89 mmol) were stirred in dry DMF (20 mL) for 1 h before 17 (1.5 g, 4.44 mmol) was added at rt. The stirring was continued for 1 h before it was heated at 100° C. for 5 h. After cooling and filtration, the mixture was purified by preparative LC/MS to give 1,7-dimethyl-3-(2-methyl-5-(5-(6-methylpyridin-3-yl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (A51) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 9.27 (d, J=2.0 Hz, 1H), 9.10 (s, 1H), 8.73 (dd, J=2.0, 8.4 Hz, 1H), 8.07 (s, 1H), 7.94 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.46 (dd, J=2.4, 8.4 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 3.85 (s, 3H), 2.87 (s, 3H), 2.79 (s, 3H), 2.19 (s, 3H). MS m/z 439.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:22])=[CH:27][CH:26]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: COc1ccc(NC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1

Procedure:
N-(4-Methoxyphenyl)-2′-methyl-5′-(5methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-methoxyaniline using method I. NMR; δH [2H6]—DMSO 10.21,(1H, b), 8.05,(2H, d), 7.90,(1H, dd), 7.79,(1H, d), 7.70,(2H, d), 7.58-7.55,(3H, m), 6.93,(2H, d), 3.74,(3H, s), 2.57,(3H, s), 2.33,(3H, s). LCMS; retention time 3.40 min, MH+ 400.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([CH3:12])([CH3:11])[CH2:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:5]=2[N:6]=1.[O-:15][C:16]#[N:17].[K+].C(O)(=O)C>O>[CH3:13][C:8]1([CH3:14])[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:16]([NH2:17])=[O:15])[S:3][C:4]=2[C:10]([CH3:12])([CH3:11])[CH2:9]1
Reactant: CC1(C)Cc2nc(N)sc2C(C)(C)C1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)Cc2nc(NC(N)=O)sc2C(C)(C)C1
Reaction time: 1 h

Procedure:
2-Amino-5,5,7,7-tetramethyl-4,5,6,7-tetrahydrobenzothiazole (0.3mole), potassium cyanate (0.3 mole) and concentrated acetic acid (90 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer. A mild exotherm is noted at the beginning of the reaction. Stirring is continued for a period of about 1 hour with no external heating. Water (90 ml) is added and the resulting mixture filtered. The filtered-off solids are recrystallized from methanol to yield the desired product N-(5,5,7,7-tetramethyl-4-5,6,7-tetrahydrobenzothiazol-2-yl)urea.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)=O.[NH2:17][C:18](N)=[O:19].[OH-].[Na+]>C(O)(=O)C>[CH3:16][N:13]1[CH2:14][CH2:15][CH:10]([C:8]2[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[NH:1][C:18](=[O:19])[N:17]=2)[CH2:11][CH2:12]1
Reactant: NC(N)=O
Reactant: CN1CCC(C(=O)c2ccccc2N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1CCC(c2nc(=O)[nH]c3ccccc23)CC1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A stirred mixture of (2-aminophenyl)(1-methylpiperidin-4-yl)methanone (1.10 g, 4.58 mmol), urea (550 mg, 9.17 mmol) and acetic acid (15 mL) was heated to overnight. The mixture was cooled to rt, neutralized with 1 N sodium hydroxide and concentrated to ˜10 mL on a rotary evaporator. The aqueous residue was extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered and concentrated on a rotary evaporator to afford 4-(1-methylpiperidin-4-yl)quinazolin-2(1H)-one as a yellow solid (1.10 g, 97%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:21][CH:22]1[CH2:29][CH:28]2[N:30]([CH3:31])[CH:24]([CH2:25][CH2:26][CH2:27]2)[CH2:23]1>>[CH3:31][N:30]1[CH:24]2[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH:22]([NH:21][C:16]([C:15]1[C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[CH:12]=[CH:13][CH:14]=1)=[O:18])[CH2:23]2
Reactant: O=C(O)c1cccc2nc(-c3ccccc3)oc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: Cl
Product: CN1C2CCCC1CC(NC(=O)c1cccc3nc(-c4ccccc4)oc13)C2
Yield: 43 %

Procedure:
N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-phenylbenzoxazole-7-carboxamide was prepared from 2-phenylbenzoxazole-7-carboxylic acid and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using the method outlined in Step C of Example 7. This compound was obtained in 43% yield and obtained as an off-white solid: mp 208-210° C.; 1H NMR (500 MHz, CDCl3) δ 8.95 (br s, 1H), 8.23 (d, J=6.9 Hz, 2H), 8.20 (d, J=2.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.57-7.65 (m, 3H), 4.58 (q, J=7.1 Hz, 1H), 3.18 (br s, 2H), 2.58 (m, 5H), 2.02-2.25 (m, 3H), 1.55 (s, 3H), 1.23 (m, 3H); MS (APCI) m/z 411 [M+H]+