Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7](=[CH:23][N:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:25]=3)[C:8]([CH2:12][CH2:13][NH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[N:9][C:10]=2[CH:11]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1>C(Cl)Cl>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:41])[N:14]([CH2:13][CH2:12][C:8]2[C:7]3=[CH:23][N:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:25]=[C:6]3[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:10]=3[N:9]=2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:35][CH:34]=1
Reactant: N#Cc1ccc(NCCc2nc3cc(Cl)ccc3c3nn(-c4ccccc4)cc23)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: N#Cc1ccc(N(CCc2nc3cc(Cl)ccc3c3nn(-c4ccccc4)cc23)C(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
A mixture of 150 mg (0.35 mmol) of the compound of Example 1, 100 mg (0.65 mmol) of p-chlorophenylisocyanate, and 10 ml of methylene chloride is stirred at ambient temperature overnight. The resulting precipitate is collected to furnish 121 mg (60%) of title compound: IR (KBr) 3360, 2220, 1660, 1590, 1520, 1500, 1490 cm-1 ; NMR (DMSO-d6) δ 9.56 (s, 1H), 8.8 (s, 1H, exchangeable), 8.8-7.26 (complex m, 16H), 4.45 (t, 2H), and 3.5 (t, 2H).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=1)[OH:14])[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:52]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([N:8]([CH2:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=1)[OH:14])[CH2:9][CH2:10][Br:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1cccc([C@@H](O)CN(CCO)Cc2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1ccccc1)c1cccc([C@@H](O)CN(CCBr)Cc2ccccc2)c1
Temperature: -20 °C

Procedure:
(R)-2-[N′-Benzyl-N′-(2-hydroxyethyl)amino]-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]ethanol (273 mg; synthesized according to the process described in WO 01/04092) and triphenylphosphine (162 mg) were dissolved in dehydrated methylene chloride (8 mL) under an argon atmosphere, followed by stirring at −20° C. After adding N-bromosuccinimide (110 mg) at a stretch, the resulting mixture was stirred for 10 minutes. The reaction mixture was purified by silica gel column chromatography (5:1-3:1 hexane/ethyl acetate) to yield (R)-2-[N′-benzyl-N′-(2-bromoethyl)amino]-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]ethanol. This was immediately dissolved in acetonitrile (4 mL), to which the compound (116 mg; obtained in the above step E) and an aqueous 1 N sodium hydroxide solution (521 μL) were added. The resulting mixture was stirred at room temperature for 16 hours and the reaction mixture was then concentrated. The residue was purified by silica gel column chromatography (5:1-1:1 hexane/ethyl acetate) to yield the title compound (243 mg).
Reaction SMILES: [CH2:1]([C:4]12[CH2:19][C:18](=O)[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=31)[C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3].NN.[OH-].[Na+]>C(O)COCCOCCO.O>[CH2:1]([C:4]12[CH2:19][CH2:18][CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=31)[C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCC12CC(=O)C(c3ccccc31)c1ccccc12
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: C=CCC12CCC(c3ccccc31)c1ccccc12
Temperature: 150 °C
Reaction time: 2.5 h

Procedure:
A mixture of 9-β-propenyl-9,10-dihydro-9,10-ethanoanthracene-11-one (280 mg), hydrazine (0.2 ml) and sodium hydroxide in triethyleneglycol was stirred at 150° C. for 30 minutes and at 190° - 200° C. for 2.5 hours. The reaction mixture was diluted with water and extracted with benzene. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified over silica gel chromatography to give 9-β-propenyl-9,10-dihydro-9,10-ethanoanthracene, M.P. 42° - 43° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[CH:14]=[CH:13][C:12]=2[Cl:29])[CH:9]=1)[C:5]#[N:6].O.NN>CO>[NH2:18][CH2:17][C:15]1[CH:14]=[CH:13][C:12]([Cl:29])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:5]#[N:6])[CH:16]=1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN3C(=O)c4ccccc4C3=O)ccc2Cl)c1
Agent: NN
Solvent: CO
Solvent: O
Product: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Reaction time: 4 h
Yield: 74.2 %

Procedure:
3-Chloro-5-({2-chloro-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}oxy)benzonitrile (1.0 g, 2.3 mmol) was dissolved in methanol (25 mL) and hydrazine monohydrate (0.3 mL, 5.9 mmol) was added. The reaction was stirred for 4 h. Additional hydrazine monohydrate (0.3 mL, 5.9 mmol) was added and stirred overnight. The solvent was evaporated and the crude product was purified by column chromatography (hexane/EtOAc) to afford the title compound (0.5 g, 72%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.77 (t, 1H), 7.53 (d, 1H), 7.40 (dd, 1H), 7.32 (t, 1H), 7.19-7.29 (m, 2H), 3.68 (s, 2H), 1.89 (br. s., 2H). MS: m/z 292.9 (M+1).
Reaction SMILES: CS([O:5][C@@:6]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[NH2:22])([C:11]#[C:12][CH:13]1[CH2:15][CH2:14]1)[C:7]([F:10])([F:9])[F:8])(=O)=O.[OH-].[Na+].[C:31]([O-])([O-])=[O:32].[Na+].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C>[CH:13]1([C:12]#[C:11][C@:6]2([C:7]([F:10])([F:9])[F:8])[C:16]3[CH:17]=[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:19]=[CH:20][C:21]=3[NH:22][C:31](=[O:32])[O:5]2)[CH2:15][CH2:14]1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)O[C@](C#CC1CC1)(c1cc(-c2ccccc2)ccc1N)C(F)(F)F
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(-c3ccccc3)cc2[C@](C#CC2CC2)(C(F)(F)F)O1
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
(R)-2-(4-Aminobiphenyl-3-yl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol methanesulfonate (CN46630-MSA) of example 2 (14.7 g, 34.4 mmol) in ethyl acetate/heptanes (1:1 v/v, 27.9 g) was charged in a jacketed 150 mL-reactor with agitator and off-gas scrubber with caustic soda. After addition of aqueous Na2CO3 (12%-w/w, 32.3 g, 36.4 mmol, formation of gas during addition!) the mixture was stirred for 15 min at 15° C. The aqueous phase was separated and discarded. Aqueous Na2CO3 (12%-w/w, 41 g, 46 mol) and ethyl acetate (20 g) were charged to the organic phase. Triphosgene (4.41 g, 14.9 mmol) was added in portions over a period of 25 min at 10° C. The reaction mixture was stirred for 2 h at 8° C. The mixture was diluted with ethyl acetate (45 g) and the phases were separated. The aqueous phase was discarded. The organic phase was washed with water (12 mL), dried over MgSO4, filtered and concentrated and dried at 50° C. under reduced pressure to obtain (R)-4-(cyclopropylethynyl)-6-phenyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (CN46685, 12.1 g, 33.9 mmol, 98%) as a yellowish solid (99.5% purity, according to Method C).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([S:18][C:19]2[N:23]4[CH:24]=[C:25]([C:28](=O)[CH3:29])[CH:26]=[CH:27][C:22]4=[N:21][N:20]=2)=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.[NH2:31][O:32][CH2:33][CH2:34][OH:35].Cl>CO>[OH:35][CH2:34][CH2:33][O:32]/[N:31]=[C:28](/[C:25]1[CH:26]=[CH:27][C:22]2[N:23]([C:19]([S:18][C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[N:10]=[CH:9][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[CH:17]4)=[N:20][N:21]=2)[CH:24]=1)\[CH3:29]
Reactant: CC(=O)c1ccc2nnc(Sc3ccc4ncc(N5CCC(O)CC5)cc4c3)n2c1
Reactant: NOCCO
Agent: Cl
Solvent: CO
Product: C/C(=N\OCCO)c1ccc2nnc(Sc3ccc4ncc(N5CCC(O)CC5)cc4c3)n2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To the solution of (76.3) (30 mg, 0.072 mmol) and 2-(aminooxy)ethanol (6.06 mg, 0.079 mmol) in MeOH (3 ml) was added a drop of 2 N HCl, sealed the tube and stirred at 50° C. for overnight. The solvent was evaporated under reduced pressure to give crude desired product as orange oil which was purified by chromatography and eluent with DCM/MeOH (30:1-20:1) to obtained pure desired product as yellow solid (25 mg, 69.4%).
Reaction SMILES: C(O[C:6]1[C:19](C)=[C:18](C)[C:17]2[O:16][C:15]3[C:10](=[C:11](C)[C:12](OCC4OC4)=[C:13](C)[C:14]=3C)[CH:9](C3C=CC=CC=3)[C:8]=2[C:7]=1C)C1OC1.O[C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=2)=[CH:40][CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C(=O)C.O>[CH:11]1[C:10]2[CH2:9][C:8]3[C:17](=[CH:18][CH:19]=[CH:6][CH:7]=3)[O:16][C:15]=2[CH:14]=[CH:13][CH:12]=1.[CH:39]1[C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:41]=2[CH:42]=[CH:43][CH:38]=1
Reactant: Cc1c(C)c2c(c(C)c1OCC1CO1)C(c1ccccc1)c1c(C)c(OCC3CO3)c(C)c(C)c1O2
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: c1ccc2c(c1)-c1ccccc1-2
Product: c1ccc2c(c1)Cc1ccccc1O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
0.972 g (manufactured by DAINIPPON INK & CHEMICALS Co., Ltd., “EXA7335”, 2 mmol) of 2,7-diglycidyloxy-1,3,4,5,6,8-hexamethyl-9-phenylxanthene, 0.372 g (2 mmol) of 4,4′-dihydroxybiphenyl, 2.62 mg (0.01 mmol) of triphenylphosphine and 1.34 g of N,N-dimethylacetamide were reacted under a nitrogen atmosphere at 160° C. for 4 hours. After cooling, the reaction solution was diluted with N,N-dimethylacetamide so as to adjust the nonvolatile content to 15% and then added dropwise in 100 ml of water. The resulting white turbid dispersion was stirred at room temperature for one hour. After the dispersion was centrifuged and suction-filtered, the resulting precipitate was washed with methanol and then vacuum-dried at 60° C. to obtain a xanthene-biphenylene copolymer type linear epoxy resin. The amount of the resulting xanthene-biphenylene copolymer type linear epoxy resin was 1.033 g and the yield was 77%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)([S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:8]#[N:9].C([N:30]([CH2:34][CH3:35])[CH:31]([CH3:33])C)(C)C>C(#N)C>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]2[CH2:31][CH2:33][C:22]3[C:35](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:34]2)[C:8]#[N:9])[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: COc1ccc(C(C#N)(CCCCCBr)Sc2ccccn2)cc1OC
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(C(C#N)(CCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccccn2)cc1OC

Procedure:
A mixture, under argon, of 1.5 g of product from Example 118, 0.790 g of 6,7-dtmethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, 7 ml of N,N-diisopropyl ethylamine and 60 ml of acetonitrile is heated at reflux temperature overnight. The reaction is cooled and concentrated tn yacuo to give an oil. The oil is purified by chromatography (silica gel: 1 and 2% methyl alcohol/methylene chloride) to give 1.1 g of the desired product as a glassy yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][N:9]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[N:7]=1.ClS([N:35]=[C:36]=[O:37])(=O)=O.O>C(#N)C>[C:36]([O:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][N:9]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[N:7]=1)(=[O:37])[NH2:35]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](c2csc(CO)n2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)O[C@@H]1C[C@@H](c2csc(COC(N)=O)n2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S, 4R)-2-[2-(hydroxymethyl)-thiazol-4-yl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl) pyrrolidine (2.1 g) in acetonitrile (50 ml) was added chlorosulfonyl isocyanate (0.48 ml) at 0°-5° C. and the mixture was stirred at ambient temperature for 1 hour. Water (3 ml) was added to the solution at the same temperature and the mixture was stirred for 20 hours. After the solvent was removed, the residue was dissolved in ethyl acetate, and washed with water, saturated sodium bicarbonate and brine successively. The dried organic layer was evaporated to give (2S,4R)2- [2-(carbamoyloxymethyl)thiazol-4-yl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl) pyrrolidine (2.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.[OH-].[K+].O.NN>C(O)COCCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: O=C(O)CCCc1ccc(Cl)cc1
Temperature: 125 °C
Yield: 93.5 %

Procedure:
A mixture of 3-(4-chlorobenzoyl) propionic acid (34) (2.50 g, 12.0 mmol), KOH (s) (1.75 g, 31.2 mmol), and hydrazine monohydrate (1.25 mL, 25.8 mmol) in 12.5 mL of diethylene glycol was refluxed azeotropically at 120-130° C. for 90 min to remove water. The reaction mixture was then refluxed at 170° C. for 3 h, cooled to RT, diluted with 12.5 mL of water, and poured into 15 mL 2.5 N HCl(aq). The precipate was filtered off, dissolved in CH2Cl2, and the solvent removed to give 35a (2.23 g, 96%) as a white solid. UV λmax 223 (8980, 95% ETHANOL); 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J=7 Hz, 2H), 7.12 (d, J=8 Hz, 2H), 2.66 (t, J=4 Hz, 2H), 2.38 (t, J=4 Hz, 2H), 1.96 (m, 2H); 13C NMR (CDCl3) δ 179.3, 140.0, 132.2, 130.2, 128.9, 34.7, 33.4, 26.4; IR (drift) 3063 (s), 3051 (s), 2955 (s), 2923 (s,b), 2905 (s), 2814, 2797, 2493 (b), 2466, 2413, 2367 (b), 2321, 1706 (s), 1492 (s), 1212 (s), cm−1; MS (EI) m/z (rel. intensity) 198 (M+, 22), 200 (7), 198 (22), 140 (32), 139 (17), 138 (99), 127 (15), 125 (48), 103 (10), 89 (13), 60 (9); HRMS (EI) calcd for 198.0448, found 198.0441.
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[O:4].[P:7]([O-:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].N1C=CC=CC=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[C:21]([O:4][CH:3]([P:7]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:14])[C:2]([OH:6])=[O:5])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=CC(=O)O
Reactant: CCOP([O-])OCC
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(OC(=O)c1ccccc1)C(=O)O
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Glyoxylic acid monohydrate (20.10 g, 218 mmol) was suspended in diethyl phosphite (28.1 mL, 1.0 equiv) and warmed to 60° C., and held there for 5 h. The reaction was cooled to 0° C., diluted with dichloromethane (200 mL), and treated with pyridine (17.7 mL, 1.0 equiv) and benzoyl chloride (25.3 mL, 1.0 equiv). The ice bath was removed and stirring continued overnight. The reaction was concentrated, diluted with ethyl acetate, washed with water, then 1M potassium bisulfate, then brine, dried over magnesium sulfate, and concentrated to give an oil. The oil was triturated with ether to give a white powder which was filtered, washed with diethyl ether, and air dried to give 29.0 g (42%). 1H-NMR (CDCl3, 500 MHz) δ 1.35 (m, 6H), 4.31 (m, 4H), 5.82 (d, J=17.7, 1H), 7.46 (m, 2H), 7.60 (m, 1H), 7.94 (bs, 1H), 8.12 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1.CO[CH:26]1[CH2:30][CH2:29][CH:28](OC)O1>C(O)(=O)C>[Cl:23][C:4]1[CH:3]=[C:2]([N:1]2[CH:26]=[CH:30][CH:29]=[CH:28]2)[CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH3:20]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(-n4cccc4)cc3Cl)c2n1
Yield: 55.7 %

Procedure:
Methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (1.00 g) was dissolved in acetic acid (5.0 ml) and 2,5-dimethoxytetrahydrofuran (420 mg) was added, which was followed by refluxing under heating for 2 hr. The reaction mixture was concentrated under reduced pressure and the residue was applied to silica gel column chromatography and eluted with chloroform:ethyl acetate=3:1. The objective fraction was concentrated under reduced pressure and ethyl acetate (10.0 ml) was added to the residue. After heating, the mixture was allowed to cool and the precipitated crystals were collected by filtration to give methyl 3-(2-chloro-4-(1-pyrrolyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (641 mg) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:28])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][S:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:33][CH:32]=1)[CH3:25]
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3CSCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH2:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1>O1CCOCC1.C(OCC)(=O)C>[NH2:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: OCc1ccccc1
Reactant: Nc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1cncc(OCc2ccccc2)n1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a stirred solution of benzyl alcohol (432 μL; 4.0 mmol) in dioxane (2 mL) was added sodium hydride (96 mg; 4.0 mmol). After stirring for 30 minutes, 2-amino-6-chloropyrazine (258 mg; 2.0 mmol) was added and the reaction was heated to 90° C. After stirring for 12 hours, the reaction was cooled to room temperature, diluted with 30 mL of ethyl acetate and washed with aqueous 10% sodium carbonate (1×30 mL), and brine (30 mL), then dried (MgSO4) and filtered. The crude product was purified using the biotage 12i cartridge eluting with hexane and ethyl acetate (3:1) to yield a white solid (33% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[CH2:26][CH2:25][C:24]4[C:19](=[CH:20][C:21]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:23]=4)[CH:18]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH3:33][I:34]>CN(C=O)C>[I-:34].[CH3:33][N+:4]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[CH2:26][CH2:25][C:24]4[C:19](=[CH:20][C:21]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:22][CH:23]=4)[CH:18]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CI
Reactant: O=C(Nc1ccc(CN2CCOCC2)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Solvent: CN(C)C=O
Product: C[N+]1(Cc2ccc(NC(=O)C3=Cc4cc(-c5ccccc5)ccc4CC3)cc2)CCOCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In DMF (4 ml) was dissolved N-[4-(morpholinomethyl)-phenyl]-7-phenyl-3,4-dihydronaphthalene-2-carboxamide (450 mg), and to the mixture was added methyl iodide (198 μl). The mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 4-methyl-4-[4-(7-phenyl-3,4-dihydronaphthalene-2-carboxamido)benzyl]morpholinium iodide (Compound 12) (575 mg) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=O)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22].CC(O)=O>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][NH:22][CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Reactant: CN(C)CCN
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(OC)c1nc2c(cc1CNCCN(C)C)CCCN2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 1.5 g, 6.35 mmol) in DCM (40 ml) at room temperature was added 2-dimethylaminoethylamine (1.387 ml, 12.70 mmol) and AcOH (0.472 mL, 8.25 mmol), followed by Na(AcO)3BH (2.69 g, 12.70 mmol) and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted with DCM, quenched with saturated aqueous NaHCO3 and stirred for 20 min. Phases were separated and the water phase was extracted with DCM. Organic phases were combined, dried using Na2SO4, filtered and concentrated. The crude product was purified via silica gel column chromatography eluting with a gradient of MeOH (0-15%) in DCM. Fractions containing the product were combined and concentrated to yield the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][CH:9]=[O:10])[S:6][CH:7]=1.[SH:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][S:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:4]=1)=[O:10]
Reactant: Sc1ccncc1
Reactant: O=CNc1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=CNc1nc(CSc2ccncc2)cs1
Temperature: 100 °C
Yield: 64.2 %

Procedure:
A mixture of 4-chloromethyl-2-formylaminothiazole (1.86 g), 4-mercaptopyridine (1.23 g) and potassium carbonate (1.8 g) in N,N-dimethylformamide (20 ml) was heated at 100° C. for 2 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-formylamino-4-(4-pyridylthiomethyl)thiazole (1.7 g, yield: 68.0%). mp: 182°-184° C. IR (Nujol): 1675, 1650, 1585, 1560, 1270 cm-1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O.[Cl:17][C:18]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:19]=1[CH2:27][CH2:28][CH2:29][OH:30]>>[Cl:17][C:18]1[CH:23]=[C:22]([NH:24][C:14](=[O:16])/[CH:13]=[CH:12]/[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:21]=[CH:20][C:19]=1[CH2:27][CH2:28][CH2:29][OH:30]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])c1ccc(CCCO)c(Cl)c1
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CCCO)c(Cl)c1

Procedure:
Prepared analogously to Intermediate product Z32a starting from (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylic acid (Z37b) and 3-(2-chloro-4-nitro-phenyl)-propan-1-ol. The crude product was purified by column chromatography (silica gel, petroleum ether/EtOAc 1:1).