Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[CH:30]=[C:29]([CH3:31])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:25]3[CH:30]=[C:29]([CH3:31])[S:28][C:26]=3[N:27]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C)sc3n2)cc1
Reactant: COc1ccc(CN)cc1OC
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(OC)c3)c3cc(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dimethoxy-benzylamine is reacted with 4-(4-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dimethoxybenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [CH:1]1([N:4]([C:12]2[C:13]3[N:14]([C:26](/[CH:29]=[C:30]4\[NH:31][C:32](=[O:36])[NH:33][C:34]\4=[O:35])=[CH:27][N:28]=3)[CH:15]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]=2)C(=O)OC(C)(C)C)[CH2:3][CH2:2]1>ClCCl.FC(F)(F)C(O)=O>[CH:1]1([NH:4][C:12]2[C:13]3[N:14]([C:26](/[CH:29]=[C:30]4/[C:34](=[O:35])[NH:33][C:32](=[O:36])[NH:31]/4)=[CH:27][N:28]=3)[CH:15]=[C:16]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(c1nc(C#Cc2ccccc2)cn2c(/C=C3\NC(=O)NC3=O)cnc12)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)/C(=C/c2cnc3c(NC4CC4)nc(C#Cc4ccccc4)cn23)N1
Reaction time: 1 h
Yield: 52 %

Procedure:
(Z)-Tert-butyl cyclopropyl(3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-6-(phenylethynyl)imidazo[1,2-a]pyrazin-8-yl)carbamate (12 mg, 0.03 mmol) was dissolved in dichloromethane (0.3 mL) and trifluoroacetic acid (0.3 mL). After 1 h, the solution was concentrated under a stream of air. The residue was triturated with Et2O and filtered to yield (Z)-5-((8-(cyclopropylamino)-6-(phenylethynyl)imidazo[1,2-a]pyrazin-3-yl)methylene)imidazolidine-2,4-dione (6 mg, 63%) as a bright yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[N:42](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:41]=[N:40][N:39]=3)=[CH:28][CH:27]=2)[C:7]([C:14]([O:16][CH2:17][C:18]2[O:19][C:20](=[O:24])[O:21][C:22]=2[CH3:23])=[O:15])=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1)[CH3:2]>C(O)(=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[NH:42][N:41]=[N:40][N:39]=3)=[CH:28][CH:27]=2)[C:7]([C:14]([O:16][CH2:17][C:18]2[O:19][C:20](=[O:24])[O:21][C:22]=2[CH3:23])=[O:15])=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[N:9]=1)[CH3:2]
Reactant: CCOCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCOCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 89.2 %

Procedure:
Following a procedure similar to that described in Example 82(b), but detritylating 456 mg of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-ethoxymethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] with a 25% v/v aqueous solution of acetic acid, 286 mg of the title compound were obtained as crystals, melting at 166°-167.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH:26]([F:28])[F:27]>O.O1CCOCC1>[F:27][CH:26]([F:28])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCOc1ccc(-c2ccc(OC(F)F)cc2)cc1
Temperature: 70 °C

Procedure:
A mixture of 20 g of 4-hydroxy-4'-octyloxybiphenyl, 13.6 g of NaOH, 100 ml of water and 150 ml of dioxane is heated to 70° C. with stirring. 10 g of chlorodifluoromethane are passed into the cooled two-phase mixture with vigorous stirring. The reaction mixture is poured into water, and the product is extracted with petroleum ether. The organic phase is dried over Na2SO4, evaporated, and the residue is filtered through a short silica gel column using petroleum ether as eluent. The product is recrystallized from acetonitrile. Colorless crystals are obtained. m.p.: 104° C., c.p.: 20° C. (extrapolated), Δn=0.093, viscosity: 17.
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH3:26])[CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][NH:21][CH2:22]3)[CH2:18]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4].[F:27][CH:28]([F:43])[O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37]OS(C)(=O)=O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][N:21]([CH2:37][CH2:36][C:33]4[CH:32]=[CH:31][C:30]([O:29][CH:28]([F:27])[F:43])=[CH:35][CH:34]=4)[CH2:22]3)[CH2:18]2)[CH3:26])(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4]
Reactant: CS(=O)(=O)OCCc1ccc(OC(F)F)cc1
Reactant: CN(CCN1CC2CNCC(C1)O2)S(=O)(=O)c1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(CCN1CC2CN(CCc3ccc(OC(F)F)cc3)CC(C1)O2)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 60 °C
Yield: 56.7 %

Procedure:
A mixture of 4-cyano-N-methyl-N-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethyl]-benzenesulfonamide dihydrochloride (0.169 g, 0.40 mmol, prep. I above), methanesulfonic acid 2-(4-difluoromethoxy-phenyl)-ethyl ester (0.107 g, 0.40 mmol, prep W above ), potassium carbonate (0.177 g, 1.28 mmol), and water (0.1 mL) in acetonitrile (4 mL) was heated in an oil bath (60° C.) for 20 h. Solid material was filtered off and the filtrate was loaded onto a cation-exchange column (SCX-2, Isolute™, 2 g/15 mL). The column was washed with a solution of methylene chloride/acetonitrile/methanol (2:1:1, 40 mL) and eluted with 20% methanol saturated with ammonia in methylene chloride (30 mL). The filtrate was concentrated in vacuo and the crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane eluent. Concentration in vacuo afforded 118 mg (57%) of the title compound as a solid white material.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH3:15][C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][NH2:19]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:19][CH2:18][CH2:17][C:16]([CH3:21])([CH3:20])[CH3:15])#[N:2]
Reactant: CC(C)(C)CCN
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: CC(C)(C)CCN=C(NC#N)c1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.5 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 ml), and 3,3-dimethylbutylamine (0.36 g, 3.6 mmol) was added. The mixture was stirred at room temperature for 20 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue was crystallized from dichloromethane-diethyl ether to give the title compound (0.46 g, 2.0 mmol, yield: 63%) as colorless needles.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCOCC1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CCCc1cn(S(=O)(=O)c2cccc([N+](=O)[O-])c2)c2ccccc12
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cccc(S(=O)(=O)n2cc(CCCC(=O)O)c3ccccc32)c1
Reaction time: 8 h
Yield: 14.1 %

Procedure:
To a solution of 4-[1-(3-nitrobenzenesulfonyl)indol-3-yl]butyric acid (1.0 g) in 1,4-dioxane (15 ml) and methanol (15 ml) was added 10% palladium on carbon (0.93 g). The mixture was hydrogenolized for 8 hours at room temperature. The catalyst was filtered off and the solvent was removed in vacuo. The residue was purified by a column of silica gel to give a yellow solid of 4-[1-(3-aminobenzenesulfonyl)indol-3-yl]butyric acid (0.13 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][NH:23][C:24](=[O:34])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH2:32][CH3:33])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][NH:23][C:24](=[O:34])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH2:32][CH3:33])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(OCc3ccccc3)c2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(O)c2)n1

Procedure:
A 4.65 g quantity of the N-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide obtained in Example 1 was dissolved in 90 ml of ethanol, and 0.45 g of 10% palladium carbon powder was added thereto. The mixture was stirred in a hydrogen atmosphere at room temperature for one hour. The catalyst was removed by filtration, and the filtrate was then concentrated under reduced pressure to give 3.7 g of white crystalline N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide.
Reaction SMILES: C[N:2](C)/C=C/C(C1SC(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)=NC=1C)=O.C[N:32](C)/[C:33](/[CH3:60])=[CH:34]/[C:35]([C:37]1[S:41][C:40]([N:42]2[CH2:46][CH2:45][N:44]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)[C:43]2=[O:58])=[N:39][C:38]=1[CH3:59])=O.O.NN>>[CH3:59][C:38]1[N:39]=[C:40]([N:42]2[CH2:46][CH2:45][N:44]([CH2:47][C:48]3[CH:49]=[CH:50][C:51]([C:54]([F:56])([F:55])[F:57])=[CH:52][CH:53]=3)[C:43]2=[O:58])[S:41][C:37]=1[C:35]1[CH:34]=[C:33]([CH3:60])[NH:32][N:2]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)/C=C/N(C)C
Reactant: C/C(=C\C(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C)N(C)C
Agent: NN
Solvent: O
Product: Cc1cc(-c2sc(N3CCN(Cc4ccc(C(F)(F)F)cc4)C3=O)nc2C)n[nH]1
Yield: 67 %

Procedure:
Following the procedure as described in Example 38, making variations as required to replace (E)-1-(5-(3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)imidazolidin-2-one with (E)-1-(5-(3-(dimethylamino)but-2-enoyl)-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)imidazolidin-2-one to react with hydrazine monohydrate, the title compound was obtained as a colorless solid in 67% yield: mp 238-239° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=7.8 Hz, 2H), 7.34 (d, J=7.8 Hz, 2H), 6.08 (s 1H), 4.52 (s, 2H), 4.04-3.99 (m, 2 H), 3.42-3.36 (m, 2H), 2.36 (s, 3H), 2.24 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 156.8, 155.8, 143.1, 139.9, 130.3, 129.9, 128.3, 125.8, 125.7, 122.1, 103.6, 47.5, 41.9, 41.8, 16.0, 10.8; MS (ES+) m/z 422.1 (M+1).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH2:16]1[C:22]2[CH:23]=[CH:24][C:25]([O:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)=[CH:26][C:21]=2[CH2:20][CH2:19][NH:18][CH2:17]1>CN(C)C=O>[CH:1]1([C:4]([N:18]2[CH2:19][CH2:20][C:21]3[CH:26]=[C:25]([O:27][CH:28]4[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]4)[CH:24]=[CH:23][C:22]=3[CH2:16][CH2:17]2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCNCC3)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCN(C(=O)C2CC2)CC3)CC1
Temperature: 25 °C

Procedure:
16 l cyclopropylcarboxylic acid are placed in 3 ml dimethylformamide, then 174 l diisopropylethylamine and 93.1 mg O-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) are added. After 15 min 77.5 mg tert-butyl 4-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylate are added. The reaction mixture is stirred at ambient temperature until there is no further reaction and the product is purified directly by preparative HPLC (method B). 70 mg of the product are obtained as a solid. Analytical HPLC-MS (method D): RT=1.37 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:13]([CH3:21])[C:14]([NH:16][CH2:17][CH2:18][S:19][CH3:20])=[O:15])=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1.[H-].[Na+].I[CH3:25]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:13]([CH3:21])[C:14]([N:16]([CH3:25])[CH2:17][CH2:18][S:19][CH3:20])=[O:15])=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CSCCNC(=O)N(C)c1cnc(-c2cncc(F)c2)s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCN(C)C(=O)N(C)c1cnc(-c2cncc(F)c2)s1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of [2-(5-fluoropyridin-3-yl)-thiazol-5-yl]-1-methyl-3-(2-methylsulfanyl-ethyl)urea (173 mg, 0.53 mmol) in DMF (5 mL) cooled to 0° C. was added NaH (26 mg, 0.65 mmol, 60% dispersion in mineral oil) and the mixture was stirred for 30 min. To this was added iodomethane (47 μL, 0.75 mmol) and the reaction mixture was stirred for 1 h. The reaction was quenched by addition of ethyl acetate and 1 N HCl. The layers were separated, and the ethyl acetate layer was washed three times with water and once with brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure to give the desired product as a yellow solid (0.110 g, 61%): mp 68-69° C.; 1H NMR (300 MHz, CDCl3) δ 8.90 (s, 1H), 8.47 (d, J=2.8 Hz, 1H), 7.93 (dt, J=9.3, 2.2 Hz, 1H), 7.45 (s, 1H), 3.54 (t, J=6.9 Hz, 2H), 3.41 (s, 3H), 2.94 (s, 3H), 2.74 (t, J=7.1 Hz, 2H), 2.16 (s, 3H); ESIMS m/z 341.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7](CP(OC)(OC)=O)=[CH:6][CH:5]=1>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CP(=O)(OC)OC)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 5.3 g (17.5 mmol) of 2,2,4,4,7,9,9-heptamethyl-3a,4,9,9a-tetrahydro-naphtho[2,3-d][1,3]-cis-dioxole-6-carbaldehyde and 5.9 g (22.8 mmol) of 4-(Dimethoxy-phosphorylmethyl)-benzoic acid methyl ester in 50 ml of toluene at 0° was added 13.4 ml of 1.7 M (22.2 mmol) potassium-tert-pentyl ate. After 1 h, the reaction was poured into brine, extracted with ethyl acetate, washed with brine, dried over sodium sulfate and adsorbed onto silica gel. The product was purified by flash chromatography (gradient elution: hexane-15% ethyl acetate/hexane) to afford 6.0 g (79%) of 4-[(E)-2-(2,2,4,4,7,9,9)-heptamethyl-3a,4,9,9a-tetrahydro-naphtho[2,3d][1,3]-cis-dioxol-6-yl)-vinyl]-benzoic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9]1[N:14]=[C:13]([CH:15]=O)[CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH3:15][C:13]1[N:14]=[C:9]([CH2:8][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cccc(C=O)n1
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1
Product: Cc1cccc(CNc2ccccn2)n1
Reaction time: 16 h

Procedure:
To a flask were added 1.9 g of 2-aminopyridine, 2.4 g of 6-methyl-2-pyridinecarboxaldehyde and 45 ml toluene. The flask was equipped with a Dean-Stark trap and heated to reflux under nitrogen. After 16 hours, the toluene was removed and 40 ml ethanol were added followed by 0.83 g of sodium borohydride. The mixture was stirred at 22 C under nitrogen for 1 hour, and then 30 ml of water were added slowly. Following removal of the ethanol, 60 ml 1M hydrochloric acid was added cautiously, and the aqueous layer was washed with 20 ml ethyl acetate. After basifying with aqueous ammonium hydroxide, the product was extracted with 50 ml ethyl acetate and the solvent was removed. The product was purified by silica gel chromatography using 74% ethyl acetate, 24% hexane, and 2% methanol resulting in 1.5 g of a yellow oil that solidified on standing.
Reaction SMILES: [NH2:1][C:2](=[N:8]O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(C)C(C)=CC=CC=1.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[C:19]#[CH:20]>C(N(CC)CC)C>[CH2:6]([O:5][C:3]([C:2]1[NH:8][CH:20]=[C:19]([C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:1]=1)=[O:4])[CH3:7]
Reactant: C#CC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(N)=NO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1nc(C(=O)OC(C)(C)C)c[nH]1

Procedure:
tert-Butyl 2-ethoxycarbonyl imidazole-4-carboxylate can be prepared as follows: the procedure is as in Example 1 but starting from 15 g of ethyl α-aminooximinoacetate, 500 ml of xylene, 19.1 of triethylamine and 14.3 ml of tert-butyl propiolate. The crude product (19 g) is chromatographed on a silica column, eluting with a mixture of cyclohexane and ethyl acetate (50-50 by volume) to give 5 g of tert-butyl 2-ethoxycarbonylimidazole-4-carboxylate, employed as such in the subsequent syntheses.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#C>>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[CH:5]=[CH:6][CH:7]=1)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]#[CH:11]
Reactant: C#CCCCCCCCCCO
Reactant: NC(=O)c1cccc(O)c1
Product: C#CCCCCCCCCOc1cccc(C(N)=O)c1

Procedure:
Synthesised from 3-hydroxybenzenecarboxamide and 10-undecyn-1-ol according to Method C, scheme 3; mp 111-112° C., HPLC-MS (method 1): m/z 274 [M+H]+, Rt=4.61 min.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C1CCN2C(=NCCC2)CC1.[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25]Br>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:25][C:24]1[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:23]=1[F:22]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: Cc1cc(O)c(Cl)c(=O)[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)[nH]1
Temperature: 80 °C
Yield: 12.8 %

Procedure:
3-Chloro-4-hydroxy-6-methyl-1H-pyridin-2-one (19.2 g, 0.12 mol) and DBU (19.9 mL, 0.13 mol) were dissolved in 70 mL of NMP. 2,4-Difluorobenzylbromide (17 mL, 0.13 mol) was added dropwise and the reaction was heated at 80° C. for 6 hours. The reaction was cooled to room temperature, the solid was filtered, and washed with NMP and hexanes. The solid was dried in a vacuum oven overnight to give a white solid (4.4 g, 13%): 1H NMR (300 MHz, DMSO-d6) δ 11.88 (br s, 1H), 7.63 (app q, J=9 Hz, 1H), 7.33 (app t, J=10 Hz, 1H), 7.16 (app t, J=9 Hz, 1H), 6.37 (s, 1H), 5.24 (s, 2H), 2.20 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH2:11]([N:29]=[C:30]=[O:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:30]([NH:29][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:31])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)Nc1cccc([N+](=O)[O-])c1
Yield: 83.3 %

Procedure:
A mixture of 0.5 g (3.6 mmol) of 3-nitroaniline, 1.2 mL (3.9 mmol) of octadecyl isocyanate 0.7 mL (5 mmol) of triethylamine and 0.1 mL of 4-dimethylaminopyridine in 30 mL of anhydrous THF was stirred at reflux for 18 hours. The reaction mixture was concentrated at reduced pressure and the residue was recrystallized from THF methanol-water to give 1.3 g of N-(3-nitrophenyl)-N'-octadecylurea.
Reaction SMILES: C(N(CC)CC)C.Br.Br[CH:10]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=1)[C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=1)=O.[NH2:35][C:36]([NH2:38])=[S:37]>C(#N)C>[CH3:20][C:15]1[CH:14]=[C:13]([C:11]2[N:35]=[C:36]([NH2:38])[S:37][C:10]=2[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:22]=2)[CH:18]=[C:17]([CH3:19])[CH:16]=1
Reactant: Cc1cc(C)cc(C(=O)C(Br)c2ccnc(OCc3ccccc3)c2)c1
Reactant: NC(N)=S
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C)cc(-c2nc(N)sc2-c2ccnc(OCc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
Triethylamine (1.4 mL, 10 mmol) was added dropwise to a solution of 2-bromo-1-(3,5-dimethylphenyl)-2-(2-phenylmethyloxy-4-pyridyl)ethanone hydrobromide (4.8 g, 9.8 mmol) and thiourea (0.77 g, 11 mmol) in acetonitrile (40 mL) and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, a saturated aqueous solution of sodium hydrogencarbonate was added to the residue and extracted with ethyl acetate. The organic layer was washed with water, dried and the solvent was distilled off. The resulting crude crystals were recrystallized from ethyl acetate to obtain 2.0 g (5.2 mmol, yield 53%) of the title compound.
Reaction SMILES: C1(C2[N:11]([CH:12]([CH3:14])[CH3:13])[CH2:10][CH:9]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][O:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)=[CH:19][CH:18]=3)[O:8]2)C=CC=CC=1>C(O)(C)C.Cl>[CH3:14][CH:12]([NH:11][CH2:10][CH:9]([OH:8])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)=[CH:19][CH:18]=1)[CH3:13]
Reactant: CC(C)N1CC(COc2ccc(CCOCC3CC3)cc2)OC1c1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)NCC(O)COc1ccc(CCOCC2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.25 g of 2-Phenyl-3-isopropyl-5-[[4-[2-(cyclopropyl methoxy)ethyl]phenoxy]methyl]oxazolidine from Example 4 was dissolved in a mixture of 10 mLs isopropanol, 10 mLs 5% aqueous hydrochloric acid. It was stirred at room temperature for 16 hrs. The isopropanol was removed under reduced pressure and 30 mLs 1% hydrochloric acid was added. The aqueous phase was washed with 15 mLs of toluene then basified and extracted twice with 10 mL portions of toluene. After removal of the solvent under reduced pressure 1.3 g of white solid was obtained (74% crude yield of betaxolol base). Betaxolol base was converted into its hydrochloride salt by dissolution in toluene and treatment with 1 equivalent of hydrochloric acid in isopropanol. Upon removal of isopropanol under reduced pressure and cooling of the toluene solution the hydrochloride salt of betaxolol was obtained. This solid is recrystallized twice from acetone, 4 mL/g, the second time with charcoal treatment to give a white crystalline solid with a melting point of 111.5°-112.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:49])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][N:12]([CH2:37][C:38]1[N:39]([S:43]([N:46]([CH3:48])[CH3:47])(=[O:45])=[O:44])[CH:40]=[CH:41][N:42]=1)[C:13](=[O:36])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([NH:28][N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])[CH2:24][CH2:23]2)=[CH:16][CH:15]=1)(=[O:5])=[O:4].Cl[C:51]([O:53][CH3:54])=[O:52]>>[CH3:47][N:46]([CH3:48])[S:43]([N:39]1[CH:40]=[CH:41][N:42]=[C:38]1[CH2:37][N:12]([CH2:11][C:7]1[N:6]([S:3]([N:2]([CH3:1])[CH3:49])(=[O:5])=[O:4])[CH:10]=[CH:9][N:8]=1)[C:13]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]([C@H:22]2[CH2:27][CH2:26][C@H:25]([NH:28][N:29]([CH2:30][CH2:31][CH3:32])[CH2:33][CH2:34][CH3:35])[CH2:24][CH2:23]2)[C:51](=[O:52])[O:53][CH3:54])=[CH:16][CH:15]=1)=[O:36])(=[O:45])=[O:44]
Reactant: COC(=O)Cl
Reactant: CCCN(CCC)N[C@H]1CC[C@H](NCc2ccc(C(=O)N(Cc3nccn3S(=O)(=O)N(C)C)Cc3nccn3S(=O)(=O)N(C)C)cc2)CC1
Product: CCCN(CCC)N[C@H]1CC[C@H](N(Cc2ccc(C(=O)N(Cc3nccn3S(=O)(=O)N(C)C)Cc3nccn3S(=O)(=O)N(C)C)cc2)C(=O)OC)CC1

Procedure:
The same operation as in Example 13 was performed, except for using the compound (200 mg) obtained in Example 16 and methyl chloroformate (54 mg), and then the obtained crude product was purified by silica gel chromatography (ethyl acetate:10%-saturated aqueous ammonia-methanol=1:0→85:15) to obtain the title compound (210 mg) having the following physical properties.