Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:8])[CH3:2].[NH2:24][CH2:25][C@@H:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[OH:27]>>[OH:27][C@H:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[CH2:25][NH:24][CH:19]1[CH2:20][CH2:21][N:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:23])=[O:8])=[CH:11][CH:12]=2)[CH2:17][CH2:18]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCOC(=O)CNC(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Product: CCOC(=O)CNC(=O)Nc1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from {3-[4-(4-oxo-piperidine-1-yl)-phenyl]-ureido}-acetic acid ethyl ester (which was obtained in Example 366) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, J=7.1 Hz, 3H), 1.20-1.40 (m, 2H), 1.80-1.95 (m, 2H), 2.50-2.70 (m, 5H), 2.92 (s, 3H), 3.40-3.50 (m, 2H), 3.83 (d, J=5.9 Hz, 2H), 4.10 (q, J=7.1 Hz, 2H), 4.47 (dd, J=8.0, 4.3 Hz, 1H), 6.28 (t, J=5.9 Hz, 1H), 6.75-6.85 (m, 3H), 7.00 (dd, J=8.3, 2.0 Hz, 1H), 7.15-7.25 (m, 3H), 8.45 (s, 1H); MS (ES) m/z: 550.5 (MH+); HRMS Calcd. for C25H36N5O7S(MH+): 550.2330. Found: 550.2319.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.O[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[C:20]([CH3:31])[C:19]=1[CH3:32].ClC1SC(COC2C=CC(CCC(OCC)=O)=C(C)C=2C)=C(C2C=CC(Cl)=CC=2)C=1>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH3:31])[C:19]=2[CH3:32])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: CCc1ccc(-c2cc(Cl)sc2CO)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Agent: CCOC(=O)CCc1ccc(OCc2sc(Cl)cc2-c2ccc(Cl)cc2)c(C)c1C
Product: CCc1ccc(-c2cc(Cl)sc2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 197 by coupling of [5-chloro-3-(4-ethylphenyl)thiophen-2-yl]methanol and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((5-chloro-3-(4-chlorophenyl)thiophen-2-yl)methoxy)-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ7.32 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.02 (s, 2H), 6.91 (d, J=8.1 Hz, 2H), 6.61 (d, J=8.4 Hz, 2H), 5.07 (s, 2H), 2.89 (t, J=7.5 Hz, 2H), 2.64-2.71 (m, 2H), 2.49 (t, J=8.4 Hz, 2H), 2.28 (s, 3H), 2.16 (s, 3H), 1.28 (t, J=7.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C24H25ClO3S, 427.1[M−H]. found 427.1.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=[O:17])[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O/[N:20]=[C:21](/[C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])(C)C)=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)\[NH2:22].N1C=CC=[CH:43][C:42]=1C1C(C(F)(F)F)=C(C2ON=C(C3C=CC(CN4CC(C(O)=O)C4)=CC=3)N=2)ON=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C)C=O>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]([O:18][N:20]=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([CH2:27][N:28]4[CH2:29][CH:30]([C:32]([O:34][CH2:35][CH2:38][CH2:42][CH3:43])=[O:33])[CH2:31]4)=[CH:39][CH:40]=3)[NH2:22])=[O:17])[S:10][C:11]=2[C:12]([F:14])([F:15])[F:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Reactant: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCOC(=O)C1CN(Cc2ccc(C(N)=NOC(=O)c3cc(-c4ccccc4)c(C(F)(F)F)s3)cc2)C1
Yield: 89 %

Procedure:
A mixture of 4-phenyl-5-(trifluoromethyl)thiophene-2-carboxylic acid (408 mg, 1.50 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int. 1 (458 mg, 1.50 mmol), HOBT (345 mg, 2.250 mmol), Hunig's Base (1.05 mL, 6.00 mmol), and EDC (431 mg, 2.25 mmol) in N,N-dimethylformamide (7.5 mL) was stirred at room temperature for 18 h. The reaction mixture was partitioned between ethyl acetate (120 mL) and a saturated aqueous solution of sodium bicarbonate (60 mL). The organic layer was washed with water (2×120 mL), washed with brine (120 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded ten-butyl 1-(4-(N′-(4-phenyl-5-(trifluoromethyl)thiophene-2-carbonyloxy)carbamimidoyl)benzyl)azetidine-3-carboxylate (744 mg, 1.33 mmol, 89% yield) as a light peach colored solid that was used in the next step without further purification. HPLC: ret. time=3.26 minutes (YMC Combi S-5 4.6×50 mm ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=560.25.
Reaction SMILES: [CH2:1]([OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Cl:24][CH2:25][C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[Cl:24][CH2:25][C:26]([O:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCO
Solvent: Cc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCCCCCOC(=O)CCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To erucyl alcohol (2) (101.5 g, 310.8 mmol) in 200 ml of toluene was added chloroacetyl chloride (38.6 g, 341.9 mmol). The reaction mixture was stirred at 25° C. for 3 hours. The reaction mixture was then washed with water (100 ml) and the aqueous and organic layers separated The organic layer was dried over sodium sulphate and the solvent removed in vacuo to yield erucyl 2-chloroacetate (3) (118.7 g, 94.3%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:36][CH:37]([CH3:39])[CH3:38])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([O:27][CH:28]([CH2:34][CH3:35])C(OCC)=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:40]([OH:42])C.[OH-:43].[Na+].Cl>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:36][CH:37]([CH3:39])[CH3:38])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([O:27][CH2:28][CH2:34][CH2:35][C:40]([OH:42])=[O:43])=[CH:15][CH:14]=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [OH-]
Reactant: CCO
Reactant: CCOC(=O)C(CC)Oc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCCCC(=O)O)cc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of ethyl {[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}butanoate (1.8 g, 3.4 mmol) in tetrahydrofuran (20 ml)-ethanol (20 ml) was added 2N aqueous sodium hydroxide solution (4 ml), and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was acidified with 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from diisopropyl ether to give 4-{[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}butanoic acid (1.3 g, yield 76%) as crystals.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.O=[C:15]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:25])[CH2:22][C:23]#[N:24])[CH2:17][CH2:16]1.[CH3:26][C:27]1[C:32]([C:33](O)=[O:34])=[C:31]([CH3:36])[N:30]=[CH:29][N:28]=1>>[CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:15]3[CH2:20][CH2:19][N:18]([C@H:21]([CH3:25])[CH2:22][CH2:23][NH:24][C:33]([C:32]4[C:27]([CH3:26])=[N:28][CH:29]=[N:30][C:31]=4[CH3:36])=[O:34])[CH2:17][CH2:16]3)=[CH:9][CH:8]=2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(c2ccc(N)cc2)OCCO1
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Reactant: Cc1ncnc(C)c1C(=O)O
Product: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(Nc2ccc(C3(C)OCCO3)cc2)CC1

Procedure:
Using general procedure A with 4-(2-methyl-[1,3]dioxolan-2-yl)-phenylamine (see EXAMPLE 173) (500 mg, 2.79 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (487 mg, 2.93 mmol), then general procedure J and then using general procedure E with the resulting amine and 4,6-dimethyl-pyrimidine-5-carboxylic acid (123 mg, 0.81 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[4-(2-methyl-[1,3]dioxolan-2-yl)-phenylamino]-piperidin-1-yl}-butyl)-amide as a pale beige solid (315 mg, 29% over 3 steps).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([OH:11])[CH:4]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>CN(C=O)C>[OH:11][C:5]1[CH:4]=[C:3]([CH2:2][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(CBr)cc1O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccnc2)cc1O
Temperature: 25 °C

Procedure:
4-bromomethyl-2-hydroxy-benzonitrile (0.22 g, 1.05 mmol) and imidazole (0.36 g, 5.23 mmol) were dissolved in DMF (10 mL) with stirring at ambient temperature. After stirring for 18 h, the reaction mixture was concentrated in vacuo and purified by silica gel chromatography eluting with 2% CH3OH/CH2C12 to 5% CH3OH/CH2Cl2 to give the title compound.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:18][C:19]([C:20]3[CH:21]=[N:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Reactant: NCc1cnc2ccccc2c1
Product: CCOC(=O)c1nc(-c2cnc3ccccc3c2)[nH]c1-c1ccc(C)cc1
Yield: 43.5 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate (10.6 g) and 3-aminomethylquinoline (8.5 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-methylphenyl)-2-(3-quinolyl)imidazole-4-carboxylate (7.0 g). 6.7 g therefrom was dissolved in ethyl alcohol (135 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-methylphenyl)-2-(3-quinolyl)imidazole-4-carboxylic acid (2.5 g), melting point 224° C. (decomposition).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:5]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:6]=2[S:7][CH:8]=1.O1CCCC1.C([Li])CCC.C([O-])(O)=O.[Na+]>CCCCCC>[C:3]([C:4]1[C:5]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:6]=2[S:7][CH:8]=1)#[CH:2]
Reactant: Cc1cccc2c(C=C(Br)Br)csc12
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#Cc1csc2c(C)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.6 g of 3-(dibromovinyl)-7-methylbenzo[b]thiophene are dissolved in abs. tetrahydrofuran and 3.38 ml of a 15% solution of n-butyllithium in n-hexane are added dropwise under inert gas and at -78°. Stirring is continued for one hour at -78° and the mixture subsequently warmed to room temperature, poured into saturated aq. NaHCO3 and extracted with ether. The organic phase is washed, dried, concentrated and directly further reacted.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22](=[O:23])[C:21]3[S:24][CH:25]=[CH:26][C:20]=3[NH:19][C:18]2=[O:27])[CH2:11][CH2:10]1.[CH2:28](I)[CH2:29][CH2:30][CH3:31]>CN(C)C=O>[CH2:28]([N:19]1[C:20]2[CH:26]=[CH:25][S:24][C:21]=2[C:22](=[O:23])[N:17]([CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]2)[C:18]1=[O:27])[CH2:29][CH2:30][CH3:31]
Reactant: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3ccsc3c2=O)CC1
Reactant: CCCCI
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCN2CCN(c3ccccc3OC)CC2)c(=O)c2sccc21
Yield: 56 %

Procedure:
The title compound was produced following the procedure of Example 13 using dimethylformamide as the solvent, the thienopyrimidine-2,4-dione (2.0 g, 5.17 mmol) from Example 19, and butyl iodide as the alkylating agent. The title compound was isolated in 56% yield (1.28 g) after recrystallization from EtOH, mp 139°-140° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][C:12]([CH:14]1[S:18][CH2:17][NH:16][C@@H:15]1[C:19]([OH:21])=O)=[O:13].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][C:12]([CH:14]1[S:18][CH2:17][NH:16][C@@H:15]1[C:19]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])=[O:13]
Reactant: O=C(CC1CCc2ccccc2C1)C1SCN[C@@H]1C(=O)O
Reactant: C1CCNC1
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: O=C(CC1CCc2ccccc2C1)C1SCN[C@@H]1C(=O)N1CCCC1
Yield: 52 %

Procedure:
Colorless crystals of 1-[3-(1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]pyrrolidine were prepared in the same manner as in Example 1, except that 3-(1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioproline and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 52%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[CH3:20])[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]3([CH3:24])[CH3:23])=[CH2:9])[CH:5]=[CH:6][CH:7]=1.[OH-:25].[Na+].Cl.[CH2:28]1[CH2:32][O:31]C[CH2:29]1>>[CH3:20][C:19]1[C:10]([C:8]([C:4]2[CH:3]=[C:2]([CH:29]=[CH:28][C:32]([OH:31])=[O:25])[CH:7]=[CH:6][CH:5]=2)=[CH2:9])=[CH:11][C:12]2[C:13]([CH3:23])([CH3:24])[CH2:14][CH2:15][C:16]([CH3:21])([CH3:22])[C:17]=2[CH:18]=1
Reactant: C=C(c1cccc(I)c1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: [OH-]
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Product: C=C(c1cccc(C=CC(=O)O)c1)c1cc2c(cc1C)C(C)(C)CCC2(C)C

Procedure:
A solution of the product of Example 7 (1.5 g, 3.7 nmol) and sodium hydroxide (1.5 g) in THF (50 ml) is refluxed for 8 h, acidified to pH 1 (concentrated HCl), extracted with ethyl acetate and washed with water. After drying, the organic phase is concentrated on a rotary evaporator under vacuum at 40° C. and the product is washed with heptane.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O)C.[F:10][C:11]([F:31])([C:27]([F:30])([F:29])[F:28])[CH2:12][CH2:13][CH2:14]OC1C=CC=C(C)C=1S([O-])(=O)=O>O>[F:10][C:11]([F:31])([C:27]([F:30])([F:29])[F:28])[CH2:12][CH2:13][CH2:14][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Cc1cccc(OCCCC(F)(F)C(F)(F)F)c1S(=O)(=O)[O-]
Solvent: O
Solvent: CCO
Product: FC(F)(F)C(F)(F)CCCN1CCNCC1
Yield: 70.7 %

Procedure:
Piperazine (777 mg, 9.0 mmol) was added to ethanol solution (10 ml) of 4,4,5,5,5-pentafluoropentyloxytoluenesulfonate (600 mg, 1.81 mmol) and then heated under refluxing for 40 hours. After adding water, the reaction solution was extracted with ethyl acetate. The solvent was distilled off under reduced pressure from the extract to obtain 315 mg (yield: 100%) of the title compound.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].O1CCCC1.Cl.[Cl:15][C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=3)[N:30]=[CH:29][CH:28]=2)[CH:19]=1)=[O:17]>CO.ClCCl>[ClH:15].[NH:7]([C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:37]([F:39])([F:38])[F:40])[CH:35]=3)[N:30]=[CH:29][CH:28]=2)[CH:19]=1)=[O:17])[C:6]([NH2:8])=[NH:5]
Reactant: N=C(N)N
Reactant: O=C(Cl)c1cn(-c2ccnc3ccc(C(F)(F)F)cc23)c2ccccc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: N=C(N)NC(=O)c1cn(-c2ccnc3ccc(C(F)(F)F)cc23)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 cm3 of methanol and 20 cm3 (10 mmol) of a 0.5M solution of sodium methoxide in methanol are added to 0.955 g (10 mmol) of guanidine hydrochloride under an argon atmosphere. After stirring at a temperature in the region of 25° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is three times successively dissolved in 20 cm3 of dichloromethane and evaporated to dryness under reduced pressure (2.7 kPa). 40 cm3 of tetrahydrofuran and 0.75 g (2 mmol) of 3-chlorocarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride, suspended in 20 cm3 of dichloromethane, are subsequently added thereto under an argon atmosphere. After stirring at a temperature in the region of 20° C. for 16 hours, the reaction mixture is concentrated to give a solid which is purified by flash chromatography [eluent: ethyl acetate/methanol (9/1 and then 8/2 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), the solid obtained is triturated in 20 cm3 of isopropyl ether and filtered off, resulting in 0.54 g of 3-guanidinocarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride in the form of a white powder melting at 260° C. Mass spectrum (EI): m/e 397 (M+•), m/e 339 (base peak).
Reaction SMILES: C1(=O)CCCCCCCCCCC1.[C:14]1([NH:26][CH:27]=[C:28]([C:34]([O:36]CC)=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[OH:36][C:34]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][N:26]=[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]=12
Reactant: CCOC(=O)C(=CNC1=CCCCCCCCCCC1)C(=O)OCC
Agent: O=C1CCCCCCCCCCC1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(c1O)CCCCCCCCCC2
Temperature: 25 °C

Procedure:
A solution of 10 g of the mixture of cyclododecanone and diethyl N-(1-cyclododecenyl)-aminomethylenemalonate in 25 ml Dowtherm® is added to 200 ml Dowtherm® at 250° under nitrogen, collecting distillate in a water separator. After heating for 0.5 hour the mixture is cooled to room temperature and the solvent distilled off under reduced pressure. The residual solid is triturated with ether and dried to give ethyl 5,6,7,8,9,10,11,12,13,14-decahydro-4hydroxycyclododeca[b]pyridine-3-carboxylate, m.p. 182°-90°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[N:16]1([CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[N:26]1[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:28][CH2:27]1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: C1CCN(CCC2CCNCC2)C1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N1CCC(CCN2CCCC2)CC1
Yield: 49.1 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with 4-[2-(pyrrolidin-1-yl)ethyl]piperidine (230 mg, 1.3 mmol) to afford the desired product (190 mg, 47%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.74 (s, 1 H), 8.18 (d, J=8.8 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 3.98-3.90 (m, 2H), 3.32-3.23 (m, 2H), 2.58-2.50 (m, 6H), 2.55 (s, 3H), 1.86-1.53 (m, 11H); ESI MS m/z 387 [M+H]+
Reaction SMILES: [CH3:1][O-].[Na+].[Cl:4][C:5]1[N:14]=[C:13]([O:15][CH3:16])[C:12]2[C:7](=[C:8]([Cl:21])[CH:9]=[C:10]([O:19][CH3:20])[C:11]=2[O:17][CH3:18])[N:6]=1>>[OH2:15].[Cl:4][C:5]1[N:14]=[C:13]([O:15][CH2:16][CH3:1])[C:12]2[C:7](=[C:8]([Cl:21])[CH:9]=[C:10]([O:19][CH3:20])[C:11]=2[O:17][CH3:18])[N:6]=1.[Cl:4][C:5]1[N:14]=[C:13]([O:15][CH2:16][CH3:1])[C:12]2[C:7](=[C:8]([Cl:21])[CH:9]=[C:10]([O:19][CH3:20])[C:11]=2[O:17][CH3:18])[N:6]=1
Reactant: C[O-]
Reactant: COc1cc(Cl)c2nc(Cl)nc(OC)c2c1OC
Agent: [Na+]
Product: CCOc1nc(Cl)nc2c(Cl)cc(OC)c(OC)c12
Product: O

Procedure:
When, in the above procedure, sodium methoxide is employed in place of sodium ethoxide the corresponding 2,8-dichloro-4-methoxy-5,6-dimethoxyquinazoline is obtained.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:10]1[CH:11]=[C:3]([CH:4]=[C:5]([O:6][CH3:7])[C:8]=1[OH:9])[CH:2]=[O:1]
Reactant: BrBr
Reactant: COc1cc(C=O)ccc1O
Solvent: CC(=O)O
Product: COc1cc(C=O)cc(Br)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.1 %

Procedure:
To a solution of vanillin (30.40 g, 0.20 mol) in glacial acetic acid (200 mL) was added bromine (46.79 g, 0.29 mol) in glacial acetic acid (20 mL) at 10° over a period of 1 h. Additional acetic acid (100 mL) was added to the thickening mixture and the reaction was stirred for 24 h at ambient temperature. The reaction was diluted with ice/water (300 mL); the precipitate was filtered and washed well with water. A light beige solid (40.69 g, 89%) was obtained after vacuum drying: MS (ES) m/z 230.0. (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[S:21]1[C:29]2[CH2:28][CH2:27][NH:26][CH2:25][C:24]=2[CH:23]=[CH:22]1>CN(C)C=O.C(O)C>[S:21]1[C:29]2[CH2:28][CH2:27][N:26]([CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]4[C:20]5[C:15](=[N:16][CH:17]=[CH:18][CH:19]=5)[O:14][N:13]=4)[CH:7]=3)[CH2:25][C:24]=2[CH:23]=[CH:22]1
Reactant: c1cc2c(s1)CCNC2
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1cccc(-c2noc3ncccc23)c1)CN1CCc2sccc2C1

Procedure:
The title compound is prepared from a mixture of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine in dimethylformamide and ethanol and 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine in ethanol essentially as described above in Example 102. Purity by LC/MS=100%, [M+H]+=408.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([NH:13][C:14]3[CH:35]=[CH:34][C:17]([CH2:18][N:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21]([CH2:28][C:29]([O:31]CC)=[O:30])=[N:20]4)=[CH:16][CH:15]=3)=[O:12])[CH:9]=[CH:10][C:2]1=2.O.[OH-].[Li+].O.Cl>O1CCCC1>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([NH:13][C:14]3[CH:35]=[CH:34][C:17]([CH2:18][N:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21]([CH2:28][C:29]([OH:31])=[O:30])=[N:20]4)=[CH:16][CH:15]=3)=[O:12])[CH:9]=[CH:10][C:2]1=2
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4c(c3)OCCO4)cc2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1nn(Cc2ccc(NC(=O)c3ccc4c(c3)OCCO4)cc2)c2ccccc12
Yield: 98.6 %

Procedure:
Ethyl 2-[1-[4-(2,3-dihydrobenzo[b][1,4]dioxin-6-carboxamido)benzyl]-1H-indazol-3-yl]acetate (260 mg, 0.551 mmol) was dissolved in tetrahydrofuran (20 mL), and in an ice bath, 10 mL aqueous solution dissolving lithium hydroxide monohydrate (70 mg, 1.67 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered and dried to obtain a white solid 241 mg, at a yield of 98.5%.