Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.CCOCC.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1>C1(C)C=CC=CC=1>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1
Reactant: C1=CCCCC1
Reactant: Oc1ccc(Br)cc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Brc1ccc(OC2CCCCC2)cc1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Boron trifluoride etherate (5.83 mL) was added to a mixture of 4-bromophenol (39.8 g) and cyclohexene (187 mL) in toluene (160 mL) to form bright orange-red solution. The mixture was stirred at 40° C. under nitrogen for 5 hr. The mixture was quenched with 2N NaOH aq. (40 mL) and water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with hexane) to give the title compound (46.3 g) as pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH:3]([CH2:31][CH3:32])[CH:4]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]=[C:15]([NH:17][CH2:18][C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=3)[C:22]([O:24]C)=[O:23])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][N:2]([CH3:33])[CH:3]([CH2:31][CH3:32])[CH:4]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]=[C:15]([NH:17][CH2:18][C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=3)[C:22]([OH:24])=[O:23])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CCC(C(c1ccc2nc(NCc3cccc(C(=O)OC)c3)sc2c1)n1ccnc1)N(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C(c1ccc2nc(NCc3cccc(C(=O)O)c3)sc2c1)n1ccnc1)N(C)C
Temperature: 50 °C

Procedure:
A solution of methyl 3-(((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]-thiazol-2-yl)amino)methyl)benzoate (18 mg, 0.037 mmol) in 500 μL THF was treated with LiOH (10 mg, 0.238 mmol, 6.5 equiv) in 500 μL water. This was heated at 50° C. overnight. Afterwards the reaction was neutralized with 240 μL of 1N HCl and concentrated in vacuo. The residue was purified by prep-TLC using a 1 mm silica plate eluting twice with 20% MeOH/DCM to provide
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8](=[S:11])SC)(=[O:3])[CH3:2].O.[NH2:13][NH2:14]>C(O)C>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8](=[S:11])[NH:13][NH2:14])(=[O:3])[CH3:2]
Reactant: NN
Reactant: CSC(=S)NCCNC(C)=O
Solvent: CCO
Solvent: O
Product: CC(=O)NCCNC(=S)NN
Temperature: 4 °C

Procedure:
A solution of methyl N-(2-acetamidoethyl)-dithiocarbamate (57.7 g) and hydrazine hydrate (14.6 cc) in absolute ethanol (300 cc) is heated under reflux for 2 hours. The mixture is then cooled to 4° C. and is filtered, and the insoluble matter is dried at 30° C. under 0.05 mm Hg. 4-(2-Acetamidoethyl)-thiosemicarbazide (39.5 g) is obtained in the form of white crystals (instantaneous m.p. [Kofler]=171° C.).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[O:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])N1C(OCC)=O.Cl>O>[O:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[N:7]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][CH:17]=1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NCc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 250-mL 3-necked round-bottom flask, was placed sodium carbonate (3.7 g, 34.91 mmol, 0.54 equiv), water (66 mL), 4-(aminomethyl)benzoic acid (9.7 g, 64.17 mmol, 1.00 equiv) and ethyl 1,3-dioxo-2,3-dihydro-1H-isoindole-2-carboxylate (14.6 g, 66.61 mmol, 1.04 equiv). The resulting solution was stirred for 3 h at 25° C. The pH value of the solution was adjusted to 4 with hydrogen chloride (1 mol/L). The solids were collected by filtration. The filter cake was washed with 1×100 mL of water. This resulted in 15.7 g (87%) of 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]benzoic acid as a white solid. MS (ESI) m/z 282 ([M+H]+).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][CH:13]=1.N>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[CH:14][CH:13]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc(F)cc1
Agent: N
Product: Fc1ccc(-c2nc(-c3cccnc3)no2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 4-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.39 (t, J=8.9 Hz, 2 H), 7.64 (ddd, J=7.9, 4.8, 0.8 Hz, 1 H), 8.27-8.35 (m, 2 H), 8.55 (ddd, J=8.1, 2.0, 1.8 Hz, 1 H), 8.74 (dd, J=5.0, 1.8 Hz, 1 H), 9.29 (dd, J=2.2, 1.0 Hz, 1 H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:13]1[S:17][C:16]([C:18]([O:20]CC)=[O:19])=[N:15][C:14]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]#[N:31])[CH:24]=1.C(=O)(O)[O-].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[S:17][C:16]([C:18]([OH:20])=[O:19])=[N:15][C:14]=2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]#[N:31])[CH:24]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OB(O)c1cc(F)cc(Cl)c1
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(C#N)c2)c(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(-c2nc(C(=O)O)sc2-c2cc(F)cc(Cl)c2)ccc1F

Procedure:
At room temperature, 256 mg (1.48 mmol) of (3-chloro-5-fluorophenyl)boronic acid are added to 350 mg (0.985 mmol) of the compound from Example 29A and 56.9 mg (0.049 mmol) of tetrakis(triphenylphosphine)palladium in 26 ml of DME. 252 mg (3.01 mmol) of sodium bicarbonate in 11 ml of water are subsequently added, and the mixture is stirred under reflux for 1 h. The reaction solution is subsequently concentrated under reduced pressure and the residue is taken up in ethyl acetate and washed with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 50.0 mg (13% of theory) and 41 mg (9% of theory, purity 84%) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:16])[C:3]=1[Cl:17].[CH:18]([O-])([O-])[O:19][CH2:20][CH3:21].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:7]([C:8]([C:10](=[CH:18][O:19][CH2:20][CH3:21])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:16])[C:3]=1[Cl:17]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)c1cnc(Cl)c(Cl)c1Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cnc(Cl)c(Cl)c1Cl

Procedure:
87.0 g (0.29 mol) of ethyl 2-(4,5,6-trichloronicotinoyl)acetate are heated with 56.2 g of (0.38 mol) of ethyl orthoformate and 65.2 g of acetic anhydride at 150°-160° C. for two hours. All volatile components are removed, initially in vacuo and then under a high vacuum up to 100° C.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8]C(C)(C)C)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][SH:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][S:20][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:13][CH:14]=1
Reactant: CN(C)CCS
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)CCSc1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 110.3 %

Procedure:
A suspension of tert-butyl 4-fluorobenzoate (300 mg), 2-(dimethylamino)-ethanethiol hydrochloride (420 mg), and potassium carbonate (620 mg) in dimethylsulfoxide (3.0 mL) is stirred at 80° C. for 4 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is concentrated in vacuo and to the residue is added 4N HCl-dioxane (1.5 mL). The mixture is stirred at room temperature overnight. The reaction mixture is diluted with ether and the precipitated crystals are collected by filtration to give 4-[2-(dimethylamino)ethylthio]-benzoic acid (380 mg, yield; 99%) as colorless crystals. MS (APCI) m/z; 226 [M+H]+
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][CH2:17][Cl:18]>C(#N)C>[Cl:18][CH2:17][CH2:16][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: ClCCOc1ccc(I)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
To a solution of 4-iodophenol (1.0 g) in acetonitrile (10 mL), cesium carbonate (3.0 g) and 1-bromo-2-chloroethane (0.8 g) were added and the mixture was heated to 100° C., at which it was stirred for 4 hours. Additional 1-bromo-2-chloroethane (1.0 g) was further added and stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=11:1) to give the titled compound (0.87 g, 68%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([C:14]1[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=1)[CH3:13]>C(O)(=O)C.CCO>[CH2:12]([C:14]1[S:18][C:17]([CH:19]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=1)[CH3:13]
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: CCc1ccc(C=O)s1
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1ccc(C=NNC(=O)c2ccc(O)cc2)s1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) and 5-ethyl-2-thiophenecarboxaldehyde (0.28 g, 0.002 mol) in abs. EtOH (10 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.53 g, in 96% yield, mp: 194.5° C. 1H NMR (CD3OD) δ 8.39 (s, 1H), 7.79 (d, 2H), 7.19 (s, 1H), 6.86 (d, 2H), 6.80 (s, 1H), 2.86 (q, 2H), 1.31 (t, 3H). 13C NMR (CDCl3) δ 166.5, 162.7, 153.1, 144.9, 137.7, 132.3, 130.8, 125.3, 124.8, 116.3, 24.7, 16.2. Anal. Calcd for C14H14N2O2S : C, 61.29; H, 5.14; N, 10.21. Found: C, 61.00; H, 5.18; N, 10.00.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[CH2:21]([C@H:9]1[CH2:10][NH:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@@H]1Cc1ccccc1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCNC[C@@H]1Cc1ccccc1

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step C, except using 1-tert-butoxycarbonyl-2(S),4-dibenzylpiperazine (4.78 g, 11.3 mmol) and 10% palladium on carbon (1.04 g). The title compound was obtained as an oil. 1HNMR (300 MHz, CD3OD) δ 7.25 (5H, m), 4.35 (1H, m), 4.00 (1H, d, J=12 Hz), 2.7-3.3 (7H, m), 1.25 (9H, s).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([CH2:26]Br)[CH:23]=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC#N>[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([CH:23]=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29])[CH2:26][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cn2cccn2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of pyrazole (93 mg, 1.4 mmol), K2CO3 (180 mg, 1.30 mmol) and 2-benzyloxy-4-bromomethyl-1-nitrobenzene (Example 83, step C) (193 mg, 0.599 mmol) in MeCN (5 mL) is stirred at RT for 1 h. Additional pyrazole (500 mg, 7.34 mmol) and K2CO3 (200 mg, 1.45 mmol) are added and the mixture is stirred at RT for an additional 15 h. The mixture is partitioned between EtOAc and water and the organic phase is dried over MgSO4. The solvent is removed under reduced pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16]([NH2:18])=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.NC[C:36](N)=[O:37]>>[NH2:18][C:16]([C@H:15]([NH:14][C:12](=[O:13])[C:11]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:9]([N:6]2[C:7](=[O:8])[C:2]([Cl:1])=[C:3]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:4]=[CH:5]2)[CH:10]=1)[CH2:36][OH:37])=[O:17]
Reactant: NCC(N)=O
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: Cl
Product: Cc1ccc(C(=O)N[C@H](CO)C(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting L-serinamide HCl for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.98 (m, 1H), 7.85 (m, 1H), 7.61 (q, 1H, J=8.4 Hz), 7.55 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.60 (m, 2H), 4.63 (m, 1H), 3.89 (d, 2H, J=5.6 Hz), 2.21 (s, 3H). ESHRMS m/z 493.1129 (M+H calculated for C22H20ClF2N4O5 requires 493.1085).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][CH2:15][CH3:16])=[C:8]([CH:12]=1)[C:9]([NH2:11])=[NH:10].[O:17]=[C:18]1NC(C2C=CC=CC=2OCC=C)=N[CH:20]=[C:19]1[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[O:17]=[C:18]1[NH:11][C:9]([C:8]2[CH:12]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=2[O:13][CH2:14][CH2:15][CH3:16])=[N:10][CH:20]=[C:19]1[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCCOc1ccc(OC)cc1C(=N)N
Reactant: C=CCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Agent: Cl
Product: CCCOc1ccc(OC)cc1-c1ncc(C(=O)OCC)c(=O)[nH]1

Procedure:
The title compound was prepared from 5-methoxy-2-n-propoxybenzamidine hydrochloride in a manner similar to that described for the preparation of ethyl 1,6-dihydro-6-oxo-2-(2-allyloxyphenyl)pyrimidine-5-carboxylate in Example 8. The product had m.p. 124°-126°.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][C@@H:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH3:20])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:27][CH3:28])=[C:5]([CH3:29])[O:4][N:3]=1.[N:30]([CH2:33][CH2:34][O:35][CH3:36])=[C:31]=S.C(Cl)CCl>CCO>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:27][CH3:28])=[CH:9][C:10]3[C:11]4[N:18]([C@@H:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=5)[CH3:20])[C:31]([NH:30][CH2:33][CH2:34][O:35][CH3:36])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: COCCN=C=S
Reactant: COc1cc2c(N[C@H](C)c3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Solvent: ClCCCl
Solvent: CCO
Product: COCCNc1nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c2n1[C@H](C)c1ccccn1
Temperature: 60 °C
Yield: 19 %

Procedure:
To a solution of 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4—((R)-1-(pyridin-2-yl)ethyl)quinoline-3,4-diamine (for a preparation, see Intermediate 25) (538 mg, 1.38 mmol) in EtOH (40 mL) was added 1-isothiocyanato-2-methoxyethane (0.30 mL, 2.76 mmol) and the mixture heated at 60° C. for 5.5 h. A further portion of 1-isothiocyanato-2-methoxyethane (0.15 mL, 1.38 mmol) was added and the reaction mixture heated at 60° C. overnight. The mixture was concentrated in vacuo, the residue dissolved in THF (40 mL), EDC (530 mg, 2.76 mmol) added, and the mixture heated at 60° C. for 4 h. The mixture was concentrated in vacuo and the residue purified by chromatography (100 g column, 2M methanolic ammonia/DCM gradient) to give the crude product which was further purified by MDAP (HpH) to give 7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-N-(2-methoxyethyl)-1-((R)-1-(pyridin-2-yl)ethyl)-1H-imidazo[4,5-c]quinolin-2-amine (122 mg, 0.258 mmol, 19% yield) as a white solid. LCMS: (Formate, 2 min), Rt 0.73 mins, MH+ 473.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:11]=[N:10][N:9]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17]C)=O)[N:8]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>>[OH:26][CH2:25][CH2:27][NH:28][C:15](=[O:17])[C:14]1[CH:19]=[CH:20][CH:21]=[C:12]([N:9]2[N:8]=[C:7]([NH:6][C:5]([NH2:22])=[N:4][CH2:3][C:2]([F:1])([F:24])[F:23])[CH:11]=[N:10]2)[CH:13]=1
Reactant: NCCO
Reactant: COC(=O)c1cccc(-n2ncc(NC(N)=NCC(F)(F)F)n2)c1
Product: NC(=NCC(F)(F)F)Nc1cnn(-c2cccc(C(=O)NCCO)c2)n1

Procedure:
A mixture of methyl 3-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]benzoate (0.2 g.) and ethanolamine (5 ml.) was heated at 80° overnight. The mixure was evaporated and the thick oily residue was purified by chromatography on silica gel using EtOAc and isopropanol (6:1 v/v) as eluant. The product was recrystallised from isopropanol to give N-(2-hydroxyethyl)-3-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]benzamide, m.p. 171°-173°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][N:8]=[C:7](C=O)[CH:6]=1)[CH3:2].[CH:14]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])OCC.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:6]=[CH:7][N:8]=[C:9]([CH:14]([O:18][CH2:19][CH3:20])[O:21][CH2:22][CH3:23])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccnc(C=O)c1
Reactant: CCOC(OCC)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccnc(C(OCC)OCC)c1
Temperature: 110 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-formyl-isonicotinic acid ethyl ester (5.0 g, 0.027 mol) in ethanol (9 mL) was added triethyl orthoformate (6.2 mL, 0.037 mol) followed by a solution of 6N hydrochloric acid in ethanol (1.5 mL). The mixture was heated to 110° C. (reflux) for 1.5 h, cooled to rt and solid potassium carbonate (1.80 g) added. The mixture was stirred for 5 min, concentrated in vacuo, and redissolved in diethyl ether (100 mL). The reaction was filtered through silica and the resulting cake washed with diethyl ether (50 mL). The filtrated was concentrated in vacuo to give 2-diethoxymethyl-isonicotinic acid ethyl ester as an oil.
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9](=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:10](=[O:12])[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH:27][C@@H:28]([CH2:41][NH2:42])[CH2:29][O:30][C:31]1[C:39]2[NH:38][C:37](=[O:40])[NH:36][C:35]=2[CH:34]=[CH:33][CH:32]=1>>[OH:27][C@@H:28]([CH2:41][NH:42][CH:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:13]=[C:9]3[S:8][C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:11][C:10]3=[O:12])=[CH:15][CH:16]=2)[CH2:25][CH2:24]1)[CH2:29][O:30][C:31]1[C:39]2[NH:38][C:37](=[O:40])[NH:36][C:35]=2[CH:34]=[CH:33][CH:32]=1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCOCC4)=NC3=O)cc2)CC1
Product: O=C1N=C(N2CCOCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one(which was obtained in Intermediate 28) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedure of Example 1 as a yellowish solid; mp>150° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.80-1.95 (m, 2 H), 2.55-2.95 (m, 4 H), 3.60-4.10 (m, 14 H), 4.90 (br s, 1 H), 6.56 (d, J=7.8 Hz, 1 H), 6.62 (d, J=8.0 Hz, 1 H), 6.87 (dd, J=7.9, 7.9 Hz, 1 H), 7.02 (d, J=8.9 Hz, 2 H), 7.45 (d, J=8.9 Hz, 2 H), 7.54 (s, 1 H), 10.65(s, 1 H), 10.75 (brs, 1 H); MS (ES) m/z: 290.0 ((M+2H)2+, 100%); 579.1 (MH+, 80%); HRMS Calcd. for C29H36N6O5S (MH+): 579.2390. Found: 579.2392.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C([O:9][C:10](=O)[CH:11]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:18]=1[F:25])[C:12](OCC)=[O:13])C.C(N(CCCC)CCCC)CCC>[OH-].[Na+]>[OH:9][C:10]1[C:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:18]=2[F:25])=[C:12]([OH:13])[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(F)cc(F)c1F
Reactant: Nc1nc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc2ncnn2c(O)c1-c1cc(F)cc(F)c1F
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
A mixture of 3-amino-1,2,4-triazole (14 g), diethyl(2,3,5-trifluorophenyl)-malonate (0.17 mol, obtained from Ex. 1) and tributylamine (50 ml) was heated at 180° C. for six hours. The reaction mixture was cooled to about 70° C. After addition of aqueous sodium hydroxide (21 g/200 ml H2O) the reaction mixture was stirred for 30 minutes. After separation of the organic phase the aqueous phase was extracted with diethyl ether. The aqueous phase was acidified with concentrated hydrochloric acid. The precipitate was collected by filtration and dried to yield 43 g of the title compound.
Reaction SMILES: [NH:1]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:22]12([CH2:32][C:33](Cl)=[O:34])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>>[C:22]12([CH2:32][C:33]([N:1]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:34])[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: C1COCCOCCOCCOCCOCCOCCN1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)N1CCOCCOCCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13,16,19-hexaoxacycloheneicosane and (1-adamantyl)acetyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)C=Cc1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C=Cc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.0 g (17.03 mmol) of methyl 4-methylcinnamate, 3.33 g (18.73 mmol) of N-bromosuccinimide and 60 mg of 2,2'-azobis(2-methylpropionitrile) in 75 ml of carbon tetrachloride was heated to reflux with a heat lamp and stirred rapidly for 30 minutes. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated to give the title compound as an oil which crystallized. NMR in CDCl3 (δ units): 3.80 (singlet, 3); 4.48 (singlet, 2); 6.44 and 7.67 (doublets, J=15 Hz, 1); 7.39, 7.49 (doublets, J=7 Hz, 2).