Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[CH:9]=[N:10][C:5]2=[C:4]([NH2:20])[CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:30][CH2:31][C:32](Cl)=[O:33].C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]3[C:12]([CH3:19])=[CH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])[CH:9]=[N:10][C:5]2=[C:4]([NH:20][C:32](=[O:33])[CH2:31][Cl:30])[CH:3]=1
Reactant: Cc1cc(C)c(-n2cnc3c(N)cc(C)nc32)c(C)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(-n2cnc3c(NC(=O)CCl)cc(C)nc32)c(C)c1
Temperature: 25 °C

Procedure:
Treat a solution of 5-methyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-ylamine (0.05 g, 1.9 mmol), and N,N-diisopropylethylamine, (0.04 mL, 0.21 mmol) in 1,2-dichloroethane (5 mL) with chloroacetyl chloride (0.017 mL, 0.21 mmol). Heat the solution to reflux for 3 h, cool to ambient temperature, and pour into an aqueous potassium carbonate solution. Extract the resulting mixture with CH2Cl2 and wash with saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter, and concentrate. Purify by preparative TLC (5% MeOH in CH2Cl2) to obtain the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][CH2:17][CH2:18][C:19](=O)[CH2:20][CH2:21][CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:18]([C:19]1([CH2:20][CH2:21][CH3:22])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1)[CH2:17][CH3:16]
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: CCCC(=O)CCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCC1(CCC)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 100 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.120 g, 0.550 mmol), 4-heptanone (1.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (1.5 mL) was stirred for 1 h at 100° C. in a sealed tube. Then, this mixture was stirred for 2 h at 120° C. and stirring was continued for 2 h at 110° C. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate, drying over magnesium sulfate, filtration and concentration at reduced pressure gave a solid. This solid was triturated with dichloromethane (10 mL), and the precipitate was collected by filtration. Then, the obtained solid was stirred at 60° C. in ethyl acetate (5 mL). After 10 min, the mixture was cooled, and the precipitate was collected by filtration to afford the title compound (0.0406 g, 23%) as a yellow solid:
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH2:3][CH:4]([NH:12][C:13]([C:15]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]=1[CH2:29][CH2:30][C:31](O)=[O:32])=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.C([N:37](CC)CC)C.ClC(OCC)=O.O.N>O1CCCC1.O>[O:22]([CH2:21][C:19]1[CH:18]=[CH:17][C:16]([CH2:29][CH2:30][C:31]([NH2:37])=[O:32])=[C:15]([C:13](=[O:14])[NH:12][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[CH2:3][CH:2]([CH3:34])[CH3:1])[CH:20]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCN(CC)CC
Reactant: CC(C)CC(NC(=O)c1cc(COc2ccccc2)ccc1CCC(=O)O)c1ccc(F)cc1
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(NC(=O)c1cc(COc2ccccc2)ccc1CCC(N)=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the compound prepared in Example 6(40) (150 mg) in tetrahydrofuran (2 ml) were added triethylamine (0.068 ml) and ethyl chloroformate (0.037 ml). The mixture was stirred at room temperature for 30 minutes under an atmosphere of argon. To the reaction mixture was added ammonia water and the mixture was stirred for 10 minutes. To the reaction mixture was added water and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and a saturated aqueous solution of sodium chloride subsequently, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with n-hexane-ethyl acetate to give the title compound (119 mg) having the following physical data.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[C:9]#[N:10].[ClH:14]>CN(C=O)C>[C:9]([C:8]1[CH:11]=[C:4]([C:3]([Cl:14])=[N:2][OH:1])[CH:5]=[CH:6][C:7]=1[O:12][CH3:13])#[N:10]
Reactant: Cl
Reactant: COc1ccc(C=NO)cc1C#N
Solvent: CN(C)C=O
Product: COc1ccc(C(Cl)=NO)cc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-[(Hydroxyimino)methyl]-2-methoxybenzonitrile, 4 M hydrochloric acid and Oxon (registered trade name) were dissolved in a solution of DMF, followed by stirring at room temperature for 12 hours to obtain 3-cyano-N-hydroxy-4-methoxybenzenecaboximidoyl chloride. NMRC: 7.01 (1H, d), 8.03 (1H, dd), 8.07 (1H, d).
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:13]([CH3:14])=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21](F)([F:23])[F:22])[CH:16]=3)[C:11](=[O:25])[C:10]([C:26]([OH:28])=[O:27])=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].F[CH:32](F)C1C=CC=CC=1B(O)O.BrC1C(=O)C(C(O)=O)=CN(CC2C=CC(C#N)=CC=2)C=1C.BrC1C(=O)C(C(O)=O)=CN(C(C2C=CC(C#N)=CC=2)C)C=1C>>[C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH:7]([N:8]2[C:13]([CH3:14])=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([F:23])[F:22])[CH:16]=3)[C:11](=[O:25])[C:10]([C:26]([OH:28])=[O:27])=[CH:9]2)[CH3:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: OB(O)c1ccccc1C(F)F
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Agent: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)c1ccc(C#N)cc1
Agent: Cc1c(Br)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Product: Cc1c(-c2cccc(C(F)F)c2)c(=O)c(C(=O)O)cn1C(C)c1ccc(C#N)cc1

Procedure:
Preparation 3 is prepared following the procedure described for preparation 1d, substituting 3-(trifluoromethyl)phenylboronic acid with 2-(difluoromethyl)phenylboronic acid and substituting preparation 1c with preparation 2b as starting material. ESI mass spectrum: [M+H]+=409; Retention time HPLC: 1.00 min (Z018_S04).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:28][CH3:29])=[C:7]([O:26][CH3:27])[CH:8]=2)[N:3]=1.[NH3:30]>C(O)C>[NH2:30][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:28][CH3:29])=[C:7]([O:26][CH3:27])[CH:8]=2)[N:3]=1
Reactant: N
Reactant: COc1cc2c(cc1OC)CN(c1nc(Cl)nc3cc(OC)c(OC)cc13)CC2
Solvent: CCO
Product: COc1cc2c(cc1OC)CN(c1nc(N)nc3cc(OC)c(OC)cc13)CC2
Temperature: 25 °C

Procedure:
The product of (A), viz, 2-chloro-6,7-dimethoxy-4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline (5.0 g.) and a saturated solution of ammonia in ethanol (60 ml.) were heated together in an autoclave at 100°C. for a period of approximately 16 hours. After the reaction mixture had been allowed to cool to room temperature (~26°C.), the solvent was removed by means of evaporation under reduced pressure and the resulting brown residue (5.0 g.) was partitioned between methylene chloride and water. The separated organic layer thus obtained was then evaported in vacuo and the residue (3.0 g.) was subsequently converted into the hydrochloride salt by conventional means. Recrystallization of the crude material from a mixture of e thanol and isopropanol then afforded 1.0 g. of pure final product as the hydrochloride hemihydrate, m.p. 245°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][N:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][C:39]2[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[CH:44][C:40]=2[C:41](O)=[O:42])=[CH:33][CH:32]=1>CN(C)C=O>[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][C:39]2[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[CH:44][C:40]=2[C:41]([NH:7][C:4]2[CH:5]=[CH:6][N:1]=[N:2][CH:3]=2)=[O:42])=[CH:33][CH:32]=1
Reactant: Nc1ccnnc1
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)O)c1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2ccnnc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Pyridazinamine (0.52 g, 5.47 mmol), EDC (0.84 g, 4.38 mmol), HOBT (0.89 g, 5.83 mmol) and N-ethylmorpholine (0.92 ml, 7.29 mmol) were added to a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-formylbenzoic acid (may be prepared by Description 105; 1 g, 3.65 mmol) in N,N-dimethylformamide (25 ml), and the mixture was stirred at room temperature for 4 hrs. The N,N-dimethylformamide was evaporated under reduced pressure on a buchi. Saturated aqueous sodium hydrogen carbonate (50 ml) and ethyl acetate (100 ml) were added to the residue and the mixture was stirred for 30 mins. The organics were separated and washed with water (50 ml), dried (MgSO4) and evaporated under reduced pressure to yield the title compound as a pale yellow solid. No further purification. No further purification carried out. 0.98 g.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:26](O)([CH3:29])([CH3:28])[CH3:27].N12CCCN=C1CCCCC2>CN(C=O)C>[C:26]([O:12][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)c1ccc2ncccc2c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a suspension of 6-quinolinecarboxylic acid (12 g, 69 mmol) in DMF (100 mL) was added 1,1′-Carbonyldiimidazole (11.2 g, 69.3 mmol) and the mixture stirred at 40° C. for 1 hour. tert-Butanol (13 mL, 139 mmol) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (10.4 mL, 69.3 mmol) were added and the mixture was stirred at 80° C. for 4 h. After cooling to room temperature the reaction mixture was quenched with water (400 mL) and extracted with ethyl acetate/heptane (1:3, 2×400 mL). The organic layer was dried over MgSO4 and concentrated to give quinoline-6-carboxylic acid t-butyl ester (14.54 g, 92%). 1H NMR (400 MHz, CDCl3) δ 1.63 (9H, s), 7.42-7.46 (1H, m), 8.10 (1H, d), 8.23 (1H, d), 8.26 (1H, d), 8.50 (1H, d), 8.96-8.98 (1H, m). LCMS: Retention time: 1.42 min. MS (ESI) m/z 230 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23]([CH:25]1[O:27][CH2:26]1)Br>C(#N)C>[O:27]1[CH2:26][CH:25]1[CH2:23][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCC1CO1
Reactant: O=C(Nc1ccccc1O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(Nc1ccccc1OCC1CO1)c1ccccc1

Procedure:
To a strred solution of N-(2-hydroxy-phenyl)-benzamide (0.81 g, 3.80 mmol), and cesium carbonate (1.61 g, 4.94 mmol) in acetonitrile was added epibromohydrin (0.63 ml, 7.60 mmol). After 4 hours the reaction mixture was partitioned between dichloromethane and water. After evaporation of the organic solvent, the residue was crystallized from petroleum ether and diethyl ether yielding the title compound (0.741 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12](OC)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Li+].[B-](CC)(CC)CC.O>C1COCC1>[NH2:1][C:2]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CO)cc1N
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
To a solution of 16.0 g (76.6 mmole) of dimethyl aminoterephthalate in 200 ml of anhydrous THF cooled to −78° C. is added 250 ml (250 mmole) of 1 M Super Hydride dropwise over 1 hour. The mixture is stirred for an additional 1.5 hours warming to 0° C. (a little starting material on TLC is observed). The mixture is poured into 300 ml of cold water and extracted with ethyl acetate. The organic layer is washed with water and the two layers are allowed to stand for 30 minutes. The organic layer is dried over MgSO4 and filtered. The filtrate is evaporated. The residue is dissolved in ethyl acetate and the solution is poured over a Buchner funnel containing silica gel, using 150 ml of ethyl acetate to wash the funnel. The filtrate is evaporated. The residue is dissolved in the minimum amount of ethyl acetate and the solution is diluted to the cloudy point with hexane. Additional hexane is added as the product precipitates. A total of 100 ml of hexane is added and the solid is collected and vacuum dried to give 8.4 g of the title intermediate material, 98-100° C. mp; 61% yield. 1H NMR (CDCl3, 300 MHz) δ 7.82 (d, 1H), 6.67 (s, 1H), 6.60 (d, 1H), 5.75 (bs, 2H), 4.62 (s, 2H), 3.86 (s, 3H), 1.83 (bs, 1H). EI MS, [M]+=181.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.Cl>ClCCl.C(N(CC)CC)C>[CH2:20]([N:22]([CH2:23][CH3:24])[C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:19])=[CH:18][CH:17]=1)[CH3:21]
Reactant: CCNCC
Reactant: O=C(O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-[2-(4-fluorophenyl)-2-oxoethyl]benzoic acid (0.560 g, 2.17 mmol, Example 3, Step 1), triethylamine (0.620 ml), and diethylamine (0.230 ml) in dichloromethane (5 ml) at room temperature was added bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (0.560 g). After 3 hours, HCl 1M (10 ml) was added and the product was extracted with dichloromethane (10 ml). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography using hexane/ethyl acetate 50% giving 0.44 g of the title compound.
Reaction SMILES: BrBr.[OH-:3].[Na+].[C:5]([C:8]1[CH:9]=[CH:10][C:11]2[O:20][C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[C:13]([CH3:22])([CH3:21])[C:12]=2[CH:23]=1)(=[O:7])C>O.O1CCOCC1>[CH3:21][C:13]1([CH3:22])[C:14]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[O:20][C:11]2[CH:10]=[CH:9][C:8]([C:5]([OH:7])=[O:3])=[CH:23][C:12]1=2
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)c1cccnc1O2
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)c2cc(C(=O)O)ccc2Oc2ncccc21
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
4.8 g of bromine is added dropwise to a solution of 3.3 g of sodium hydroxide in 28 ml of water at below 0°C, and the mixture is allowed to stand at 0°C for 15 minutes. To the mixture is added dropwise and slowly a solution of 2.4 g of 7-acetyl-5,5-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine in 10 ml of dioxane. The whole mixture is allowed to stand at room temperature for 2 hours, and then the solvent is removed by distillation under reduced pressure. To the residue are added water and benzene, and the mixture is warmed to 30°-40°C. The aqueous layer is neutralized with hydrochloric acid. The crystalline precipitate is recrystallized from aqueous acetic acid to give 1.9 g of 5,5-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-carboxylic acid melting at 241°-242°C.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][Si:9](Cl)([CH3:11])[CH3:10]>>[CH3:8][Si:9]([CH3:11])([CH3:10])[O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)Cl
Reactant: OC1CCCCC1
Product: C[Si](C)(C)OC1CCCCC1

Procedure:
Trimethyl-cyclohexyloxy-silane was prepared according to the same procedure of Example 2, except that the raw materials were changed as cyclohexanol and trimethylsilyl chloride.
Reaction SMILES: BrC1C(C)=CC2C(C)(C)CCC(C)(C)C=2C=1.C([N:20](C(C)C)[C:21]([C:23]1[C:28](C(=O)C)=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:22])(C)C>>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]([NH2:20])=[O:22]
Reactant: CC(=O)c1cccnc1C(=O)N(C(C)C)C(C)C
Agent: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Product: NC(=O)c1ccccn1
Yield: 80 %

Procedure:
2-Bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene 33 (620 mg, 2.2 mmol) and the acetylpyridineamide 36a (500 mg, 2 mmol) were converted by a similar method as described above to obtain the intermediate 34 in over 80% yield. To a solution of the pyridine amide 34 (432 mg, 1 mmol) in 5 mL of THF at −78° C. was added 1.5 M DIBAL toluene solution (0.7 mL, 1.05 mmol) and the resulting yellow clear solution was warmed up to −20° C. slowly in 60 min. and then was quenched with water. Removal of solvent and chromatography of the crude mixture afforded the pyridinealdehyde 35 in 83% yield as a white solid. 1H-NMR (CDCl3) δ1.25 (s,2(CH3)), 1.29 (s,2(CH3)), 1.70 (s,2(CH2)), 1.96 (s,CH3), 5.47 (s,═CH), 5.92 (s,═CH), 7.10 (s,Ar—CH), 7.11 (s,Ar—CH), 7.70 (d,J=8.0 Hz,Pyr—CH), 7.88 (d,J=8.0 Hz,Pyr—CH), 8.72 (s, Pyr—CH), 10.06 (s,CHO).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([O:19]CC)=[O:18])[S:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([OH:19])=[O:18])[S:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)c1cccc(-c2nc(-c3ccc(C)c(C)c3)cs2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(-c2csc(-c3cccc(C(=O)O)c3)n2)cc1C
Yield: 72 %

Procedure:
A mixture of ethyl 3-[4-(3,4-dimethylphenyl)-2-thiazolyl]benzoate (1.25 g), a 1N aqueous solution of sodium hydroxide (10 ml), tetrahydrofuran (10 ml) and ethanol (10 ml) was stirred at 60 to 70° C. for 1 hour. The reaction mixture was poured into 1N hydrochloric acid, and precipitated crystals were collected by filtration, and then washed with water. The product was recrystallized from acetone-hexane to obtain 3-[4-(3,4-dimethylphenyl)-2-thiazolyl]benzoic acid (825 mg, yield: 72%). Colorless prisms. Melting point: 235 to 236° C.
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:19]Br>P(OC)(OC)(OC)=O>[Br:19][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:1]=1
Reactant: c1ccc2c(c1)c1ccccc1c1ccccc21
Reactant: BrBr
Solvent: COP(=O)(OC)OC
Product: Brc1ccc2c3ccccc3c3ccccc3c2c1
Temperature: 80 °C
Yield: 69.8 %

Procedure:
3.2 g (14 mmol) of triphenylene was dissolved in 60 mL of trimethyl phosphate. To the suspension was added 2.23 g (14 mmol) of bromine in 10 mL of trimethyl phosphate at room temperature under N2. The mixture was then heated up to 80° C. The reaction was monitored by HPLC. The reaction was quenched by pouring into ice water, then extracted with dichloromethane and washed with saturated sodium bisulfite solution. After drying with magnesium sulfate, the solvent was evaporated. The crude product was run through a short silica gel plug using dichloromethane. 3.0 g of product was obtained after drying under vacuum. The product contains triphenylene, 1-bromotriphenylene, 2-bromotriphenylene, and a mixture of dibromotriphenylene isomers.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][C:5]1[C:6]([S:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=2)=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.O>C1COCC1>[CH2:1]([NH:3][C:24](=[O:25])[C:23]1[CH:22]=[CH:21][C:20]([S:19][C:6]2[C:5]([CH3:4])=[CH:14][C:13]3[C:12]([CH3:15])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:18])([CH3:17])[C:8]=3[CH:7]=2)=[CH:28][CH:27]=1)[CH3:2]
Reactant: CCN
Reactant: Cc1cc2c(cc1Sc1ccc(C(=O)Cl)cc1)C(C)(C)CCC2(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)c1ccc(Sc2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
640 μl (8 mmol) of a 70% solution of ethylamine and 20 ml of THF were introduced into a round-bottomed flask. A solution of 735 mg (2 mmol) of 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoyl chloride dissolved in 30 ml of THF was added dropwise and the mixture was stirred at room temperature for three hours. The reaction medium was poured into water, extracted with ethyl acetate, the organic phase decanted off, dried over magnesium sulfate and evaporated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][SH:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([S:31][CH2:30][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:21]3[CH:32]=[CH:33][C:18]([F:17])=[CH:19][CH:20]=3)=[CH:29][CH:28]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(COc2ccc(CS)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)SCc2ccc(OCc3ccc(F)cc3)cc2)CC1
Temperature: 100 °C
Yield: 45.3 %

Procedure:
5.84 g (23.5 mmol) 4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester were added to a solution of 6.0 g (24.2 mmol) 4-(4-fluoro-benzyloxy)-phenyl-methanethiol in 14.6 ml pyridine. The solution was heated to 100° C. for 3.5 h, then cooled to rt, 10 ml of water added and the volume reduced to a third. The resulting precipitate is collected, washed with water and dried. The crude product is re-crystallized from hexane/AcOEt. Flash chromatography on silica gel provided 4.90 g 4-[4-(4-fluoro-benzyloxy)-benzylsulfanylcarbonyl]-piperazine-1-carboxylic acid tert-butyl ester as colourless powder, mp: 123–124° C. 1H-NMR (CDCl3): 1.46 s, 9H; 3.38–3.60 m, 8H; 4.13 s, 2H; 5.00 s, 2H; 6.89 d, 2H, 7.06 t, 2H, 7.28 d, 2H and 7.40 dd, 2H.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)[CH3:2].C([Li])CCC.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]>O1CCCC1.CCCCCC>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:23]([C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[F:20])[OH:24])[CH3:2]
Reactant: O=Cc1ccccc1F
Reactant: CCOC(OCC)c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(OCC)c1ccccc1C(O)c1ccccc1F
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
A solution of 345 g of 2-bromobenzaldehyde diethyl acetal in 3 l of dry tetrahydofuran was cooled to −40° C. In one portion, 913 ml of a 1.6 M solution of butyllithium in hexane were added under vigorous stirring. The resulting solution was stirred for 0.5 h at −25° C., after which a solution of 140 ml of 2-fluorobenzaldehyde in 350 ml tetrahydrofuran was added drop-wise. In a period of 4 h, the mixture was allowed to reach room temperature. The resulting mixture was pored upon ice-water and extracted several times with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulphate and evaporated to dryness under reduced pressure to yield 404 g of 2-(diethoxymethyl)-α-(2-fluorophenyl)-benzenemethanol as an oil, M.S. (C.I.) (M/Z): 305 [M+H]+.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:47][C:48]1[CH:53]=[C:52]([NH:54][NH2:55])[CH:51]=[CH:50][N:49]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:54]([C:52]3[CH:51]=[CH:50][N:49]=[C:48]([Cl:47])[CH:53]=3)[N:55]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Reactant: NNc1ccnc(Cl)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccnc(Cl)c2)n1

Procedure:
690 mg (1.77 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 350 mg (1.94 mmol) of 2-chloropyridin-4-yl-hydrazine hydrochloride. After hydrolysis, 475 mg (58% of theory) of the title compound is obtained.