Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:4])Cl.[NH2:5][C:6]1[N:11]=[C:10]([SH:12])[N:9]=[C:8]([O:13][CH3:14])[N:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:5][C:6]1[N:11]=[C:10]([S:12][CH:2]([F:4])[F:1])[N:9]=[C:8]([O:13][CH3:14])[N:7]=1
Reactant: FC(F)Cl
Reactant: COc1nc(N)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc(N)nc(SC(F)F)n1

Procedure:
10.0 g of gaseous difluorochloromethane are introduced, during a period of 90 minutes at a temperature of 70° to 75° C., into a suspension of 5.0 g of 2-amino-4-mercapto-6-methoxy-1,3,5-triazine and 4.8 g of potassium carbonate in 100 ml of dimethylformamide. The reaction mixture is concentrated by evaporation, the residue is stirred up with water, and the solid precipitate is separated. The yield is 1.6 g of 2-amino-4-difluoromethylthio-6-methoxy-1,3,5-triazine, m.p. 146° to 150° C. (compound No. 1.14).
Reaction SMILES: [CH:1]1[C:14]2[C:5]3=[C:6]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH2:15][C:4]3=[CH:3][CH:2]=1.[H][H]>CCO.[Pd]>[CH:10]1[C:11]2[CH2:12][CH2:13][C:14]3[CH:1]=[CH:2][CH:3]=[C:4]4[CH2:15][C:7]([C:6]=2[C:5]=34)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: c1cc2c3c(c1)ccc1cccc(c13)C2
Agent: [Pd]
Solvent: CCO
Product: c1cc2c3c(c1)Cc1cccc(c1-3)CC2
Yield: 85 %

Procedure:
10.0 g (52.6 mmol) of 4H-cyclopenta[def]phenanthrene and 8.40 g of 5% Pd/C were dissolved in 70 ml of EtOH in a Par reactor bottle, and the resultant solution was stirred at room temperature for 24 hours with hydrogen pressure being maintained at 40 psi. After the reaction was completed, the reaction solution was filtered and the solvent was evaporated therefrom to obtain 8.60 g of white target material (yield: 85.0%). The obtained compound was confirmed by liquid chromatography-mass spectrometry (LC-MS).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C@@H:11]1[CH2:16][C@H:15]([N:17]([CH:19]([CH3:21])[CH3:20])[CH3:18])[CH2:14][CH2:13][C@@H:12]1[NH:22][C:23](=[O:36])[CH2:24][NH:25]C(=O)OCC1C=CC=CC=1)([CH3:10])[CH3:9]>CO.[Pd]>[NH2:25][CH2:24][C:23]([NH:22][C@H:12]1[CH2:13][CH2:14][C@@H:15]([N:17]([CH:19]([CH3:20])[CH3:21])[CH3:18])[CH2:16][C@H:11]1[CH:8]([CH3:10])[CH3:9])=[O:36]
Reactant: CC(C)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CN
Reaction time: 3 h
Yield: 122.6 %

Procedure:
A solution of benzyl 2-((1S,2S,4R)-2-isopropyl-4-(isopropyl(methyl)amino)cyclohexylamino)-2-oxoethylcarbamate trifluoroacetate (188 mg) in MeOH (10 mL) was charged with 10% Pd/C, Degussa (30 mg). The reaction flask was evacuated and then back-filled with hydrogen; this was repeated three more times. The reaction was stirred under 1 atm of H2 for 3 h and then filtered and concentrated to afford 2-amino-N-((1S,2S,4R)-2-isopropyl-4-(isopropyl(methyl)amino)cyclohexyl)acetamide (120 mg). MS found: (M+H)+=270.3.
Reaction SMILES: CO[C:3]([C:5]1[C:18]2[C:17](=O)[C:16]3[C:11](=[CH:12][CH:13]=[C:14](C)[CH:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[NH2:21][NH2:22]>>[N:21]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:10][C:9]3[C:18]=2[C:5]([CH:6]=[CH:7][CH:8]=3)=[CH:3][N:22]=1
Reactant: NN
Reactant: COC(=O)c1cccc2oc3ccc(C)cc3c(=O)c12
Product: c1ccc2c(c1)Oc1cccc3cnnc-2c13

Procedure:
Prepared from the compound 11 (R=H) and 1.5 equivalent of hydrazine to give benzopyrano[4,3,2-de]phthalazine according to General Procedure C. To a solution of 0.3g of benzopyrano[4,3,2-de]phthalazine in 7.5 mL of concentrate sulfuric acid is dropwise added 2.0 mL of fuming sulfuric acid at 0 OC. The mixture is stirred for 3 hours at 0° C. and poured into 100 mL of ice-cold water. The precipitation is collected by filtration, washed with water to give of a white solid product, mp >300° C. (dec.). 1H-NMR (400 MHz, DMSO-d6):12.7 (s, 1 H), 8.35 (s, 1 H), 7.92-7.90 (m, 2 H), 7.76-7.71 (m, 2 H), 7.38 (d, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C@H:22]3[CH2:26][O:25]C(C)(C)[O:23]3)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C@H:22]([OH:23])[CH2:26][OH:25])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CC1(C)OC[C@H](c2cnc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)cn2)O1
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc([C@H](O)CO)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-propionamide (8.85 g, 17.4 mmol) in tetrahydrofuran (50 mL) was treated with a 1N aqueous hydrochloric acid solution (50 mL). The resulting milky reaction mixture was stirred at 25° C., and within 15 min, the milky reaction mixture became clear. The stirring was continued at 25° C. for 16 h. The reaction was concentrated in vacuo, and the residue was extracted with methylene chloride (1×100 mL then 2×50 mL). Each organic extract was washed with a saturated aqueous sodium bicarbonate solution (50 mL) and a saturated aqueous sodium chloride solution (50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40 L, Silica, 1/1 ethyl acetate/hexanes then 100% ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S),2-dihydroxy-ethyl)-pyrazin-2-yl]-propionamide (7.15 g, 88%) as a colorless foam. (ES)+-HRMS m/e calcd for C21H26ClN3O5S (M+H)+ 468.1355, found 468.1360.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C:12]2[C:13]([C:24]([O:26]CC)=[O:25])=[N:14][N:15]([CH:21]3[CH2:23][CH2:22]3)[C:16]=2[C:17]([F:20])([F:19])[F:18])[CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C:12]2[C:13]([C:24]([OH:26])=[O:25])=[N:14][N:15]([CH:21]3[CH2:23][CH2:22]3)[C:16]=2[C:17]([F:19])([F:18])[F:20])[CH:3]=1
Reactant: CCOC(=O)c1nn(C2CC2)c(C(F)(F)F)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(NC(c2ccc(Cl)cc2)c2c(C(=O)O)nn(C3CC3)c2C(F)(F)F)cc(Cl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a solution of ethyl 4-(((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (Step 40.3) (350 mg, 0.569 mmol) in THF (3 mL) and MeOH (3 mL) was added 2M NaOH (2.84 mL, 5.69 mmol). The resulting mixture was stirred at RT for 1 hr. Volatiles were evaporated and the resulting aq. phase was adjusted to pH 5 with 2N HCl, extracted twice with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude was triturated in EtOAc to afford the title product (222 mg, 0.443 mmol, 78% yield) as an off-white solid. tR: 1.00 min (LC-MS 2); ESI-MS: 501/503 [M+H]+, ESI-MS: 499/501 [M−H]− (LC-MS 2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]1[CH:24]([CH3:25])[CH2:23][CH2:22][CH:21]1[OH:26].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]1[CH:21]([O:26][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:22][CH2:23][CH:24]1[CH3:25]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2C(C)CCC2O)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2C(C)CCC2OS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A 250 mL round bottom flask was charged with 66.56D (mixture of diastereomers) (0.61 g, 1.7 mmol), DCM (10 mL), and TEA (0.28 mL, 2.0 mmol) and cooled to 0° C. To the cold solution was added methanesulfonyl chloride (available from Aldrich) (0.16 mL, 2.0 mmol) dropwise. The cooling bath was removed, and the mixture was stirred for 1 hour at ambient temperature. The mixture was diluted with EtOAc, washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (0-40% EtOAc/hexane) to afford 66.56E (mixture of diastereomers) (0.69 g, 93% yield) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Pb+2].[OH-]>[Pt].CN(C)C=O>[CH2:9]([NH:16][C:7](=[O:8])[C:3]1[CH:4]=[CH:5][CH:6]=[N:1][CH:2]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cccnc1
Reactant: NCc1ccccc1
Agent: [Pt]
Agent: [OH-]
Agent: [Pb+2]
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1cccnc1
Yield: 23 %

Procedure:
In the same flask as in Example 1 were charged 2 g of pyridine-3-aldehyde, 5 g of benzylamine, 40 g of N,N-dimethylformamide and 3 g of a catalyst in which 5 percent by weight of platinum metal together with lead hydroxide with an atomic ratio of Pt to Pb being 1 to 1 had been supported on alumina. The reaction was conducted at a reaction temperature of 25° C. by introducing air into the flask at a rate of 6 l/hour for 2 hours to give nicotinic acid benzylamide at a yield of 23%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:33]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(Cl)c3)c(=O)c2-c2ccc(F)cc2)cc1
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(Cl)c3)c(=O)c2-c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 380 mg, 47%). mp 208-210° C. 1H NMR (300 MHz, DMSO-d6) δ 7.15 (t, 2H), 7.27 (m, 2H), 7.43 (s, 1H), 7.45 (bs, 2H) 7.51 (d, J=9 Hz, 4H), 7.6 (t, 1H), 7.7 (m, 1H), 7.75 (d, J=9 Hz, 2H), 7.94 (dd, 1H), 8.25 (s, 1H). MS (DCI/NH3) m/z 474 (M+H)+, 491 (M+NH4)+. Anal. calc. for C22H14F2Cl2N3O3S.0.5 H2O: C, 55.76; H, 2.98; N, 8.87. Found: C, 56.05; H, 3.42; N, 8.65.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:33][CH2:32][O:31][CH2:30]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH:29]2[CH2:33][CH2:32][O:31][CH2:30]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCC1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(3-bromopropyl)tetrahydrofuran.
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.[N:17]([CH2:20][C:21]1[CH:25]=[CH:24][S:23][C:22]=1[CH2:26][C:27](O)=[O:28])=[N+:18]=[N-:19].Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.O>[N:17]([CH2:20][C:21]1[CH:25]=[CH:24][S:23][C:22]=1[CH2:26][C:27]([NH:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:11][N:12]=[N:13][N:14]=3)[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]12)=[O:28])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=NCc1ccsc1CC(=O)O
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)S[C@@H]2C(NC(=O)Cc3sccc3CN=[N+]=[N-])C(=O)N2C1c1nnn[nH]1
Reaction time: 2.5 h
Yield: 88 %

Procedure:
A solution of 5.48 g. (0.0228 mole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 200 m.l of 1:1 tetrahydrofuran-water is adjusted to pH 7.5, and then 4.5 g. (0.0228 mole) of 2-(3-azidomethyl-2-thienyl)acetic acid is added. The mixture is cooled to 0°-5° C., and 4.37 g. (0.0288 mole) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride is added. The reaction mixture is stirred at pH 6 and at 0°-5° C. for 2.5 hours. At this point, the tetrahydrofuran is removed by evaporation in vacuo and the pH is adjusted to 7.5. The aqueous residue is washed with ethyl acetate and then the pH is lowered to 2.2. The product is extracted into ethyl acetate. The ethyl acetate is dried and evaporated in vacuo. This affords 8.1 g. (88% yield) of the title compound as a foam. IR (KBr disc): 2100, 1800, 1666, 1529 and 1250 cm-1. NMR (CDCl3): 7.3 (d, 1H), 7.0 (d, 1H), 5.7 (m, 2H), 5.3 (s, 1H), 4.4 (s, 2H), 3.9 (s, 2H), 1.6 (s, 3H) and 1.1 ppm (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Br[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[N:15]1[CH:16]=[CH:17][CH:18]=[N:19][C:14]=1[C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Brc1ncccn1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(O)c1ccc(-c2ncccn2)cc1
Temperature: 90 °C
Yield: 89 %

Procedure:
To a suspension of 4-carboxybenzeneboronic acid (0.660 g, 3.98 mmol) and 2-bromopyrimidine (0.630 g, 3.98 mmol) in dry acetonitrile (20 mL) was added 0.4 M aqueous sodium carbonate (20 mL) and the mixture was purged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (240 mg) was then added and the reaction mixture heated to 90° C. for 17 hours. The hot reaction mixture was filtered through celite and concentrated in vacuo to remove the acetonitrile. The resulting aqueous suspension was washed with dichloromethane (2×30 mL) and then acidified to pH 1 by the addition of concentrated hydrochloric acid. The resulting white suspension was diluted with water (20 mL), filtered and the solid product dried in vacuo at 50° C. overnight to give the title compound (0.709 g, 89%) as a white solid, m.p. 237° C.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[CH3:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[O:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=2)=[CH:11][CH:10]=1.C(Cl)Cl>O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2=[C:13]3[C:18]=1[CH:17]=[CH:16][CH:15]=[C:14]3[C:2](=[O:3])[C:23]1[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20][C:19]=12
Reactant: COc1ccc(-c2cc3ccccc3o2)c2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c3c(cccc13)C(=O)c1c-2oc2ccccc12
Reaction time: 1.5 h

Procedure:
Alternatively, 3-methoxy-7-oxo-7H-benzo[b]-phenaleno[2,1-d]furan was prepared by addition of 0.38 ml. (45 mmol.) of oxalyl chloride followed by 1.2 ml. (0.01 mol.) of stannic chloride to a solution of 1 g. (37 mmol.) of 2-(4-methoxynaphthyl)benzofuran in 100 ml. of methylene chloride at 0°. The reaction mixture was stirred for 1.5 hours at 0° then poured into water. The layers were separated and the organic phase was washed with 10% aqueous sodium carbonate, dried (MgSO4) and evaporated to dryness. The residue was chromatographed on silica with chloroform as eluant to give the product.
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH3:11])[CH2:6][CH:7]([CH3:10])[CH2:8][Cl:9].[CH3:12][N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:16](=[O:24])[C:15]2=[CH:25][S:26][CH:27]=[C:14]12.Cl>CCOCC.CN(C)C=O>[ClH:9].[CH3:4][N:5]([CH3:11])[CH2:6][CH:7]([CH3:10])[CH2:8][N:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:13]([CH3:12])[C:14]2=[CH:27][S:26][CH:25]=[C:15]2[C:16]1=[O:24]
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Reactant: CC(CCl)CN(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(CN(C)C)CN1C(=O)c2cscc2N(C)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.47 g. of 55% sodium hydride-mineral oil dispersion and 0.91 g. of 3-dimethylamino-2-methylpropylchloride hydrochloride in 35 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.6 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water and extracted with chloroform. The dried chloroform extracts are concentrated to an oil, which is chromatographed on silica gel preparative thin layer chromatographic (tlc) plates with 10:1 benzene:methanol to give an oil. An ethanolic solution of the oil is treated with anhydrous hydrogen chloride and diluted with ether to give a white solid, m.p. 231°-233°C. (dec.).
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([N:7]([CH3:20])[CH:8]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[N:4][CH:3]=1.[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[C:21]([OH:27])=[O:22].[F:1][C:2]1[S:6][C:5]([N:7]([CH3:20])[CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[N:4][CH:3]=1
Reactant: CN(c1ncc(F)s1)C1CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1ncc(F)s1)C1CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of 590 mg (1.96 mmol) tert.-butyl 3-((5-fluorothiazol-2-yl)(methyl)amino)-pyrrolidine-1-carboxylate in DCM (10 ml) was combined with 5 ml of TFA and stirred for 1 h at RT. The mixture was then evaporated under a vacuum, redissolved with MeOH and again evaporated, 611 mg (1.94 mmol, 99%) of 5-fluoro-N-methyl-N-(pyrrolidin-3-yl)thiazol-2-amine trifluoroacetate being obtained which were further reacted without being purified.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:6]([CH3:8])[CH:7]=1.C([Li])(C)(C)C.CCCCC.[CH2:28]([N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:44])[C:36]1=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>COCCOC>[CH2:28]([N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]([C:2]2[CH:3]=[C:4]([CH3:17])[C:5]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]([CH3:8])[CH:7]=2)([OH:44])[C:36]1=[O:45])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1cc(Br)cc(C)c1OCc1ccccc1
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: COCCOC
Product: Cc1cc(C2(O)C(=O)N(Cc3ccccc3)c3ccccc32)cc(C)c1OCc1ccccc1
Temperature: -70 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
Dissolve 5-bromo-1,3-dimethyl-2-(phenylmethoxy)-benzene (2.56 g, 8.8 mmol) in ethylene glycol dimethyl ether (40 mL) under nitrogen. Cool to −70° C. with a dry ice/acetone bath and add slowly a 1.7M solution of t-butyllithium in pentane (10.4 mL, 17.6 mmol). After 15 min add 1-benzyl-1H-indole-2,3-dione (1.90 g, 8 mmol) in ethylene glycol dimethyl ether (32 mL). Remove the bath and allow to warm to room temperature with stirring for 18 h. Quench with saturated NH4Cl solution and extract with ethyl acetate (2×). Wash combined organics with brine and then dry (Na2SO4), filter and concentrate in vacuo to give 3.42 g of a dark purple oil. Purify initially by flash chromatography (25% EtOAC/hexanes) to give 1.20 g of material which by TLC is mostly starting material and product. Purify further by chromatography (step gradient of CH2Cl2, 5% acetonitrile/CH2Cl2, 10% acetonitrile/CH2Cl2) to give 803 mg (22%) of the title compound as a yellow foam. MS (ES): m/z=432 (M+1−H2O); 1H NMR(DMSO-d6); δ7.50-7.18 (m, 12H), 7.00 (m, 2H), 6.95 (s, 2H), 6.77 (s, 1H), 4.93 (q, J=2 Hz, J=18 Hz, 2H), 4.77 (s, 2H), 2.20 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1COc1cccc(Cl)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(3-chlorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[C:9]([NH:13][NH2:14])([CH3:12])([CH3:11])[CH3:10]>C(O)C>[C:9]([N:13]1[C:6]([NH2:7])=[CH:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:14]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)NN
Reactant: N#CCC(=O)C1CC1
Solvent: CCO
Product: CC(C)(C)n1nc(C2CC2)cc1N

Procedure:
1-tert-Butyl-3-cyclopropyl-1H-pyrazol-5-amine was prepared by reacting 3-cyclopropyl-3-oxopropanenitrile (5.0 mmol, 545 mg) and tert-butylhydrazine (3.5 mmol, 440 mg) in ethanol under reflux conditions for 6 h. Solvent was removed in vacuo. 1H NMR (400 MHz) CDCl3: 5.36 (s, 1H), 3.61 (s, 1H), 2.51-2.45 (m, 1H), 1.75 (s, 9H, t-Bu), 1.107-1.104 (m, 2H), 0.73-0.72 (m, 2H).
Reaction SMILES: Cl[Sn](Cl)(Cl)Cl.[CH3:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]=1.[CH3:16][O:17]C(Cl)Cl.Cl>C(Cl)Cl>[CH3:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[CH:16]=[O:17]
Reactant: COC(Cl)Cl
Reactant: Cc1cc2ccccc2s1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1sc2ccccc2c1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
SnCl4 (20 mL, 67 mmole) was added over 5 min to a stirred solution of 2-methylbenzo[b]thiophene (5.0 g, 33.7 mmole) in CH2Cl2 (75 mL) at 0° C. under argon. After 15 minutes, dichloromethyl methyl ether (3.7 mL, 41 mmole) was added. The reaction became a yellowish colored suspension. The reaction was allowed to warm to RT and stirred for 16 h, then was poured onto ice water (200 mL). The aqueous mixture was acidified with 1.0 N HCl (100 mL) and stirred until the suspension dissolved. The organic phase was separated, dried (MgSO4), and concentrated under vacuum. Purification by flash chromatography on silica gel (10% ethyl acetate/hexane) gave the title compound (5.83 g, 98%) as a white crystalline solid: 1H NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 8.61 (d, J=8.1 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.48 (t, 1H), 7.39 (t, 1H), 2.93 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:16]=2)[N:11]=1.C(O)C>O>[O:20]([C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccco1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc2ccc(Oc3ccccc3)nc2n1)c1ccco1
Temperature: 4 °C
Yield: 86.7 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2-furancarboxylic acid (7.5 g), N,N'-carbonyldiimidazole (10.9 g) and 2-amino-7-phenoxy-1,8-naphthyridine (11.9 g). The product produced by precipitation in water (15.7 g; m.p. 164° C.) is dissolved in boiling ethanol (200 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (15 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-2-furancarboxamide (14.4 g) is produced, m.p. 167° C.