Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:35]1[CH2:38][CH:37]([N:39]2[CH2:44][C@H:43]([CH3:45])[O:42][C@H:41]([CH3:46])[CH2:40]2)[CH2:36]1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:35]4[CH2:38][CH:37]([N:39]5[CH2:44][C@H:43]([CH3:45])[O:42][C@H:41]([CH3:46])[CH2:40]5)[CH2:36]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: C[C@@H]1CN(C2CNC2)C[C@H](C)O1
Product: C[C@@H]1CN(C2CN(C3=NC(=O)C(=Cc4ccc5c(cnn5Cc5ccc(C(F)(F)F)cc5C(F)(F)F)c4)S3)C2)C[C@H](C)O1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(2,6-cis-dimethylmorpholin-4-yl)azetidin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4-Azetidin-3-yl-2,6-(cis)-dimethyl-morpholine following General Procedure C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([Cl:13])[N:6]=[C:7]2Cl.[CH3:14][O-:15].[Na+]>O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([Cl:13])[N:6]=[C:7]2[O:15][CH3:14]
Reactant: Clc1cc2c(Br)cccc2c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1nc(Cl)cc2c(Br)cccc12
Temperature: 70 °C

Procedure:
A mixture of 5-bromo-1,3-dichloroisoquinoline (580 mg, 2.1 mmol) and NaOMe (0.5 M in MeOH, 5.0 mL, 2.5 mmol) was heated at 70° C. for one hour. The mixture was poured into water then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, then concentrated to afford the title compound: 1H NMR (500 MHz, CDCl3): δ 8.23 (d, J=9.0 Hz, 1H), 7.96 (d, J=7.5 Hz, 1H); 7.65 (s, 1H), 7.39 (t, J=8.5 Hz, 1H), 4.20 (s, 3H). LC6: 3.86 min. (M+H) 272.
Reaction SMILES: [O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5]Cl.[I-].[Na+].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5][N:30]1[CH2:29][CH2:28][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=2)[CH2:32][CH2:31]1
Reactant: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(C(=O)CCCN3CCN(c4cccc(Cl)c4)CC3)ccc2N1
Reaction time: 2 h

Procedure:
5.0 Grams of 6-(1-oxo-4-chlorobutyl)-3,4-dihydrocarbostyril and 7.5 g of sodium iodide were dispersed in 120 ml of anhydrous dimethylformamide and the mixture was stirred at 50°-60° C. for 2 hours. To this reaction mixture were added 10 g of 4-(3-chlorophenyl)piperazine and 5 ml of triethylamine and was stirred at 50°-60° C. for 6 hours, then stirred at a room temperature for 24 hours. The reaction mixture was concentrated under a reduced pressure to obtain a residue. To the residue thus obtained was added 80 ml of 5%-sodium hydrogencarbonate solution and the organic layer was extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation. The residue thus obtained was crystallized with ether to obtain crude crystals and the crude crystals were recrystallized from ethanol to obtain 6.5 g of 6-{1-oxo-4-[4-(3-chlorophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril in colorless needle-like crystals.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[C:33]([NH:38][S:39](Cl)(=[O:41])=[O:40])(=[O:37])[CH2:34][CH2:35][CH3:36].C(N(CC)CC)C>ClCCl>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:39]([NH:38][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])(=[O:41])=[O:40])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CCCC(=O)NS(=O)(=O)Cl
Reactant: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CCC(C)C)C1=O)N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.7 %

Procedure:
A mixture of the product of Example 34B (52.2 mg, 0.110 mmol) and the product of Example 99A (102 mg, 0.55 mmol) in dichloromethane (5 mL) was treated with triethylamine (66.5 mg, 0.658 mmol). The mixture was stirred at r.t. for 15 minutes. The reaction mixture was partitioned between dichloromethane and 1N hydrochloric acid, and the aqueous phase extracted with additional dichloromethane. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by HPLC to give the title compound (38 mg, 59%). 1H NMR (300 MHz, DMSO-d6) δ 0.41 (m, 1H) 0.69 (m, 9H) 0.79 (m, 1H) 1.37 (m, 4H) 1.56 (s, 3H) 2.04 (m, 1H) 2.11 (t, J=7.35 Hz, 2H) 2.22 (m, 1H) 7.48 (dd, J=8.82, 2.21 Hz, 1H) 7.53 (m, 1H) 7.59 (d, J=2.21 Hz, 1H) 7.71 (d, J=8.82 Hz, 1H) 7.76 (d, J=4.04 Hz, 2H) 8.15 (d, J=7.72 Hz, 1H) 10.95 (s, 1H) 11.99 (s, 1H) 13.81 (s, 1H). MS (ESI+) m/z 589.1 (M+H)+, 606.1 (M+NH4)+, (ESI−) 587.2 (M−H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[C:5](Br)=[C:6](Br)[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+].[Br-:14].C([N+](CC)(CC)CCCCC)C>C(Cl)Cl>[Br:1][C:2]([Br:14])=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [Br-]
Reactant: BrCCc1cccc(Br)c1Br
Agent: CCCCC[N+](CC)(CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: BrC(Br)=Cc1ccccc1

Procedure:
A solution of 147.90 g. (0.431 mole) of 2-bromoethyldibromobenzene in 250 ml. of methylene chloride was stirred for 7 ks (2 hours) at 5 Hz (300 rpm) at 313 K. (40° C.) with 150 g (2.25 mole) of 60 percent sodium hydroxide solution and 3.12 g. (0.0124 mole) of triethylpentyl ammonium bromide. The product was washed with three 500-ml portions of water, dried over calcium sulfate (Drierite), and stripped of solvent in a rotary evaporator at a bath temperature of 323 K. (50° C.). The yield of product was 106.97 g. (77.2 per cent of theory). GC analysis showed 27.1 percent of the desired ar-dibromostyrene, the remainder being largely unreacted starting material.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:15]1[CH:16]=[C:17]([NH2:22])[C:18]([NH2:21])=[CH:19][CH:20]=1.[F-].[Cs+].[CH:25]1(N)CCCCC1N.C(OCC)(OCC)OCC>[Cu]I>[NH:22]1[C:17]2[CH:16]=[CH:15][C:20]([N:9]3[C@@H:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:12][O:11][C:10]3=[O:13])=[CH:19][C:18]=2[N:21]=[CH:25]1
Reactant: NC1CCCCC1N
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: Nc1ccc(I)cc1N
Agent: [Cu]I
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(OCC)OCC
Product: O=C1OC[C@H](Cc2ccccc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from (S)-4-benzyloxazolidin-2-one (0.089 g, 0.5 mmol), 4-iodobenzene-1,2-diamine (0.117 g, 0.5 mmol), copper(I) iodide (0.010 g, 0.05 mmol), cesium fluoride (0.276 g, 1 mmol), cyclohexane-1,2-diamine (0.006 mL, 0.05 mmol), triethyl orthoformate (3 mL) as described in method 5 step D.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10]([C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH:19]=[N:20][N:21]([CH3:22])[C:3]=12.C(=O)([O-])[OH:24].[Na+]>C(O)(=O)C>[ClH:1].[NH2:16][C:15]1[CH:17]=[CH:18][C:12]([C:10]2[C:11]3[C:2](=[O:24])[C:3]4[N:21]([CH3:22])[N:20]=[CH:19][C:4]=4[NH:5][C:6]=3[CH:7]=[CH:8][CH:9]=2)=[CH:13][CH:14]=1
Reactant: O=C([O-])O
Reactant: Cn1ncc2nc3cccc(-c4ccc(N)cc4)c3c(Cl)c21
Agent: [Na+]
Solvent: CC(=O)O
Product: Cl
Product: Cn1ncc2[nH]c3cccc(-c4ccc(N)cc4)c3c(=O)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
A mixture of 4-(9-chloro-1-methyl-1H-pyrazolo[4,3-b]quinolin-8-yl)aniline (EXAMPLE 41, step 2, 41 mg, 0.13 mmol) in 50% aqueous acetic acid (2 ml) was refluxed for 18 h. After cooling to room temperature, saturated sodium hydrogen carbonate (5 ml) was added to the mixture. The formed solid was collected by filtration, washed with water and dried. The obtained solid was dissolved in 10% methanolic hydrochloric acid (3 ml) and the mixture was stirred at room temperature for 18 h. The mixture was concentrated and recrystallized from ethanol to afford 19 mg (46%) of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[C:9](OC)(=[O:12])[CH2:10][CH3:11].ClCCl>CO>[NH:1]1[C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=2[CH:11]=[CH:10][C:9]1=[O:12]
Reactant: NC1=CC(=O)CCC1
Reactant: CCC(=O)OC
Solvent: ClCCl
Solvent: CO
Product: O=C1CCCc2[nH]c(=O)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
With stirring, 113.79 g (1.02 mol) of 3-aminocyclohex-2-en-1-one and 114.37 ml (1.19 mol) of methyl propionate were heated at 105° C. for 1 hour. The dark homogeneous solution formed was then slowly heated further to 170° C. After 20 min (temperature: 135° C.), a viscous material formed, and there was a marked evolution of gas. After a further 15 min (temperature: 160° C.), the reaction material became even more viscous while the evolution of gas subsided. After a total of 42 min, a temperature of 170° C. had been reached. After a further 13 min at this temperature, the reaction material was cooled to room temperature. 200 ml of dichloromethane were then added, the mixture was heated briefly and placed into an ultrasonic bath and the crystalline residue formed was filtered off. This procedure was repeated once more with a further 200 ml of dichloromethane. The crystalline residues obtained in this manner were combined, taken up in 1.6 liters of methanol and then heated with stirring until the solid had dissolved completely. This solution was then slowly cooled to room temperature and then stored in a fridge at about 4° C. for 2 days. The crystalline precipitate was filtered off and dried under reduced pressure. This gave 47.65 g (0.29 mol, 29% of theory) of the target product.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].BrCC1OC(C(F)(F)F)=CC=1.[F:18][C:19]1[C:20]([F:37])=[CH:21][C:22]2[O:36][CH2:35][C:25]3([C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:34])[C:23]=2[CH:24]=1.CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[F:18][C:19]1[C:20]([F:37])=[CH:21][C:22]2[O:36][CH2:35][C:25]3([C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])[C:26]3=[O:34])[C:23]=2[CH:24]=1
Reactant: O=C1Nc2ccccc2C12COc1cc(F)c(F)cc12
Reactant: CC(C)CCBr
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CC(C)CCN1C(=O)C2(COc3cc(F)c(F)cc32)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 1-bromo-3-methylbutane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 5,6-difluoro-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (96%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.34 (t, J=7.7 Hz, 1H), 7.16-7.04 (m, 2H), 6.93 (d, J=7.8 Hz, 1H), 6.77 (dd, J=10.3, 6.3 Hz, 1H), 6.50 (t, J=8.5 Hz, 1H), 4.95 (d, J=9.1 Hz, 1H), 4.70 (d, J=9.1 Hz, 1H), 3.88-3.67 (m, 2H), 1.72-1.60 (m, 3H), 1.01 (d, 6.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ176.3, 156.6 (d, JC-F=11.0 Hz), 151.1 (dd, JC-F=248.1, 14.5 Hz), 145.6 (dd, JC-F=241.3, 14.0 Hz), 142.3, 131.6, 129.2, 123.8, 123.3, 111.5 (d, J=20.5 Hz), 108.7, 99.9 (d, J=22.3 Hz), 80.7, 57.7, 38.8, 36.0, 26.0, 22.4, 22.3; MS (ES+) m/z 344.4 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][CH:15]([S:18](Cl)(=[O:20])=[O:19])[CH2:14][CH2:13]1.[NH3:22].C1COCC1>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][CH:15]([S:18]([NH2:22])(=[O:20])=[O:19])[CH2:14][CH2:13]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(S(=O)(=O)Cl)CC1
Reactant: N
Solvent: C1CCOC1
Product: NS(=O)(=O)C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-sulfonyl chloride (5 g, 15.2 mmol) in NH3/THF (150 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was dissolved into about 100 mL of hot water and the solid was filtered under hot condition. The filtrate was concentrated in vacuo to give 4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-sulfonamide (3 g, 64%) as an off-white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([SiH2:7][CH:8](Cl)Cl)=[CH:4][CH2:5][Cl:6].C1[CH2:15][O:14]CC1.[CH3:16][OH:17].N(CC)(CC)CC>CCOCC>[Cl:1][CH2:2][C:3]([SiH2:7][CH:8]([O:14][CH3:15])[O:17][CH3:16])=[CH:4][CH2:5][Cl:6]
Reactant: CO
Reactant: C1CCOC1
Reactant: ClCC=C(CCl)[SiH2]C(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(OC)[SiH2]C(=CCCl)CCl
Yield: 80 %

Procedure:
11.5 g (48 mmols) of 1,4-dichloro-2-(dichloromethyl)silyl-2-butene, 1.0 ml of THF, 5.9 ml (48×2×1.5 mmols) of CH3OH, 20 ml (48×2×1.5 mmols) of (C2H5)3N, and 30 ml of (C2H5)2O were used and subjected to vacuum distillation, thereby obtaining 8.8 g of 1,4-dichloro-2-(dimethoxymethyl)silyl-2-butene.
Reaction SMILES: N1C=CC=CC=1.[S:7]([NH:11][C:12]([NH2:14])=[O:13])([CH3:10])(=[O:9])=[O:8].[C:15](Cl)([Cl:17])=[O:16]>ClCCl>[S:7]([NH:11][C:12]([NH:14][C:15]([Cl:17])=[O:16])=[O:13])([CH3:10])(=[O:9])=[O:8]
Reactant: CS(=O)(=O)NC(N)=O
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC(=O)NC(=O)Cl

Procedure:
6.1 parts by volume of pyridine were added dropwise, while cooling, to a mixture of 10.5 parts by weight of N-mesylurea, 60 parts. by volume of dichloromethane and 15.0 parts by weight of phosgene, while cooling, and after some hours at 0°C the excess of the phosgene was removed, the precipitate present was filtered off and the filtrate was completely concentrated in vacuo. A viscous oil remained, which had an absorption at 1800 cm-1 in the carbonyl region of the IR-spectrum. The substance was used without further purification for the production of the penicillin.
Reaction SMILES: [OH:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:17]([CH:19]1[O:21][CH2:20]1)[Cl:18]>N1CCCCC1>[Cl:18][CH2:17][CH:19]([OH:21])[CH2:20][O:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: O=c1c2ccccc2oc2c(O)cccc12
Solvent: C1CCNCC1
Product: O=c1c2ccccc2oc2c(OCC(O)CCl)cccc12
Yield: 38 %

Procedure:
A mixture of 4-hydroxy-9-oxoxanthene (1.1 g), epichlorohydrin (4 g) and piperidine (0.01 g) is heated on a boiling water-bath for 5 hours. Excess epichlorohydrin is then removed by distillation and the residue is dissolved in ethyl acetate (50 ml). The organic solution is washed with 2N NaOH (20 ml) and concentrated to dryness yielding 1-chloro-2-hydroxy-3-(9-oxoxanth-4-yloxy)propane (0.6 g) as a raw product. A solution of this product in absolute ethanol (20 ml) is then added to a solution of 2-aminotetralin (0.3 g) in ethanol (10 ml) and the mixture is refluxed for 4 hours and then evaporated to dryness. The obtained residue is taken up in hydrogen chloride saturated-isopropanol affording the desired N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy -3-oxoxanth-4-yloxypropanamine hydrochloride ((i): R=H, Ar=radical 29, wherein Z is >C=0, and the chain is attached to position 2 of the tetralin moiety)(Ex. 91). Analogously, but starting from 4-hydroxyxanthene, N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-xanth-4-yloxypropanamine hydrochloride is obtained ((i): R=H, Ar=radical 29, wherein Z is a methylene group, and the chain is attached to position 2 of the tetralin moiety) (Ex. 92).
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=1[F:33])[C:26](=[NH:29])[NH:27]O.O>CN1C(=O)CCC1>[F:9][C:2]1([F:1])[CH2:3][CH:4]([C:6]2[O:8][N:29]=[C:26]([C:25]3[CH:30]=[CH:31][C:32]([F:33])=[C:23]([CH:24]=3)[NH2:22])[N:27]=2)[CH2:5]1
Reactant: N=C(NO)c1ccc(F)c(N)c1
Reactant: O=C(O)C1CC(F)(F)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1cc(-c2noc(C3CC(F)(F)C3)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,3-difluorocyclobutanecarboxylic acid (0.90 g, 6.6 mmol) in NMP (5 mL) was slowly added CDI (1.07 g, 6.6 mmol). The resulting mixture was stirred at room temperature for 30 minutes. Then 3-amino-4-fluoro-N-hydroxybenzimidamide (87) (0.56 g, 3.3 mmol) was added and stirred for another 30 minutes until LCMS indicated complete reaction. The mixture was then heated at 125° C. for 15 minutes in a microwave reactor and poured into water (100 mL). The mixture was extracted with EtOAc (2×50 mL), dried over Na2SO4, filtered and concentrated to give a crude product which was purified by silica-gel chromatography (0-60% EtOAc in hexanes) to afford 5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-fluoroaniline (88). 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J=2.0, 8.4 Hz, 1H), 7.43-7.48 (m, 1H), 7.10 (dd, J=10.8, 8.4 Hz, 1H), 3.90 (br, 2H), 3.67 (m, 1H), 3.09-3.18 (m, 4H). MS m/z 270.1 (M+1)+.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.[C:11]([CH2:13][C:14]([NH2:16])=[S:15])#[N:12]>>[CH:5]1([C:3]2[N:16]=[C:14]([CH2:13][C:11]#[N:12])[S:15][CH:2]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: N#CCC(N)=S
Reactant: O=C(CBr)C1CCCCC1
Product: N#CCc1nc(C2CCCCC2)cs1
Yield: 80 %

Procedure:
This compound was synthesized from 2-bromo-1-cyclohexylethanone and 2-cyanothioacetamide as described in example 1 step 1 (0.4 g, yield 80%). 1H NMR (300 MHz, CDCl3) δ 6.88 (s, 1H), 4.11 (s, 2H), 2.74 (m, 1H), 2.06-2.04 (m, 2H), 1.84-1.72 (m, 4H), 1.44-1.31 (m, 4H). MS (ESI) m/z: Calculated for C11H14N2S: 206.09. found: 207.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]([O:17]C(C)C)=[O:16])[N:9]=2)[CH:5]=[C:4]([O:21][CH3:22])[N:3]=1.[OH-].[Li+].CCOC(C)=O.CCCCCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]([OH:17])=[O:16])[N:9]=2)[CH:5]=[C:4]([O:21][CH3:22])[N:3]=1
Reactant: COc1cc(-c2ncn(/C=C\C(=O)OC(C)C)n2)cc(Cl)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(-c2ncn(/C=C\C(=O)O)n2)cc(Cl)n1
Temperature: 25 °C
Yield: 29.6 %

Procedure:
In a 25-mL, 3N round-bottomed flask equipped with Thermometer pocket and rubber septum, (Z)-isopropyl 3-(3-(2-chloro-6-methoxypyridin-4-yl)-1H-1,2,4-triazol-1-yl)acrylate (0.7 g, 1.0 eq.) dissolve in THF (4 ml) was added lithium hydroxide (0.182 g, 2.0 eq.) (dissolved in water), resulting reaction mixture was stir at RT. The progress of the reaction was followed by TLC analysis on silica gel with 20% EtOAc-hexane as mobile phase which shows that starting material was consumed after 5 h. THF was removed under reduce pressure, aqueous layer washed with ethyl acetate then acidified to 3-5 pH and extract by ethyl acetate (30 ml×3), combined organic layer were dried over sodium sulfate and concentrate under reduce pressure to obtain crude material (0.228 g), crude material was subjected to column purification. The crude compound was purified by column chromatography using 60/120 silica gel and ethyl acetate in hexane as mobile phase. The column was packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection. The compound started eluting from 10% ethyl acetate in hexane. Fractions containing such TLC profile were collected together to obtain pure compound 0.180 g yield (29.97%); LCMS (%): 93.46% [M+H]+ 280.81 RT: 3.213 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:15])[CH:11]=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=2[OH:25])(O)[C:7]1=[O:26])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]([C:17]2[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=2[OH:25])[C:7]1=[O:26])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)C(O)(c2cc(F)c(F)cc2O)c2c(Br)cccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1C(=O)C(c2cc(F)c(F)cc2O)c2c(Br)cccc21
Temperature: 90 °C
Yield: 43.4 %

Procedure:
A mixture of ethyl[4-bromo-3-(4,5-difluoro-2-hydroxyphenyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate (0.90 g, 2.00 mmol), triethylsilane (2.00 mL, 12.2 mmol) and trifluroacetic acid (0.94 mL, 12.2 mmol) was heated at 90° C. for two days. After cooling down to ambient temperature, the mixture was diluted with ethyl acetate (200 mL), washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexanes, 1/3) to give the title compound (0.37 g, 43%): 1H NMR (300 MHz, CDCl3) δ 7.35-7.22 (m, 3H), 6.82-6.71 (m, 2H), 6.52 (t, 1H), 5.10 (s, 1H), 4.45 (s, 2H), 4.21 (q, 2H), 1.23 (t, 3H); MS (ES+) m/z 426.4 (M+1), 428.4 (M+1).
Reaction SMILES: O[C:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[S:4][N:3]=1.Cl.[NH+]1C=CC=CC=1.P(=O)(O)(O)O.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[S:4][N:3]=1
Reactant: Oc1nsc2c1CCCC2
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: O=P(O)(O)O
Agent: c1cc[nH+]cc1
Product: Clc1nsc2c1CCCC2
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of 3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisothiazole 22a (4.74 g), pyridinium hydrochloride (12.7 g), phosphoric acid (2.1 g) and phosphorus oxychloride (25 mL) was stirred at 90° C. for 5 h. The reaction mixture was evaporated and ethyl acetate (130 mL) was added to the residue. A saturated solution of sodium hydrogencarbonate (130 mL) was added and after 10 min of stirring the phases were separated. The aqueous phase was extracted with ethyl acetate (2×150 mL) and the combined organic phases were dried and evaporated to give an oil. Column chromatography on silica gel (eluent:toluene-ethyl acetate 1:1) gave the title compound as a yellow oil (2.8 g).
Reaction SMILES: [K].[NH:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[C:7]([C:11]1(CBr)[O:15][C:14]([CH3:25])([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH2:13][O:12]1)([CH3:10])([CH3:9])[CH3:8].[CH3:28]N(C)C=O>>[C:7]([C:11]1([N:2]2[CH:6]=[N:5][CH:4]=[N:3]2)[O:15][C:14]([CH3:25])([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH:13]([CH3:28])[O:12]1)([CH3:8])([CH3:9])[CH3:10]
Reactant: c1nc[nH]n1
Reactant: CN(C)C=O
Reactant: CC1(Oc2ccc(Cl)cc2Cl)COC(CBr)(C(C)(C)C)O1
Agent: [K]
Product: CC1OC(n2cncn2)(C(C)(C)C)OC1(C)Oc1ccc(Cl)cc1Cl
Reaction time: 24 h

Procedure:
3.5 g of 1,2,4-triazole potassium salt in 100 ml of absolute dimethylformamide are heated to 100°. To the hot solution are added dropwise 9 g of 2-tert-butyl-2-bromomethyl-4-(2,4-dichlorophenoxy)-methyl-1,3-dioxolane dissolved in 50 ml of absolute dimethylformamide. The reaction mixture is subsequently stirred for 24 hours at 130°; the solvent is then removed in vacuo and the residue is extracted with diethyl ether; the ether phase is washed with water and dried over sodium sulfate. The yield after concentration by evaporation is 7 g of a viscous oil which, after the addition of n-hexane, crystallises to give the cis isomer, m.p. 113°-114°. The trans isomer, m.p. 73°-74°, can be obtained from the mother liquor.