Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([C:10]2([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:9])=[N:4][CH:3]=1.[OH-].[K+].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30]>C(O)C>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30][C:2]1[S:6][C:5]([NH:7][C:8]([C:10]2([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:9])=[N:4][CH:3]=1
Reactant: Sc1ccccc1Cl
Reactant: COc1ccc(C2(C(=O)Nc3ncc(Br)s3)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2(C(=O)Nc3ncc(Sc4ccccc4Cl)s3)CC2)cc1
Yield: 26 %

Procedure:
1-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid (5-bromo-thiazol-2-yl)-amide (35 mg, 0.10 mmol) was dissolved in ethanol (0.50 mL) containing potassium hydroxide (11 mg, 0.20 mmol). 2-Chloro-benzenethiol (11 L, 0.10 mmol) is added and the mixture is subjected to microwave irradiation for 15 minutes at 115° C. The crude reaction mixture is then separated by reverse-phase preparative liquid chromatography to yield the pure product (11 mg, 0.026 mmol, 26%). ESI-MS m/z calc. 416.0. found; 417.1 (M+1)+ Retention time 4.03 minutes.
Reaction SMILES: NC1C=C(N2CCOCC2)C=CC=1O.C[O:16][C:17]1[C:22]2[N:23]=[C:24]([NH:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:25][C:21]=2[C:20]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:19][CH:18]=1>>[OH:16][C:17]1[C:22]2[N:23]=[C:24]([NH:26][C:27](=[O:34])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[S:25][C:21]=2[C:20]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccccc3)nc12
Agent: Nc1cc(N2CCOCC2)ccc1O
Product: O=C(Nc1nc2c(O)ccc(N3CCOCC3)c2s1)c1ccccc1

Procedure:
The title compound was prepared using 2-amino-4-morpholin-4-yl-phenol as described for N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide and obtained as a light brown solid in 14% overall yield, MS: m/e=356(M+H+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:17][CH:18]([CH2:22][CH2:23]Br)[C:19](Cl)=[O:20].[OH-].[K+]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Br:17][CH:18]1[CH2:22][CH2:23][N:9]([C:5]2[C:6]([CH3:8])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:19]1=[O:20]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: Cc1nc(Br)ccc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1nc(Br)ccc1N1CCC(Br)C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 500 mL round-bottom flask was charged with 6-bromo-2-methylpyridin-3-amine (8.15 g, 43.6 mmol), THF (180 mL) and triethylamine (9.72 mL, 69.7 mmol). The mixture was cooled to 0° C. and 2,4 dibromobutanoyl chloride (6.39 mL, 48.4 mmol) in THF (45 mL) was added dropwise into the reaction mixture over 30 min. A LC/MS analysis indicated the consumption of the starting material in 1 hour at room temperature. To the reaction mixture was added tetrabutylammonium bromide (0.702 g, 2.179 mmol), followed by 20 mL of 5 M aq KOH solution dropwise. The reaction mixture was stirred at room temperature under argon overnight. A LC/MS analysis confirmed the reaction was complete. Ethyl acetate (50 mL) was added to the reaction. The organic layer was separated and washed with water (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated to a dark solid (18.5 g), which was used directly to next step. MS (ESI) 334 (M+H).
Reaction SMILES: BrC1C=C(CCO)C=CC=1C.[Br:12][C:13]1[CH:14]=[C:15]([CH2:21][C:22](O)=[O:23])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].BrC1C=C(CC(O)=O)C=CC=1C>>[Br:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][OH:23])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(CC(=O)O)cc1Br
Agent: Cc1ccc(CC(=O)O)cc1Br
Agent: Cc1ccc(CCO)cc1Br
Product: COc1ccc(CCO)cc1Br

Procedure:
By working as described for preparation 1b), but using compound 2a) from the previous step instead of compound 1a), the title compound is obtained.
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:40])[C:5]1[CH:9]=[C:8]([CH:10]([F:12])[F:11])[N:7]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[S:23][CH:24]=[C:25]([C:27]4[CH2:31][CH:30]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[CH2:38]Cl)[O:29][N:28]=4)[N:26]=3)[CH2:18][CH2:17]2)=[O:15])[N:6]=1.O.ClCCl.[CH3:45][O:46][CH2:47][CH2:48][OH:49]>>[F:3][CH:4]([F:40])[C:5]1[CH:9]=[C:8]([CH:10]([F:12])[F:11])[N:7]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[S:23][CH:24]=[C:25]([C:27]4[CH2:31][CH:30]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[CH2:38][O:49][CH2:48][CH2:47][O:46][CH3:45])[O:29][N:28]=4)[N:26]=3)[CH2:18][CH2:17]2)=[O:15])[N:6]=1
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4CCl)C3)cs2)CC1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCCOCc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Methoxyethanol (1.5 ml) was admixed at room temperature with sodium hydride (60%, 17 mg) and then stirred at room temperature for 2 hours. To this mixture was added dropwise a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(chloromethyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone (0.20 g) in 2-methoxyethanol (1.5 g), and the mixture was then stirred at room temperature for 16 hours. Subsequently, the reaction mixture was admixed with water and dichloromethane. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(5-{2-[(2-methoxyethoxy)methyl]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (0.11 g).
Reaction SMILES: [CH:1]1([C:5]2[C:6]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[CH:21]1([CH2:24][C:25]([C:28]2[N:32]=[C:31]([CH3:33])[O:30][N:29]=2)([NH2:27])[CH3:26])[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][C:25]([NH:27][C:11]([C:8]2[CH:7]=[C:6]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])[C:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)=[CH:10][N:9]=2)=[O:13])([CH3:26])[C:28]2[N:32]=[C:31]([CH3:33])[O:30][N:29]=2)[CH2:23][CH2:22]1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CCC1)C(F)(F)F
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3CCC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 23b, using 5-Cyclobutyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 110e) and 1-cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-amine (Example 66d) as starting materials and isolated (85 mg, 68%) as colorless oil; MS (ESI, m/z): 453.6 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][C:17]1[CH:18]=[C:19]([CH:45]=[CH:46][CH:47]=1)[CH2:20][N:21]([S:33]([C:36]1[C:41]([CH3:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=1[CH3:44])(=[O:35])=[O:34])[C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30](O)=[O:31])=[CH:24][CH:23]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[N:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][C:30](=[O:31])[CH:29]=[CH:28][C:25]2[CH:26]=[CH:27][C:22]([N:21]([CH2:20][C:19]3[CH:45]=[CH:46][CH:47]=[C:17]([O:16][CH:11]4[CH2:12][CH2:13][CH2:14][CH2:15][O:10]4)[CH:18]=3)[S:33]([C:36]3[C:41]([CH3:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=3[CH3:44])(=[O:35])=[O:34])=[CH:23][CH:24]=2)=[CH:5][CH:6]=1
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(C=CC(=O)O)cc2)c(C)c1
Reactant: NCCc1ccncc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(C=CC(=O)NCCc3ccncc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 102.5 %

Procedure:
A solution of 4-(2-aminoethyl)pyridine (0.017 g, 0.14 mmol) in 0.3 mL methylene chloride was added to 3-{4-[[3-(tetrahydro-pyran-2-yloxy)-benzyl]-(2,4,6-trimethyl-benzenesulfonyl)-amino]-phenyl}-acrylic acid (0.050 g, 0.09 mmol). Triethylamine (0.07 mL, 0.50 mmol), 1-propanephosphonic acid cyclic anhydride (0.06 mL of a 50 wt. % solution in ethyl acetate, 0.20 mmol), and catalytic DMAP were added. The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added and the aqueous solution was washed with methylene chloride. The organic layer was separated, PS-trisamine resin (0.050 g) was added, and the mixture was stirred at room temperature for three days. The resin was filtered off and the filtrate was concentrated to afford 0.059 g of the title compound of Step A. MS 640.4 (M+1)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:4].C([N:31]=[C:32]=[S:33])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.C(NCC)C>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:32](=[S:33])[NH2:31])[N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]c2ccccc12
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Solvent: CCNCC
Product: COC(=O)c1nn(C(N)=S)c2ccccc12

Procedure:
1-Thiocarbamoyl-1H-indazole-3-carboxylic acid methyl ester was prepared (113 mg) following general procedure D using 1H-Indazole-3-carboxylic acid methyl ester (120 mg, 0.69 mmol), Fmoc isothiocyanate (213 mg, 0.76 mmol), and diethyl amine (0.5 mL). LCMS m/z: 236 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=[N:16][NH2:17])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1F)=[O:7])[CH3:2].[I:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C:5]1[C:6](=[O:7])[C:8]2[C:9](=[C:10]([Cl:14])[CH:11]=[CH:12][CH:13]=2)[N:17]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([I:19])=[CH:21][CH:22]=2)[N:16]=1)=[O:18])[CH3:2]
Reactant: CCOC(=O)C(=NN)C(=O)c1cccc(Cl)c1F
Reactant: BrCc1ccc(I)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nn(Cc2ccc(I)cc2)c2c(Cl)cccc2c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl-3-(3-chloro-2-fluorophenyl)-2-hydrazinylidene-3-oxopropanoate [(Example 60, Step 2) 1.61 g, 5.90 mmol] and 4-iodobenzyl bromide (2.28 g, 7.68 mmol, 1.3 equiv) were dissolved in degassed N,N-dimethylformamide (20 mL), cooled to 0° C. and treated with sodium hydride (378 mg, 9.45 mmol, 1.6 equiv). After stirring for 2 hours at 0° C., the mixture was treated with ammonium chloride (25 mL, 25% aqueous), warmed to ambient temperature, diluted with water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed once with water and brine, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 20:80; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [C:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([N+:19]([O-:21])=[O:20])=[CH:11][C:10]=1[NH:22][C:23](C(OCC)=O)=[O:24])(C(OCC)=O)=[O:2]>Cl>[OH:2][C:1]1[C:23]([OH:24])=[N:22][C:10]2[CH:11]=[C:12]([N+:19]([O-:21])=[O:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]=2[N:8]=1
Reactant: CCOC(=O)C(=O)Nc1cc([N+](=O)[O-])c2ccccc2c1NC(=O)C(=O)OCC
Agent: Cl
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2ccccc12
Reaction time: 3 h

Procedure:
A suspension of 1,2-diethoxalylamino-4-nitronapthalene (3.0 g, 7.4 mmol) in 100 ml of 4M hydrochloric acid was refluxed with stirring for 3 h. The mixture was cooled, and the product was isolated by filtration and washed wi water, ethanol and ether. Yield 1.8 g (94%), m.p. >300° C., IR (KBr): 1710 cm-1,1H-NMR (DMSO-d6 ): 7.47-7.83 (m, 2H, ArH), 8.21 (s, 1H,H-5), 8.33-8.73 (m, 2H, ArH), 12.25 (s, 1H,0H), 12,40 (s,1H,0H).
Reaction SMILES: [C:1]([C:5]([C:8]([Cl:11])(Cl)Cl)([F:7])[F:6])([F:4])([F:3])[F:2].[OH:12]S(O)(=O)=O.O=S(=O)=O.BrBr>>[C:1]([C:5]([C:8]([Cl:11])=[O:12])([F:7])[F:6])([F:4])([F:3])[F:2]
Reactant: FC(F)(F)C(F)(F)C(Cl)(Cl)Cl
Reactant: O=S(=O)(O)O
Agent: BrBr
Agent: O=S(=O)=O
Product: O=C(Cl)C(F)(F)C(F)(F)F
Yield: 73 %

Procedure:
In the test apparatus as described in Example I, and following the procedure of Example I, 75 g (0.315 mole) of CF3CF2CCl3, 100 g 65% oleum (0.80 mole as SO3) and 5 g bromine were heated from 25° C. to 60° C. over a 5 hour period. Fractional distillation of the cold trap product, 50 g, gave 42 g (0.23 mole) of CF3CF2COCl, bp 9° C., for a 73% conversion.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:49])C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]([OH:49])[C:16]([C:22]3[CH:23]=[C:24]([Cl:29])[CH:25]=[C:26]([Cl:28])[CH:27]=3)([C:18]([F:20])([F:19])[F:21])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2O)ccc1C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (preparation of similar compounds described in, for example, EP 1,731,512) (2.83 g) in tetrahydrofuran (25 ml) that was stirred at −78° C. for 5 minutes under argon, was slowly added lithium bis(trimethylsilyl)amide (“LiHMDS”) (1M in hexane) (6.9 ml). After 3 hours at −78° C., a cold (−20° C.) solution of 2-benzenesulfonyl-3-phenyl-oxaziridine (commercially available) (2.34 g) in tetrahydrofuran (10 ml) was added quickly. The temperature was kept below −65° C. for 4 hours and 30 minutes. The reaction was quenched by addition of aqueous ammonium chloride (saturated) at −78° C. tert-Butyl methyl ether (“TBME”) was added and the phases were separated. The organic layer was washed successively with ammonium chloride and brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: heptane/TBME 9:1) to give 4-[5-(3,5-dichloro-phenyl)-4-hydroxy-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (738 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][C:14]3([CH:20]=[CH:19][C:18]4[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=4[O:16]3)[CH2:13][CH2:12][N:11]2[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].I[CH2:40][CH3:41]>C(OCC)(=O)C.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][C:14]3([CH:20]=[CH:19][C:18]4[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=4[O:16]3)[CH2:13][CH2:12][N:11]2[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:5]=[C:6]([F:9])[C:7]=1[O:8][CH2:40][CH3:41]
Reactant: CCOC(=O)CN1CCC2(C=Cc3ccccc3O2)CC1c1cc(F)c(O)c(F)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC2(C=Cc3ccccc3O2)CC1c1cc(F)c(OCC)c(F)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To ethyl (3,5-difluoro-4-hydroxyphenyl)spiro[2H-1-benzopyran-2,4′-piperidine]-1′-acetate (350 mg), cesium carbonate (412 mg) and sodium iodide (13 mg) was added N,N-dimethylformamide (9 cm3) followed by iodoethane (1.7 mole equiv.). The resulting mixtures were heated to 65° C. with stirring for 3 h. Upon cooling, the reaction was diluted with ethyl acetate (90 cm3) then washed with water (5×35 cm3) and dried (Na2SO4). This solution of crude material was then filtered through a pad of silica before the solvent was removed in vacuo to afford the product in a homogeneous state.
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12](#[N:14])[CH3:13].C[O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2)=[CH:21][CH:20]=1)=O>O1CCCC1>[C:12]([CH2:13][C:17]([C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]2[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2)=[CH:23][CH:24]=1)=[O:16])#[N:14]
Reactant: COC(=O)c1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C(=O)CC#N)cc2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium 1.6 M in hexane (1.63 ml, 2.61 mmol) was diluted with tetrahydrofuran (2 ml) and cooled to −78° C. Acetonitrile (107 mg, 0.137 ml, 2.61 mmol) was added dropwise and stirring was continuing for 1 hour. (S)-tert-butyl 2-(4-(methoxycarbonyl)phenyl)morpholine-4-carboxylate (420 mg, 1.31 mmol) dissolved in tetrahydrofuran was slowly added to the white slurry over a 10 min period. After 3 hours, the reaction was quenched by addition of saturated ammonium chloride solution (5 ml) and extracted with diethyl ether (10 ml). The organic layer was dried over MgSO4 and evaporated.
Reaction SMILES: [Na].[CH2:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH2:3][CH3:4].Cl.[CH:14]([N:17]([CH2:21][CH2:22]Cl)[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>C(O)C>[CH2:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:22][CH2:21][N:17]([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])[CH2:3][CH3:4]
Reactant: CCCOc1ccccc1O
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCOc1ccccc1OCCN(C(C)C)C(C)C

Procedure:
The compound was prepared as described in Example 1, using sodium (3.45 g; 150 mole), 0-propoxyphenol (11.4 g; 75 mmole) and diisopropylaminoethylchloride hydrochloride (15.0 g; 75 mmole) in 200 ml of ethanol. Yield 12.7 g (64%) of product, boiling at 109°-110° C under a pressure of 0.001 mm.Hg, nD25 : 1.4961. Calcd. for C17H29NO2 : C 73.07%, H 10.46%, N 5.01%. Found C 73.2% H 10.5%, N 4.96%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][N:18]([C@@H](C3C=CC(O)=CC=3)C)[C:17](=[O:29])[CH2:16]2)[CH3:14])[C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.C(O)(C(F)(F)F)=O>>[OH:1][C:2]1[CH:3]=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][NH:18][C:17](=[O:29])[CH2:16]2)[CH3:14])[C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1nc2cc(O)cc(O[C@H](C)[C@@H]3CC(=O)N([C@H](C)c4ccc(O)cc4)C3)c2s1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cc(O)cc(O[C@H](C)[C@H]3CNC(=O)C3)c2s1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
The crude product from Step 4 was dissolved in TFA (10 mL, 130 mmol). The resulting solution was heated to 70° C. After stifling 17 h, the reaction mixture was concentrated, and the resulting residue was dissolved in EtOAc (100 mL) and washed with a 1:1 mixture of brine and saturated NaHCO3 (100 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (50 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated to afford (R)-4-((R)-1-(5-hydroxy-2-methylbenzo[d]thiazol-7-yloxy)ethyl)pyrrolidin-2-one that was used without further purification.
Reaction SMILES: [SH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:46]([O:48][C:49](=[O:56])/[CH:50]=[C:51](\[CH3:55])/[CH2:52][CH2:53]O)[CH3:47]>C(OCC)(=O)C.C1COCC1>[CH2:46]([O:48][C:49](=[O:56])/[CH:50]=[C:51](\[CH3:55])/[CH2:52][CH2:53][S:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1)[CH3:47]
Reactant: CCOC(=O)/C=C(\C)CCO
Reactant: Sc1nnnn1-c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C(\C)CCSc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
This reaction was performed with reference to the literature (Mitsunobu, O., Synthesis, 1981, 1-28.). 5-Mercapto-1-phenyltetrazole (16.30 g, 91.20 mmol), triphenylphosphine (27.30 g, 104 mmol) and diisopropyl azodicarboxylate (95%, 21.10 g, 104 mmol) were added to a THF (410 ml) solution of ethyl-(2E)-5-hydroxy-3-methylpent-2-enoate (13.80 g, 86.90 mmol) while ice cooling. The reaction solution was warmed to room temperature and stirred for four hours. After the reaction solution was diluted with ethyl acetate, it was washed with distilled water and brine. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane:ethyl acetate=5:1) to obtain the title compound (27.16 g) as a white solid.
Reaction SMILES: [O:1]=[C:2]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:3][CH2:4][C:5]1[S:9][C:8]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C@H:19]3[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[O:12])=[N:7][N:6]=1.[BH4-].[Na+].CN(C=O)C.O>CO>[OH:1][CH:2]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:3][CH2:4][C:5]1[S:9][C:8]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C@H:19]3[CH2:20][CH2:21][C@H:22]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)=[O:12])=[N:7][N:6]=1
Reactant: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(CCC(=O)c4ccccc4)s3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(CCC(O)c4ccccc4)s3)cc2)CC1

Procedure:
0.159 g of tert-butyl trans-(4-{4-[5-(3-oxo-3-phenylpropyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenyl}cyclohexyl)acetate (0.3 mmol, 1 eq.) is placed in 5 mL of methanol with stirring. The reaction medium is cooled on an ice bath and 0.012 g of sodium borohydride (0.33 mmol, 1.1 eq.) is added. 3 mL of DMF are added. After stirring for 16 hours, the reaction medium is cooled on an ice bath and 0.023 g of sodium borohydride (0.6 mmol, 2 eq.) and 3 mL of DMF are added. After stirring for 2 hours, the reaction medium is poured into water and extracted twice with ethyl acetate. The organic phase is washed three times with water, dried over magnesium sulfate and evaporated to give 0.146 g of tert-butyl trans-(4-{4-[5-(3-hydroxy-3-phenylpropyl)-[1.3.4]thiadiazol-2-ylcarbamoyl]phenyl}cyclohexyl)acetate,
Reaction SMILES: [N:1]1([C:7]2[N:8]=[N:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>ClCCl>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[N:9]=[N:8][C:7]([N:1]2[CH2:2][CH2:3][N:4]([C:30]([C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[C:27]([F:26])([F:37])[F:38])=[O:31])[CH2:5][CH2:6]2)=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: c1ccc(-c2ccc(N3CCNCC3)nn2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(-c3ccccn3)nn2)CC1
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a stirred mixture of 3-piperazin-1-yl-6-pyridin-2-ylpyridazine (0.240 g, 1.000 mmol) and triethylamine (0.7 mL) in dichloromethane (15 mL) at room temperature was added 2-trifluoromethylbenzoyl chloride (0.210 g, 1.000 mmol). After 15 minutes, the mixture was washed with citric acid and NaHCO3. The organic layer was separated, dried over anhydrous MgSO4 and evaporated to yield solid residue, which was crystallized from ether to afford the title compound as a white solid in 23% yield (0.097 g). 1H NMR (300 MHz, CDCl3) δ 8.6 (d, J=4.4 Hz, 1H), 8.5 (d, J=8.0 Hz, 1H), 8.3 (d, J=9.5 Hz, 1H), 7.8 (m, 1H), 7.7 (d, J=7.7 Hz, 1H), 7.6 (t, J=7.3 Hz, 1H), 7.5 (t, J=7.5 Hz, 1H), 7.35 (d, J=7.3 Hz, 1H), 7.28 (m, 1H), 7.0 (d, J=9.5 Hz, 1H), 4.1-3.6 (m, 6H), 3.35-3.31 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.6, 159.3, 153.9, 151.4, 148.9, 137.0, 134.4, 132.3, 127.3, 126.8, 123.6, 120.3, 113.1, 46.5, 44.9, 44.6, 41.3. MS (ES+) m/z 414.1 (M+1).