Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[CH:1]1([N:6]2[C:7]3[C:12](=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=3)[CH:13]=[CH:33][S:34]2(=[O:36])=[O:35])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ncc2c(n1)N(C1CCCC1)S(=O)(=O)C=C2
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 18.7 %

Procedure:
A solution of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (prepared as described in WO 98/33798 (incorporated herein by reference)) (30 g, 126 mmol) was suspended in dry THF (700 mL) under argon, and the mixture was cooled to −70° C. A solution of lithium bis(trimethylsilyl) amide, 1.0M in hexane (316 mL, 316 mmol) was added dropwise with stirring over 30 minutes. A solution of methanesulfonylchloride (10.5 ml, 136 mmol) in dry THF (25 mL) was added over 5 minutes, and then the reaction mixture was left to stir at −55° C. for at least 1 hour. An additional portion of methanesulfonylchloride (9 ml, 78 mmol) was added over 2 hours as the temperature was allowed to reach 0° C. The reaction was then cooled to −70° C. and left undisturbed overnight. The reaction mixture was then evaporated in vacuo to an oil and poured into a mixture of diethyl ether (1 L) and 1N citric acid solution (375 ml). The pH of the mixture was adjusted to 8 by addition of 4N NaOH, agitated, and the ether phase was decanted. The aqueous phase was extracted with diethylether, the organic phases were combined, washed with water, brine, and dried over anhydrous magnesium sulfate. After removal of the drying agent and evaporation of the solvent, the crude product was purified by chromatography on 300 g silica gel (10%–20% ethyl acetate in hexanes) to yield 7.01 g (18.7% yield) 1-Cyclopentyl-7-methylsulfanyl-1H-2-thia-1,6,8-triaza-naphthalene 2,2-dioxide as a colorless solid. MS: APCI: M+1: 298.1 (M: 297.4).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7]C)=[O:6])[CH3:2].[OH-].[K+]>CO.O>[CH2:1]([O:3][C:4]([CH3:10])([CH3:9])[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(C)(C)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A solution of methyl 2-ethoxy-2-methylpropanoate (1.6 g, 10.95 mmol) in MeOH (14 mL) was treated drop-wise with a solution of KOH (1.228 g, 21.89 mmol) in water (7 mL) and stirred at RT overnight. The mixture was treated with water, washed with Et2O (2×) and the aqueous layer was acidified to pH 2 with 2M HCl. The mixture was extracted with EtOAc (4×) and the combined organics were dried over MgSO4 and concentrated to dryness to afford 2-ethoxy-2-methylpropanoic acid (1.1 g, 76%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 12.42 (s, 1H), 3.34 (q, J=7.0 Hz, 2H), 1.28 (s, 6H), 1.06 (t, J=7.0 Hz, 3H).
Reaction SMILES: O[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C@H:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[ClH:29].O=S(Cl)[Cl:32]>C(Cl)Cl>[ClH:32].[Cl:29][CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C@H:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccc(C(O)c2ccccc2)cc1)[C@@H]1CC(c2cccnc2)=NO1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(C(Cl)c2ccccc2)cc1)[C@@H]1CC(c2cccnc2)=NO1

Procedure:
) (5S)-4,5-dihydro-N-[4-(hydroxyphenylmethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide (0.027 mol) was suspended in CH2Cl2 (250 ml). HCl, gas (excess) was allowed to bubble through the suspension for 2 minutes. SOCl2 (0.097 mol) was added dropwise and the reaction mixture was stirred and refluxed for 4 hours. The solvent was evaporated under reduced pressure. Toluene was added and azeotroped on the rotary evaporator (2×). The residue was stirred in toluene. The precipitate was filtered off, washed with toluene and dried, yielding 11.5 g (100% crude yield) of (5S)-N-[4-(chlorophenylmethyl)phenyl]4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide monohydrochloride (compound 500).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:10][CH2:9]2)C=CC=CC=1.Cl.[H][H]>C(O)C.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:10][CH2:9]1
Reactant: O=C(CCc1cccnc1)NCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Temperature: 45 °C

Procedure:
100 g (219.5 mmol) N-[4-(1-diphenylmethyl-piperidin-4-yl)-butyl]-3-(pyridin-3-yl) -propionamide (substance 54) are dissolved in 500 ml ethanol and added to 8.0 g palladium (5%) on activated carbon (moistened with 40 ml water) and 25 ml conc. hydrochloric acid. The mixture is heated to ca. 45° C. and stirred ca. five hours long under hydrogen atmosphere until the consumption of the theoretical amount of hydrogen to be taken up. After cooling, this is filtered from the catalyst and the solvent is removed under vacuum. The residue is taken up in 200 ml water and washed three times with a total of 200 ml CHCl3. The organic phases are discarded and the aqueous phase is made alkaline with 11 g sodium hydroxide and extracted three times, each with 100 ml CHCl3. After washing the organic phase with 30 ml water, the solvent is removed under vacuum. The oily residue is filtered over silica gel with CHCl3/CH3OH/NH4OH (80/20/2). Yield of a slowly hardening resin: 53.0 g (83%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][S:7][CH:8]=1.[CH:9]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:9]([N:22]1[CH2:27][CH2:26][N:25]([CH2:3][C:4]2[N:5]=[CH:6][S:7][CH:8]=2)[CH2:24][CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: ClCc1cscn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)N2CCN(Cc3cscn3)CC2)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
A mixture of 4-chloromethylthiazole monohydrochloride (1.7 g), 1-benzhydrylpiperazine (3.21 g) and potassium carbonate (5.3 g) in N,N-dimethylformamide (40 ml) was stirred at 65° C. for 2 hours. After concentration of the reaction mixture, the concentrate was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then evaporated to dryness to give a residue, which was chromatographed on silica gel (120 g) using a mixture of chloroform and methanol (50:1 by volume) as an eluent. The eluates containing the desired compound were collected and evaporated to dryness under reduced pressure to give crystals, which were recrystallized from chloroform to obtain white crystals (1.2 g) of 4-(4-benzhydrylpiperazin-1-ylmethyl)thiazole, mp 114°-116° C.
Reaction SMILES: [CH:1]1([O:11][CH2:12][C:13]#[C:14][C:15]2[C:23]3[C:18](=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[C:31]([O:33]CC)=[O:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1.CO>[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[NH:17][C:16]([C:31]([OH:33])=[O:32])=[C:15]2[C:14]#[C:13][CH2:12][O:11][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1[nH]c2c(-c3ccccc3C)cccc2c1C#CCOC1CCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1-c1cccc2c(C#CCOC3CCCc4ccccc43)c(C(=O)O)[nH]c12

Procedure:
To a solution of EXAMPLE 564B (180 mg) and 1-(prop-2-ynyloxy)-1,2,3,4-tetrahydronaphthalene (165 mg) in triethylamine (5 ml) was added bis(triphenylphosphine)palladium(II) dichloride (18.71 mg) and copper(I) iodide (4.23 mg). The reaction mixture was stirred at 70° C. for 3 hours, cooled and concentrated. The residue was dissolved in dichloromethane and purified by flash chromatography, eluting with dichloromethane, to provide ethyl 3-(3-(1,2,3,4-tetrahydronaphthalen-1-yloxy)prop-1-ynyl)-7-o-tolyl-1H-indole-2-carboxylate. This ester was hydrolyzed with aqueous NaOH in tetrahydrofuran and methanol to provide the title compound. 1H NMR (400 MHz, methanol-d4) 7.76 (dd, J=7.98, 1.23 Hz, 1H), 7.52 (dd, J=6.75, 2.46 Hz, 1H), 7.34-7.40 (m, 2H), 7.27-7.31 (m, 2H), 7.26 (d, J=7.98 Hz, 1H), 7.13-7.19 (m, 3H), 7.07-7.12 (m, 1H), 4.97 (t, J=3.99 Hz, 1H), 4.52-4.71 (m, 2H), 2.79-2.90 (m, 1H), 2.68-2.78 (m, 1H), 2.14-2.21 (m, 1H), 2.12 (s, 3H), 1.91-2.06 (m, 2H), 1.73-1.84 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]3[NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].[CH2:44](Cl)[CH:45]=[CH2:46]>>[CH3:43][O:42][C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]3[N:29]([CH2:46][CH:45]=[CH2:44])[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reactant: C=CCCl
Product: C=CCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 7.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine (prepared from (+)-1-(3,4,5-trimethoxybenzoyl)-3-(2-hydroxyethyl)-3-phenylpyrrolidine) and allyl chloride to give the title compound.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:40])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:18]([O:29][CH2:30][CH2:31][OH:32])=[C:17]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CO.CC[O:45]C(C)=O.CCOC(C)=O.[K+].[Br-]>C(O)=O>[CH2:1]([NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])[C:18]([O:29][CH2:30][C:31]([OH:45])=[O:32])=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH:20]=1)=[O:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNC(=O)c1cc(-c2ccc(OC)cc2)c(OCCO)c(-c2ccccc2F)c1
Reactant: CCOC(C)=O
Agent: [Br-]
Agent: [K+]
Solvent: O=CO
Solvent: CO
Product: CCCCCCCCCCCCNC(=O)c1cc(-c2ccc(OC)cc2)c(OCC(=O)O)c(-c2ccccc2F)c1

Procedure:
The tide compound was prepared as a white solid (0.229 g, 47%) from N-dodecyl-3-(2-fluorophenyl) 5-(4-methoxyphenyl)4-(2-hydroxyethoxy)benzamide using a procedure similar to step 3 of example 1. The product was purifed by preparatory plate chromatography (4% Methanol/EtOAc) followed by flash chromatography (15% EtOAc/Hex and 20% EtOAC/Hex, both with 1% formic acid); 1H NMR (400 MHz, DMSO-d6) δ0.84 (t, J=6.8 Hz, 3H), 1.17-1.27 (m, 18H), 1.44-1.51 (m, 2H), 3.22 (dd, J=6.8, 13.0 Hz, 2H), 3.78 (s, 3H), 3.81 (s, 2H), 6.99-7.02 (m, 2H), 7.23-7.28 (m, 2H), 7.42-7.47 (m, 2H), 7.50-7.57 (m, 2H), 7.71 (d, J=2.2 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 8.47 (t, J=5.5, 1H), 12.48 (broad s, 1H); IR (KBr) 3375, 2925, 2850, 1730, 1615, 1200 cm−1; mass spectrum [(+)ESI], m/z 564 (M+H)+; Anal. Calcd. for C34H42FNO5: C, 72.44; H, 7.51; N, 2.48, Found: C, 72.48; H, 7.67; N, 2.46.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:6]=1[S:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])C.C(OCC)C.B>C1COCC1>[Br:11][C:9]1[CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:6]([S:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])=[C:5]([CH2:4][OH:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(Br)cc([N+](=O)[O-])c1SC(=O)N(C)C
Agent: B
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)C(=O)Sc1c(CO)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
5-Bromo-2-dimethylcarbamoylsulfanyl-3-nitro-benzoic acid ethyl ester (3.0 g, 9.4 mmol) is taken up in THF (40 mL)/diethyl ether (10 mL) and cooled to zero with an ice bath. Borane in THF (1M, 20 mL, 2.1 mmol) is added dropwise to the reaction and then the reaction warmed to room temperature. An additional equivalent of borane is added, and the reaction warmed to 45° C. The reaction is stirred at 45° C. for 4 hours and then the reaction cooled to zero and quenched by the slow addition of saturated NH4Cl. The reaction is poured into water and then extracted with ethyl acetate. The combined organic layers were dried filtered and evaporated. The residue is purified on silica gel with DCM/MeOH as the eluent to afford 2.5 g (91%) of the title product. LCMS (ESMS): m/z 336.9 (M+H+).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16](=[O:30])[C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](Br)=[CH:21][CH:20]=1)=[O:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:14][O:15][C:16](=[O:30])[C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([NH:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[CH:12]=2)=[CH:21][CH:20]=1)=[O:18]
Reactant: Nc1ccnc(N2CCOCC2)c1
Reactant: COC(=O)C(=O)c1ccc(Br)c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)C(=O)c1ccc(Nc2ccnc(N3CCOCC3)c2)c2ccccc12
Reaction time: 18 h
Yield: 40.6 %

Procedure:
2-Morpholin-4-yl-pyridin-4-ylamine (159 mg, 0.88 mmol) and (4-Bromo-naphthalen-1-yl)-oxo-acetic acid methyl ester (18) (260 mg, 0.89 mmol) were suspended in 6 mL toluene/Dioxane 1/1 and Pd(OAc)2 (6 mg, 3 mol %), BINAP (27 mg, 5 mol %) and CS2CO3 (858 mg, 2.64 mmol) were added. The reaction mixture was stirred from 80° C. to 80° C. over 18 hrs. The cooled mixture was purified by column chromatography (0-100% EtOAc/Hex) to yield 140 mg of product. This product was subjected to the methods described previously to obtain the final compounds of interest.
Reaction SMILES: [CH:1]1([C:7]2[NH:8][S:9](=[O:28])(=[O:27])[C:10]3[CH:16]=[C:15]([S:17](=[O:24])(=[O:23])[N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:14]=[C:13]([CH:25]=O)[C:11]=3[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CCO.[Pd]>[CH:1]1([C:7]2[NH:8][S:9](=[O:27])(=[O:28])[C:10]3[CH:16]=[C:15]([S:17](=[O:24])(=[O:23])[N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:14]=[C:13]([CH3:25])[C:11]=3[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCN(CC)S(=O)(=O)c1cc(C=O)c2c(c1)S(=O)(=O)NC(C1CCCCC1)=N2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCN(CC)S(=O)(=O)c1cc(C)c2c(c1)S(=O)(=O)NC(C1CCCCC1)=N2
Yield: 0.1 %

Procedure:
3-Cyclohexyl-7-(N,N-diethylsulphamoyl)-5-formyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (0.20 g, 0.46 mmol) was dissolved in 99% EtOH (60 ml). One small drop of concentrated hydrochloric acid was added to ensure fully hydrogenation. The mixture was hydrogenated using Pd/C (10%, 10 mg) at 4 bar pressure for 24 h. The mixture was filtered through a pad of Celite T and evaporated to dryness. The residue was dissolved in EtOAc (50 ml) and washed with water (10 ml), dried (Na2SO4) and evaporated to dryness yielding 0.18 mg (95%) of 3-cyclohexyl-7-(N,N-diethylsulphamoyl)-5-methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless powder. The product was further transformed by Method F. M.p. 206–208° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])/[CH:4]=[C:5](\C)/[CH:6]=[CH:7][C:8]1[N:9]([CH:24]([CH3:26])[CH3:25])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH-:29].[NH4+].[Cl-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5](=[O:29])/[CH:6]=[CH:7]/[C:8]1[N:9]([CH:24]([CH3:26])[CH3:25])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: [OH-]
Reactant: COC(=O)/C=C(\C)C=Cc1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.63 g (1.49 mmol) of (E)-5-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3-methylpenta-2,4-dienoic acid methyl ester in 20 ml of THF are introduced into a 50 ml round-bottomed flask equipped with a magnetic stirrer and nitrogen delivery line, 4 ml of 1N ammonium hydroxide solution are added, and the mixture is stirred for 6 hours at room temperature. The reaction mixture is poured into 200 ml of saturated sodium chloride solution and extracted twice with 100 ml of ethyl acetate, and the organic phase is washed three times with 50 ml of water, dried over magnesium sulfate, filtered and concentrated by evaporation. The crude product is purified by means of flash chromatography (hexane/ethyl acetate=9:1). An orange resin is obtained which, according to NMR, is the product in a keto-enol equilibrium of approximately 3:1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[N:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(c1ccc(F)cc1)c1cnc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccc(F)cc1)c1cnc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=424.1, tR (minutes, Method F)=3.19. [α]D20=+16.4 (c=6.80 mg/mL,CHCl3)
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[N:3]=1>CCOC(C)=O.O=[Pt]=O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([N:4]2[N:3]=[C:2]([Br:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:12])=[CH:14][CH:15]=1
Reactant: O=c1c2ccccc2c(Br)nn1-c1ccc([N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: Nc1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Reaction time: 2 h
Yield: 66.5 %

Procedure:
4-Bromo-2-(4-nitro-phenyl)-2H-phthalazin-1-one (see Method B) (1.0 g, 2.9 mmol) and PtO2 (0.13 g, 0.58 mmol) were dissolved in EtOAc (40 ml) at RT. The mixture was hydrogenated at ambient pressure for 2 h, before the catalyst was filtered off to yield title compound (0.61 g, 67% yield). 1H-NMR: (400 MHz, D6-DMSO) 8.34 (1H, d), 8.07 (1H, t), 7.99 (2H, t), 7.18 (2H, d), 6.63 (2H, d), 5.35 (2H, s); MS (ESI+)=318.42 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[N:31]1([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:16][C:11]1([CH3:17])[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:15]=3)[C:7]=2[C:8](=[O:30])[C:9]2[CH:21]=[CH:20][C:19]([N:39]3[CH2:40][CH2:41][CH:36]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:37][CH2:38]3)=[CH:18][C:10]1=2
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(N3CCC(N4CCCC4)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and 4-pyrrolidin-1-yl-piperidine.
Reaction SMILES: CCN(CC)CC.C(O[C:16](=[O:32])[CH2:17][C:18](=O)[CH2:19][O:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2)C1C=CC=CC=1.Cl.[CH:34]1([NH:40][NH2:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CCO>[C:21]12([O:20][CH2:19][C:18]3[CH:17]=[C:16]([OH:32])[N:40]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[N:41]=3)[CH2:28][CH:27]3[CH2:29][CH:23]([CH2:24][CH:25]([CH2:26]3)[CH2:30]1)[CH2:22]2
Reactant: NNC1CCCCC1
Reactant: O=C(COC12CC3CC(CC(C3)C1)C2)CC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1cc(COC23CC4CC(CC(C4)C2)C3)nn1C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
NEt3 (800 μl, 5.7 mmol) was added to a solution of 4-(adamantan-1-yloxy)-3-oxo-butyric acid benzyl ester (1.91 g, 5.6 mmol), and cyclohexyl hydrazine hydrochloride (877 mg, 5.82 mmol) in EtOH (30 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 4 h. The precipitated white solid was filtered and dried to afford the product as a white solid, (1.23 g, 66%.).
Reaction SMILES: C1(C)C=CC=CC=1.Cl.[O:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[N:26][O:27][CH3:28])[C:23]([NH2:25])=[O:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[O:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1/[C:22](=[N:26]\[O:27][CH3:28])/[C:23]([NH2:25])=[O:24])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CON=C(C(N)=O)c1ccccc1Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CO/N=C(/C(N)=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
Toluene (26 ml) and conc. hydrochloric acid (1.1 ml) were added to 2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (E/Z=6/94) (3.48 g, 0.013 mol), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water (80 ml) was added. The mixture was extracted with ether (80 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give (E)-2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (3.25 g, Yield: 93.4%).
Reaction SMILES: FC(F)(F)S([CH:6](S(C(F)(F)F)(=O)=O)[CH2:7][CH:8]([S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(=O)=O.[C:32]([C:36]1[CH:41]=C[C:39]([OH:42])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>C(#N)C>[F:21][C:19]([F:20])([F:22])[S:16]([CH:8]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[CH2:7][C:6]1[CH:41]=[C:36]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:37]=[CH:38][C:39]=1[OH:42])(=[O:17])=[O:18]
Reactant: O=S(=O)(C(CC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)c1ccc(O)cc1
Solvent: CC#N
Product: CC(C)(C)c1ccc(O)c(CC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)c1
Reaction time: 1 h

Procedure:
1,1,3,3-Tetrakis(trifluoromethylsulfonyl)propane [4] (148.8 mg, 0.264 mmol) was added to an acetonitrile (0.25 ml) solution of 4- t-butylphenol (43.6 mg, 0.29 mmol) at room temperature. After 1 hour of stirring, the reaction solution was concentrated under a reduced pressure. An obtained residue was purified by Kugelrohr distillation (190-210° C./5 mmHg) thereby obtaining 2-(2,2-bis(trifluoromethylsulfonyl)ethyl-4- t-butylphenol [1o] with an approximately quantitative yield (97.0 mg, 0.24 mmol).