Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH:10]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[C:11]([OH:14])([CH3:13])[CH3:12])(=[O:9])=[O:8].FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([CH:10]([S:7]([NH2:6])(=[O:8])=[O:9])[C:11]([OH:14])([CH3:13])[CH3:12])=[CH:16][CH:17]=1
Reactant: COc1ccc(CNS(=O)(=O)C(c2ccc(Br)cc2)C(C)(C)O)c(OC)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)C(c1ccc(Br)cc1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-1-(4-bromophenyl)-2-hydroxy-2-methylpropane-1-sulfonamide from the above reaction in 150 ml of dichloromethane was admixed with 50 ml of trifluoroacetic acid and stirred at room temperature for 17 hours. The starting solution was coevaporated twice with 100 ml of toluene and the crude product was purified using a Flashmaster with an n-heptane/ethyl acetate gradient by means of normal phase chromotography. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (16 g) with a molecular weight of 308.2 g/mol (C10H14BrNO3S).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:12])=[O:11].C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)Cl.CCOC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:36])(=[O:11])=[O:12]
Reactant: COC(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)CCS(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a solution of methyl 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)propanoate (181 mg, 0.43 mmol) in CH2Cl2 (4 ml) was added mCPBA (153 mg, ˜0.64 mmol). The reaction was stirred at room temperature for 1 hour, diluted with EtOAc, extracted with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (25-100% EtOAc in hexane, then 10% MeOH in CH2Cl2) to yield the title compound (87 mg, 46%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:44])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][OH:24])[CH:17]=[C:16]([C:29]([O:31]CC)=O)[C:15]3=[O:34])=[C:8]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:39]=2)[CH:7]=1)[CH3:2].[CH3:45][NH2:46].C(O)C>>[CH2:1]([NH:3][C:4](=[O:44])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][OH:24])[CH:17]=[C:16]([C:29]([NH:46][CH3:45])=[O:31])[C:15]3=[O:34])=[C:8]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:42])([F:41])[F:43])[N:39]=2)[CH:7]=1)[CH3:2]
Reactant: CN
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@H](CO)CC(C)C)cn1
Solvent: CCO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)NC)cn3[C@H](CO)CC(C)C)cn1
Yield: 80 %

Procedure:
A solution of (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-4-methylpentan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 119, 280 mg, 0.44 mmol) in 33 wt. % methylamine solution in absolute ethanol (4 mL, 32.13 mmol) was heated in the microwave at 80° C. for 30 min The reaction mixture was concentrated under reduced pressure. Purification via column chromatography to provide (silica, 95:5 methylene chloride/methanol) gave (S)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-4-methylpentan-2-yl)-N-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide as a light yellow solid (219.2 mg, 80%).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[C:10](=O)[CH3:11].[C:13](O)(=O)C.[CH:17]([NH2:19])=[NH:18]>C(O)CCC>[CH3:1][CH:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[C:10]1[CH:11]=[CH:13][N:19]=[CH:17][N:18]=1
Reactant: N=CN
Reactant: CC(=O)C1C(C)C=CCC1(C)C
Reactant: CC(=O)O
Solvent: CCCCO
Product: CC1C=CCC(C)(C)C1c1ccncn1
Temperature: 130 °C
Reaction time: 24 h

Procedure:
A 100 mL reaction flask is charged with 1-(2,6,6-trimethyl-cyclohex-3-enyl)-ethanone (10 g, 0.06 mol, commercially available at IFF), formamidine acetate (31 g, 0.3 mol), and butanol (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sulfuric acid (10%, 100 mL) followed by twice with brine (30 mL). Butanol is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 4-(2,6,6-trimethyl-cyclohex-3-enyl)-pyrimidine (˜10 g) is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].C([Li])CCC.CN(C)[C:16](=[O:18])[CH3:17].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:7][C:3]1[C:2]([CH2:8][C:16](=[O:18])[CH3:17])=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)N(C)C
Reactant: Cc1cccnc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)Cc1ncccc1C
Temperature: 0 °C

Procedure:
To a stirred solution of 2,3-lutidine (3.21 g) in tetrahydrofuran (20 ml) was added a solution of n-butyllithium in n-hexane (1.56M, 23.1 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (3.63 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×3). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, n-hexane:ethyl acetate=1:2) to give 1-(3-methylpyridin-2-yl)propan-2-one (3.70 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]([O:20][CH2:21][C:22](O)=O)[CH3:19].[OH-].[Na+]>O>[CH2:18]([O:20][CH2:21][C:22]1[N:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:19]
Reactant: CC(C)CCNc1c(N)cnc2ccccc12
Reactant: CCOCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CCC(C)C
Temperature: 25 °C

Procedure:
3-Amino-4-(3-methylbutylamino)quinoline (7 g, 0.03 mole; Example 106) was combined with ethoxyacetic acid (8 mL, 0.08 mole) and heated at 150°-160° C. for about 2 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL), made basic with sodium hydroxide and then extracted with ethyl acetate. The extract was dried over magnesium sulfate then evaporated to provide the crude product as a crystalline solid. The solid was recrystallized from hexane to provide the desired product as a solid, m.p. 64°-65° C. Analysis: Calculated: % C, 72.7; % H, 7.8; % N, 14.1; Found: % C, 72.5; % H, 7.7; % N, 14.1.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:25]([C:26]4([OH:30])[CH2:29][O:28][CH2:27]4)=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:15]([F:31])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)C(O)=O>ClCCl>[C:1]12([CH2:11][O:12][C:13]3[C:25]([C:26]4([OH:30])[CH2:27][O:28][CH2:29]4)=[CH:24][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:31])[CH:14]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(C)(C)OC(=O)c1cc(C2(O)COC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(C2(O)COC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-(3-hydroxyoxetan-3-yl)benzoate ((330 mg, 0.76 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL) and the reaction mixture was stirred for 2 hour at ambient temperature. Removal of all volatiles in vacuo gave 4-(adamantan-1-ylmethoxy)-2-fluoro-5-(3-hydroxyoxetan-3-yl)benzoic acid as an oily residue (0.29 g, quant.).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])=[CH:31][CH:30]=1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: Nc1ccc(F)cc1
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ncc(C(=O)Nc3ccc(F)cc3)c(=O)n12
Reaction time: 0.08 h
Yield: 76.9 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -12° C. and -17° C. during 25 minutes. After stirring for 5 minutes, 9.78 g (0.088 mol) of 4-fluoroaniline dissolved in 80 ml of chloroform are dropped to the above solution at -13° C. during 30 minutes. The reaction mixture is stirred below -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 18.3 g (77%) of the named compound as yellow crystals after recrystallization from n-propanol, m.p.: 202°-204° C.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:13]1[CH2:18][CH2:17][C:16]([CH3:20])(O)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-:21].[Na+].[C:23](#[N:25])[CH3:24]>>[CH2:6]([N:13]1[CH2:18][CH2:17][C:16]([NH:25][C:23](=[O:21])[CH3:24])([CH3:20])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: CC#N
Reactant: CC1(O)CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)NC1(C)CCN(Cc2ccccc2)CC1

Procedure:
Concentrated sulphuric acid (3 ml) was added dropwise to a solution of 1-benzyl-4-methyl-4-piperidinol (640 mg, 2.56 mmol) in acetonitrile (4 ml) at 0° C. After 1 hour the reaction was cautiously poured onto 2N sodium hydroxide (20 ml), the layers separated and the aqueous extracted with dichloromethane (3×). The combined organic extracts were washed with water, brine, dried (K2CO3), filtered and evaporated under reduced pressure to afford the title compound as a clear oil, 600 mg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[F:23])[CH:3]=1.[C:24]([CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:31]2[CH:32]=[C:27]([CH2:26][C:24]#[N:25])[CH:28]=[CH:29][CH:30]=2)[CH:3]=1
Reactant: COc1nc(Cl)cc(NCCc2ccc(C(F)(F)F)cc2F)n1
Reactant: N#CCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(CC#N)c2)n1
Reaction time: 1 h

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine [800 mg, 2.29 mmol, see Example 52, step 1], (3-cyanomethyl-phenyl)-boronic acid, pinacol ester (563 mg, 3.43 mmol), and Cs2CO3 (1.86 g, 5.72 mmol) in ethylene glycol dimethyl ether (15 mL) and water (4 mL) is degassed by bubbling with Argon gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium (0) (132 mg, 0.11 mmol) at room temperature. After 1 h at 85° C., the mixture is diluted with water (50 mL), and extracted with EtOAc (2×50 mL). The extracts are dried (MgSO4), filtered through a pad of SiO2, and concentrated to afford (3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-acetonitrile (1.2 g). LCMS: RT=2.47 minutes, 92% purity. MS: 431 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=O)[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15].[CH3:17][CH2:18][Mg+].[Br-]>>[CH2:17]([C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH3:13])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=1)[CH3:18]
Reactant: CC[Mg+]
Reactant: COc1cc2c(cc1C)C(=O)CCC2(C)C
Agent: [Br-]
Product: CCC1=CCC(C)(C)c2cc(OC)c(C)cc21
Yield: 39.6 %

Procedure:
Following General Procedure F, 6-methoxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (compound 30, 1.0 g, 4.6 mmol) was reacted with a solution of 3M EtMgBr (8 mL, 23.0 mmol), and the crude product was purified by flash column (hexane:ethyl acetate=96:4) to give 0.42 g (40%) of the title compound as a clear oil. PNMR (300 MHz, CDCl3) δ 1.36 (t, 3H, J=6.0 Hz), 1.46 (s, 6H), 2.35 (d, 2H, J=4.5 Hz), 2.42 (s, 3H), 2.65 (q, 2H, J=7.5 Hz), 4.03 (s, 3H), 5.82 (t, 1H, J=2.5 Hz), 7.02 (s, 1H), 7.28 (s, 1H).
Reaction SMILES: [H-].[Na+].ClC[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:16][CH:17]=2)=[N:9][CH:10]=1.[C:24]1([C:30]2[C:34]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:33][NH:32][N:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.[CH3:43]N(C)C=O>>[C:24]1([C:30]2[C:34]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:33][N:32]([CH2:43][C:7]3[C:8]([O:11][CH2:12][C:13]4[N:14]=[C:15]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[S:16][CH:17]=4)=[N:9][CH:10]=[CH:5][CH:6]=3)[N:31]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)CCc1c[nH]nc1-c1ccccc1
Reactant: CN(C)C=O
Reactant: ClCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2cccnc2OCc2csc(-c3ccccc3)n2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 5-chloromethyl-2-(2-phenyl-4-thiazolylmethoxy)pyridine (554 mg), ethyl 3-(3-phenyl-1H-pyrazol-4-yl)propionate (428 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-phenyl-1-[2-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionate (678 mg, yield: 74%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 88–89° C.
Reaction SMILES: [C:1]([S:5][CH2:6][CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:20]([O:27][C:28](=[O:31])[CH2:29][NH2:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C1COCC1>[CH2:20]([O:27][C:28](=[O:31])[CH2:29][NH:30][C:8](=[O:10])[CH:7]([CH2:6][S:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)SCC(Cc1cccc(Br)c1)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)SCC(Cc1cccc(Br)c1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a 25 ml pear-shaped flask containing 2-(S-t-butylsulfanylmethyl)-3-(3-bromophenyl)propionic acid (0.22 g, 0.665 mmol) and THF (7 ml), at 0° C. were added dropwise a solution of glycine benzyl ester hydrochloride (0.134 g, 0.665 mmol) and a solution of triethylamine (93 μl, 67.3 mg, 0.665 mmol) in CH2Cl2 (7 ml), followed by dropwise additions of a solution of HOBT (0.102 g, 0.665 mmol) in THF (5 ml) and a solution of 1,3-dicyclohexyl carbodiimide (0.164 g, 0.796 mmol) in CH2Cl2 (6 ml). The ice/water cooling bath was removed and the mixture was stirred at room temperature overnight. After concentration under reduced pressure, the residue was partitioned between water and CH2Cl2, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography eluting with 0 to 50% ether in hexane to give 2-[3-(3-bromophenyl)-2-(S-t-butylsulfanylmethyl)propionylamino]acetic acid benzyl ester as a colorless viscous oil, 0.25 g, 79% yield. HPLC purity: 100%. 1H NMR (CDCl3) δ 1.29 (s, 9H), 2.51 (m, 1H), 2.64 (m, 1H), 2.85 (m, 3H), 4.02 (m, 2H), 5.16 (s, 2H), 5.95 (m, 1H), 7.12 (m, 2H), 7.35 (m, 7H); MS (ES+) [M+H+]: 478, 480; (ES−) [M−H+]: 476, 478.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([CH3:25])=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=1[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC(=O)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([CH3:25])=[C:19]([CH:20]=[CH:21][C:22]=1[CH3:23])[O:24][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(O)c(C)c1NCc1cc(-c2cccc(F)c2)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(C)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
A solution of 3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-2,4-dimethyl-phenol (340 mg, 1.0 mmol, 1.0 eq) and Cs2CO3 (489 mg, 1.5 mmol, 1.5 eq) in 2-butanone (20 mL) was stirred at room temperature for 30 min. Ethyl 2-bromoacetate (167 mg, 1.0 mmol, 1.0 eq) was added and the reaction mixture was stirred at for 3 h then quenched by addition of water. The aqueous layer was extracted with EtOAc and the organic extract dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:4) to give the title compound as a gummy solid (300 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH2:8][OH:9])[S:4][N:3]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[C:10]([O:9][CH2:8][C:5]1[S:4][N:3]=[C:2]([Cl:1])[C:6]=1[Cl:7])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1snc(Cl)c1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(OCc1snc(Cl)c1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
3.0 g (16.3 mmol) of the above-produced (3,4-dichloroisothiazol-5-yl)methanol and 2.52 g (17.9 mmol) of benzoyl chloride were dissolved in 70 ml of toluene. Thereto was dropwise added, under ice-cooling, 1.98 g (19.6 mmol) of triethylamine. The mixture was stirred at room temperature for 3 hours. Water was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The resulting crystals were washed with hexane to obtain 4.1 g (yield: 87%) of (3,4-dichloroisothiazol-5-yl)methyl benzoate as colorless crystals (melting point: 79 to 80° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][O:25][C:26]1[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@@:9]([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)([O:23][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:33]([O:37][CH3:38])=[C:34]([O:35][CH3:36])[C:26]=3[O:25][CH3:24])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: COc1ccc(C(=O)O)c(OC)c1OC
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1ccc(OC)c(OC)c1OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 2,3,4-trimethoxy-benzoic acid to yield (3aR,4S,7aR)-4-m-tolylethynyl-4-(2,3,4-trimethoxy-benzoyloxy)-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester elimination ion); RT=8.527 min; HPLC Method I
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[H-].[Na+].[Cl:14][C:15]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:16]=1[N:23]=[C:24]=[S:25].[CH3:26][O:27][CH2:28]Cl>O1CCCC1>[Cl:14][C:15]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[C:17]2[C:16]=1[N:23]=[C:24]([S:25][CH2:26][O:27][CH3:28])[C:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])=[C:3]2[OH:5]
Reactant: Fc1ccc(N=C=S)c(Cl)c1F
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(SCOC)nc2c(Cl)c(F)c(F)cc2c1O
Reaction time: 0.25 h

Procedure:
To a solution of 45 g of diethyl malonate in 500 ml of abs. tetrahydrofuran, 11.2 g of 60% sodium hydride oil suspension was added under ice cooling with stirring. After 15 minutes, 57 g of 2-chloro-3,4-difluorophenyl isothiocyanate was added to the reaction mixture at room temperature with stirring. The reaction mixture was stirred for 15 minutes and then 22.5 g of chloromethyl methyl ether was added at the same temperature.
Reaction SMILES: C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O.C([O:23][C:24]1[CH:51]=[CH:50][C:49]([C:52]2[O:56][CH:55]=[N:54][CH:53]=2)=[CH:48][C:25]=1[C:26]([NH:28][C:29]1[CH:41]=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:39]=[CH:38][C:30]=1[C:31]([O:33]C(C)(C)C)=[O:32])=[O:27])C1C=CC=CC=1>>[OH:23][C:24]1[CH:51]=[CH:50][C:49]([C:52]2[O:56][CH:55]=[N:54][CH:53]=2)=[CH:48][C:25]=1[C:26]([NH:28][C:29]1[CH:41]=[C:40]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:39]=[CH:38][C:30]=1[C:31]([OH:33])=[O:32])=[O:27]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2cnco2)ccc1OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(-c2cnco2)ccc1O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78 %

Procedure:
Thioanisole (2.3 mL) and trifluoroacetic acid (7.7 mL) were added to the obtained tert-butyl 2-(2-(benzyloxy)-5-(oxazol-5-yl)benzamido)-4-phenylbenzoate (0.21 g), followed by stirring at room temperature for 9 hours and 40 minutes. The solvent was evaporated under reduced pressure, and methanol was added to the residue. The solid substance was collected by filtration to obtain 0.12 g of 2-(2-hydroxy-5-(oxazol-5-yl)benzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CCOC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1
Product: CCOC(=O)C[C@H]1C[C@@H](CCn2c(C(C)C)cc(-c3ccccc3)c2-c2ccc(F)cc2)OC(C)(C)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and ethyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate.