Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:11][C:12]([OH:14])=[O:13]
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc(Cl)c1

Procedure:
It is furthermore known from J. Pharm. Sci. 67(1) 1978, 81, to prepare the chloro-substituted indanonecarboxylic acid ester 5-chloro-2-methoxycarbonyl-1-indanone starting from 3-chlorobenzaldehyde. Here, 3-chlorobenzaldehyde is initially reacted in pyridine with malonic acid to give 3-chlorocinnamic acid. Following hydrogenation of the ethylenic double bond and cyclization to the 5-chloro-1-indanone, the latter is then reacted with dimethyl carbonate in the presence of sodium hydride and benzene as solvent to give 5-chloro-2-methoxycarbonyl-1-indanone. This synthesis method has the disadvantage of the multistep mechanism which considerably increases the likelihood of the formation of various by-products, which is reflected in only a low yield of 48%. Additionally, the total reaction requires the repeated use of substances such as sodium hydride and benzene, which are expensive, problematic with respect to safety or hazardous to health.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[O:3]1.[CH3:17][C:18]([CH3:23])=[CH:19][C:20](Cl)=[O:21].O>C1COCC1>[CH3:17][C:18]([CH3:23])=[CH:19][C:20]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)[CH:10]=1)=[O:21]
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: CC(C)=CC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 g, 0.00456 mol) in THF (5 mL) at 0° C., were added TEA (0.552 g, 0.000547 mol) and dimethylacryloyl chloride (0.648 g, 0.00456 mol) and stirred for 15 mins at 0° C. The reaction was poured into water (200 mL) and extracted with EtOAc (300 mL×2). The combined extracts was washed with brine (200 mL), dried over sodium sulphate, and concentrated under vacuum to afford 3-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-enamide (0.7 g, Yield: 51%).
Reaction SMILES: O([C:8]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][N+:10]([O-:12])=[O:11])C1C=CC=CC=1.[NH2:20][CH2:21][CH2:22][S:23][CH2:24][C:25]1[N:26]=[C:27]([CH2:30][N:31]([CH3:33])[CH3:32])[S:28][CH:29]=1.C(O)(C)C>C(Cl)Cl>[CH3:33][N:31]([CH2:30][C:27]1[S:28][CH:29]=[C:25]([CH2:24][S:23][CH2:22][CH2:21][NH:20][C:8]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:9][N+:10]([O-:12])=[O:11])[N:26]=1)[CH3:32]
Reactant: O=[N+]([O-])C=C(Oc1ccccc1)Oc1ccccc1
Reactant: CN(C)Cc1nc(CSCCN)cs1
Solvent: ClCCl
Solvent: CC(C)O
Product: CN(C)Cc1nc(CSCCNC(=C[N+](=O)[O-])Oc2ccccc2)cs1

Procedure:
A solution of 0.4 g (1.32 mmol) of 85% pure 1,1-diphenoxy-2-nitroethene, 0.35 g (1.52 mmol) of 4-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-thiazolemethanamine, 5 ml of isopropyl alcohol and 5 ml of methylene chloride ws stirred at room temperature for about two hours to provide N-[2-[[[2-[(dimethylamino)methyl]-4-thiazolyl]methyl]thio]ethyl]-2-nitro-1-phenoxy-1-etheneamine in situ. The product was not isolated but used directly in the reaction described in part B.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[CH2:38]1[CH2:42][O:41][CH2:40][CH2:39]1>C(N(CC)CC)C>[C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][S:20]([C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:5](=[O:11])[O:6][CH2:7][CH:40]2[CH2:39][CH2:38][CH2:42][O:41]2)=[CH:19][CH:18]=1)(=[O:22])=[O:21])(=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccccc2)cc1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccccc2)cc1)OCC1CCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triphosgene (28 mg, 1/3 equiv) was dissolved in 1 mL of THF and the solution cooled to 0° C. A solution of 4-amino-N-(2-benzoylphenyl)benzenesulfonamide (100 mg) in 3 mL of THF and 0.15 mL of triethylamine was added therto, and the reaction mixture was warmed to rt and stirred for 30 minutes. A solution of tetrahyhdrofurfuryl alcohol (44 mg, 1.5 equiv) in 3 mL of THF and 0.15 mL of triethylamine was added thereto and the reaction mixture was left stirring overnight. The reaction was quenched with water and diluted with EtOAc. The organic layer was washed once each with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The title product was obtained following flash chromatography (10% to 95% EtOAc/hexanes). ESMS, M+H+ found: 481.8.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][CH:9]([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][N:11]=1)[CH2:3][CH2:4][CH2:5][NH2:6].[C:22]([NH:24][C:25](=[N:33][CH2:34][CH2:35][S:36][CH2:37][C:38]1[N:39]=[C:40]([NH:43][C:44]([NH2:46])=[NH:45])[S:41][CH:42]=1)OC1C=CC=CC=1)#[N:23]>>[C:22]([NH:24][C:25]([NH:33][CH2:34][CH2:35][S:36][CH2:37][C:38]1[N:39]=[C:40]([NH:43][C:44]([NH2:46])=[NH:45])[S:41][CH:42]=1)=[N:6][CH2:5][CH2:4][CH2:3][N:2]([CH2:7][CH2:8][CH:9]([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][N:11]=1)[CH3:1])#[N:23]
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Reactant: CN(CCCN)CCC(c1ccccc1)c1ccccn1
Product: CN(CCCN=C(NC#N)NCCSCc1csc(NC(=N)N)n1)CCC(c1ccccc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.85 g (3 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,3-propanediamine and 1.12 g (3 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%])=565 ([M+H]+, 2), 196 (100); IR (KBr): 2162 cm-1 (C≡N). For analytical purposes a sample is converted into the maleic acid salt and recrystallised from ether/isopropanol; m.p.: 110°-112° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[N:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.I[CH2:46][C:47]([NH2:49])=[O:48].O>CN(C)C=O>[NH2:49][C:47](=[O:48])[CH2:46][N:17]1[C:12](=[N:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:21][CH:20]=2)=[CH:16]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(NC(=O)OCc4ccccc4)cc3)cn2)cc1
Reactant: NC(=O)CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3ccc(NC(=O)OCc4ccccc4)cc3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.5 %

Procedure:
To a solution of benzyl {4-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}carbamate (23.8 g, 48.6 mmol) in N,N-dimethylformamide (238 mL) were added N,N-diisopropylethylamine (11.0 mL, 63.2 mmol) and iodoacetamide (11.7 g, 63.2 mmol), and the mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate/tetrahydrofuran. The combined organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate and collected by filtration to give the title compound (20.6 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)=[N:9][OH:10])=[CH:4][CH:3]=1.[ClH:27]>C(O)C.[Ni].CO>[OH2:10].[ClH:27].[ClH:27].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:15][CH2:16]2)[NH2:9])=[CH:6][CH:7]=1.[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:15][CH2:16]2)[NH2:9])=[CH:6][CH:7]=1.[ClH:27].[ClH:27]
Reactant: ON=C(c1ccc(F)cc1)C1CCN(CCCOc2ccccc2)CC1
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: NC(c1ccc(F)cc1)C1CCN(CCCOc2ccccc2)CC1
Product: O
Yield: 54.2 %

Procedure:
A suspension of the (4-fluorophenyl)[1-(3-phenoxypropyl)-4-piperidinyl]methanone oxime (5.00 g, 0.014 mol) in 100 mL of ethanol was subjected to hydrogenation (52 psi) in the presence of Raney nickel for 16 hours at room temperature. The catalyst was removed by filtration, and ethanol was removed by the rotary evaporator to give a clear oil. This oil was converted to the HCl salt in methanol using ethereal HCl. A white solid was isolated and dried in vacuo 16 hours at 80° C. in the presence of phosphorus pentoxide. This process provided 3.22 g (54.2%) of white crystalline solid, mp 247°-248° C. (dec).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16](Br)=[C:17](Br)[N:18]3[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])[C:7]([C:10]([OH:12])=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Na+].[H][H].O>C(O)C.[OH-].[OH-].[Pd+2].CO>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])[C:7]([C:10]([OH:12])=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1ncc(C(=O)O)n1Cc1cccc2c1c(Br)c(Br)n2-c1ccccc1C#N
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCO
Product: CCCCc1ncc(C(=O)O)n1Cc1cccc2c1ccn2-c1ccccc1C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 2-butyl-1-[[2,3-dibromo-1-(2-cyanophenyl)-1H-indol-4-yl]methyl]-1H-imidazole-5carboxylic acid in ethanol (26 ml, 0.032M), sodium hydroxide water solution (1N, 2.923 ml, 2,923 mmol, 3.5 eq.), and palladium hydroxide on carbon (186 mg) were added. The mixture was placed under a balloon of hydrogen gas and stirred at room temperature. After 1.5 hours, 20 ml water and 40 ml methanol were added and the reaction was filtered. The filtrate was concentrated to about 20 ml and acidified with 1N HCl to pH~2. The mixture was extracted with 10% methanol in methylene chloride. The extract was washed with brine and concentrated. The residue was chromatographed on silica gel eluting with EtOAc: Pyridine:AcOH:H2O (40:1:1:0.5) to give the title B compound (200 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:20])[C:9](N2[C@@H](C(C)C)COC2=O)=[O:10])=[CH:4][CH:3]=1.[OH:21]O.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH3:20])[C:9]([OH:10])=[O:21])=[CH:6][CH:7]=1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](C)c1ccc(F)cc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](C(=O)O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a solution of (4S)-3-[(2S)-2-(4-fluorophenyl) propanoyl]-4-isopropyl-1,3-oxazolidin-2-one (2.40 g, 8.60 mmol) in 160 mL THF/H2O (3:1) at 0° C., was added 30% H2O2 (7.8 mL, 68.8 mmol) followed by LiOH (722 mg, 17.2 mmol). The resulting mixture was stirred at 0° C. for 2 h and the excess peroxide was quenched at 0° C. with 1.5 N aqueous Na2SO3 (51 mL). After buffering to pH 9–10 with aqueous NaHCO3 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL×3). The aqueous layer was acidified with 3N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 0.92 g (5.47 mmol, 64%) of (2S)-2-(4-fluorophenyl)propanoic acid; [α]D=+70° (C=1, MeOH): 1H NMR (400 MHz, CDCl3) δ 12.2–11.4 (br, 1 H), 7.31–7.24 (m, 2 H), 7.04–6.97 (m, 2 H), 3.72 (q, 1 H, J=7.3 Hz), 1.49 (d, 3 H, J=7.3 Hz); ESMS m/e: 167.2 (M−H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH2:11]([N:9]1[C:8](=[O:15])[N:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[C:3]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:4]2=[N:10]1)[CH:12]([CH3:14])[CH3:13]
Reactant: Cc1ccc(-c2c(Br)ccn3c(=O)n(CC(C)C)nc23)cc1
Reactant: COc1ccc(B(O)O)cc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccn3c(=O)n(CC(C)C)nc3c2-c2ccc(C)cc2)cc1
Temperature: 150 °C
Yield: 90.3 %

Procedure:
To a stirring, degassed mixture of 7-bromo-2-isobutyl-8-p-tolyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.015 g, 0.04 mmol), 4-methoxyphenylboronic acid (0.026 g, 0.17 mmol), and tetrakis(triphenylphosphine)palladium (2.5 mg, 0.002 mmol) in dioxane (0.3 mL) at 20° C. was added K2CO3 (0.024 g, 0.17 mmol) in water (0.11 mL). The resulting reaction mixture was heated in a microwave reactor at 150° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate 14 mg of the title compound as a yellow solid. MS: [M+H]+=389.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:13]([C:14]#[N:15])=[C:12]([S:16][CH3:17])[S:11][N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:18]O.O>S(=O)(=O)(O)O.C(O)(=O)C.C(OC(=O)C)(=O)C>[CH:1]1([CH2:7][O:8][C:9]2[C:13]([C:14]([NH2:15])=[O:18])=[C:12]([S:16][CH3:17])[S:11][N:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CSc1snc(OCC2CCCCC2)c1C#N
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CSc1snc(OCC2CCCCC2)c1C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
3-Cyclohexylmethoxy-5-methylsulfanyl-isothiazole-4-carbonitrile (3) (6.3 g, 23.5 mmol) is dissolved in conc. sulfuric acid (31.5 mL) and stirred at room temperature for 24 hrs. Ice was added and the resulting suspension was filtered and washed with water and then washed with 1N NaOH. The solids were dried in vacuo to obtain crude 3-cyclohexylmethoxy-5-methylsulfanyl-isothiazole-4-carboxylic acid amide (4, 8.7 g). This solid is slurried in acetic acid (37 mL) and acetic anhydride (37 mL). Hydrogen peroxide (30%, 18.5 mL) is then added and the reaction is stirred at room temperature for 18 hours. More hydrogen peroxide (30%, 18.5 mL) is then added and the reaction is stirred at room temperature for 3 days. Water is then added and the suspension is filtered and the solids are further dried in vacuo to provide 5 (5.06 g, 62%). 1H NMR (d6 DMSO): δ 7.97 (1H, s), 7.87 (1H, s), 4.14 (2H, d, J=6.0 Hz), 3.54 (3H, s), 1.59–1.78 (6H, m), 1.09–1.25 (3H, m), 0.94–1.03 (2H, m); LRMS (M+): 318.9.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].C(OC(=O)C)(=O)C.[N+:17]([O-])([OH:19])=[O:18]>>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:17]([O-:19])=[O:18])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(N)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CCc1ccc(N)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Ethylaniline (15.0 g, 124 mmol) was carefully added to acetic anhydride (100 mL, 1.06 mol) that was pre-cooled to 0° C., and the mixture was warmed to rt over 30 min, then recooled to 0° C., and nitric acid (7.90 mL of a 70% v/v aq. solution, 124 mL) was added dropwise. After 30 min, the reaction mixture was quenched into an ice-water bath, the resulting slurry was filtered, and the filter cake was dried in vacuo. The crude solid product was dissolved in 6M HCl (100 mL) and dioxane (60 mL), and the resulting mixture was heated at 0° C. After 3 h, the reaction mixture was cooled to rt and concentrated in vacuo. The crude residue was suspended in EtOAc and neutralized via addition of 6N NaOH. The layers were separated, and the aq. layer was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound, i-6a, m/z (ES) 167 (MH)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[NH2:3].C(N(CC)CC)C.[C:21](Cl)(Cl)=[S:22].[NH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][C:30]([N:39]([CH3:41])[CH3:40])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>C(Cl)(Cl)Cl>[CH3:40][N:39]([CH3:41])[C:30]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:31][CH2:32][CH:27]([CH2:26][NH:25][C:21]([NH:3][CH:2]([CH3:1])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[S:22])[CH2:28][CH2:29]1
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Reactant: S=C(Cl)Cl
Reactant: CC(N)Cc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(Cc1c[nH]c2ccccc12)NC(=S)NCC1CCC(c2ccccc2)(N(C)C)CC1
Temperature: -5 °C
Reaction time: 20 h

Procedure:
α-methyltryptamine (261.4 mg, 1.5 mmole) was dissolved in dry chloroform (15 ml) and combined with triethylamine (422 μl, 3 mmole). The mixture was cooled to −5° C. Thiophosgene (115 μl, 1.5 mmole) dissolved in chloroform (10 ml) was then added dropwise, resulting in the formation of a precipitate. After a reaction time of 18 h at RT, (4-aminomethyl-1-phenyl-cyclohexyl)-dimethylamine (348.55 mg, 1.5 mmole) dissolved in chloroform (10 ml) was added. After 20 h stirring at RT, the reaction mixture was clear. Working up was performed by washing the batch with saturated NaHCO3 solution (3×5 ml) and water (5 ml). The organic phase was dried with Na2SO4 and evaporated. The product was a mixture of two diastereoisomers. These were purified and separated by column chromatography [silica gel 60 (70 g); eluent: MeOH/EE 1:5 (1500 ml)]. The more nonpolar diastereoisomer of 1-(4-dimethylamino-4-phenylcyclohexylmethyl)-3-[2-(1H-indol-3-yl)-1-methyl-ethyl]thiourea (177 mg, m.p. 99-104° C., 26%) and also the more polar diastereoisomer of 1-(4-dimethylamino-4-phenylcyclohexylmethyl)-3-[2-(1H-indol-3-yl)-1-methylethyl]thiourea (152 mg, m.p. 93-95° C., 23%) were colorless solids.
Reaction SMILES: C(OC([NH:8][C:9]1[S:10][C:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:23])=[O:22])[CH:16]=2)=[CH:12][N:13]=1)=O)(C)(C)C.[C:24](N1CCNCC1)(=O)C.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:24][O:23][C:21](=[O:22])[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([S:14][C:11]2[S:10][C:9]([NH2:8])=[N:13][CH:12]=2)[CH:16]=1
Reactant: CC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Sc2cccc(C(=O)O)c2)s1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Sc2cnc(N)s2)c1
Temperature: 55 °C
Yield: 100.1 %

Procedure:
A suspension of 2-tert-butoxycarbonylamino-5-[(3-carboxyphenyl)thio]thiazole (528 mg, 1.5 mmol), N-acetylpiperazine (239 mg, 1.87 mmol), ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (400 mg, 2 mmol), 1-hydroxy-7-azabenzotriazole (272 mg, 2 mmol) and diisopropylethylamine (560 μL, 4 mmol) in THF (20 mL) was heated to 55° C. for 2 h. The mixture was cooled to rt. and concentrated. The residue was purified using column chromatography on silica gel eluted with 2% methanol in dichloromethane followed by 5% methanol in dichloromethane to obtain the titled compound (400 mg, 58%) as a white foam. E. 4-Acetyl-1-[3-[(2-aminothiazol-5-yl)thio]benzoyl]piperazine
Reaction SMILES: C(N[C@]1([C@@H](CC)C)CCN([C@@H](CCC2C=CC=CC=2)C(N[C@@H](CC2C=C(F)C=C(F)C=2)[C@@H]([C@H]2C[C@@H](O)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=O)C1=O)(=[O:3])C.[C:58]([NH:61][C@:62]1([C@@H:111]([CH2:113][CH3:114])[CH3:112])[CH2:66][CH2:65][N:64]([C@@H:67]([CH2:102][CH2:103][C:104]2[CH:109]=[CH:108][CH:107]=[CH:106][CH:105]=2)[C:68]([NH:70][C@@H:71]([CH2:93][C:94]2[CH:99]=[C:98]([F:100])[CH:97]=[C:96]([F:101])[CH:95]=2)[C@@H:72]([C@H:74]2[CH2:79]CCC[N:75]2[CH:80]([C:87]2C=CC=CC=2)C2C=CC=CC=2)[OH:73])=[O:69])[C:63]1=[O:110])(=[O:60])[CH3:59].C(O)(=O)C.[H][H]>CO.[Pd]>[C:58]([NH:61][C@:62]1([C@@H:111]([CH2:113][CH3:114])[CH3:112])[CH2:66][CH2:65][N:64]([C@@H:67]([CH2:102][CH2:103][C:104]2[CH:105]=[CH:106][CH:107]=[CH:108][CH:109]=2)[C:68]([NH:70][C@@H:71]([CH2:93][C:94]2[CH:99]=[C:98]([F:100])[CH:97]=[C:96]([F:101])[CH:95]=2)[C@H:72]([OH:73])[C@H:74]2[CH2:79][O:3][CH2:87][CH2:80][NH:75]2)=[O:69])[C:63]1=[O:110])(=[O:60])[CH3:59]
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@@H](O)CN2C(c2ccccc2)c2ccccc2)C1=O
Reactant: [H][H]
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CCCCN2C(c2ccccc2)c2ccccc2)C1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2COCCN2)C1=O
Yield: 58.8 %

Procedure:
Step 16 (B): To 20 mg of 10% Pd/C was added a solution of the entire sample of the compound of step 16 (A) in 5 ml of MeOH under nitrogen. A 0.3 ml portion of acetic acid was added. The mixture was shaken in a Parr apparatus with 50 psi of hydrogen for 3.5 hours. The suspension was filtered over Celite, and the product was purified by HPLC under standard conditions to give 30 mg (58.8% yield for the two steps) of the title compound of Example 16. 1H NMR (500 MHz, CDCl3) δ ppm 0.90 (d, J=6.71 Hz, 3 H) 1.02 (t, J=7.17 Hz, 3 H) 1.13 (m, 1 H) 1.72 (m, 2 H) 2.00 (s, 3 H) 2.12 (m, 1 H) 2.21 (q, J=7.12 Hz, 2 H) 2.38 (m, 1 H) 2.57 (m, 1 H) 2.74 (m, 2 H) 3.23 (dd, J=14.34, 2.75 Hz, 1 H) 3.31 (m, 5 H) 3.42 (m, 2 H) 3.70 (m, 1 H) 3.77 (m, 1 H) 3.91 (m, 2 H) 3.99 (m, 2 H) 4.21 (dd, J=12.51, 3.05 Hz, 1 H) 6.73 (tt, J=9.16, 2.14 Hz, 1 H) 6.87 (d, J=7.94 Hz, 2 H) 7.19 (d, J=5.80 Hz, 3 H) 7.27 (m, 2 H) 8.12 (s, 1 H) 8.25 (d, J=8.85 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[CH:18]1([S:21][CH2:22][C:23]2[CH:24]=[C:25]([CH:27]=[C:28]([F:30])[CH:29]=2)[NH2:26])[CH2:20][CH2:19]1>>[CH:18]1([S:21][CH2:22][C:23]2[CH:24]=[C:25]([NH:26][C:2]3[N:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=4[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=3)[CH:27]=[C:28]([F:30])[CH:29]=2)[CH2:19][CH2:20]1
Reactant: Nc1cc(F)cc(CSC2CC2)c1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Product: COc1cc(F)ccc1-c1nc(Nc2cc(F)cc(CSC3CC3)c2)ncc1F

Procedure:
Intermediate 50.3 was prepared under similar conditions as described in the preparation of Intermediate 20.1 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and 3-[(cyclopropylsulfanyl)-methyl]-5-fluoroaniline. The batch was purified by chromatography (hexane to hexane/ethyl acetate 50%) to give the desired product.