Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8](=S)[NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:13][C:14]([CH2:16][C:17](=O)[CH3:18])=[O:15]>O1CCCC1>[NH:7]([C:8]1[C:16]([C:14](=[O:15])[CH3:13])=[C:17]([CH3:18])[NH:10][N:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(=S)Nc1ccccc1
Reactant: CC(=O)CC(=O)CCl
Solvent: C1CCOC1
Product: CC(=O)c1c(Nc2ccccc2)n[nH]c1C
Reaction time: 12 h

Procedure:
50 g of 4-phenylthiosemicarbazide is suspended in 300 ml of tetrahydrofuran and 0.5 ml of concentrated HCL is added. Then 40.4 g of 3-chloroacetyl acetone is allowed to run in all at once and the whole is cooled with an ice-bath. After 12 hours' stirring, the precipitate formed is suction filtered, washed with acetone and then boiled in a water/acetone mixture (1:1). This hot solution is filtered off from the sulfur and neutralized with aqueous ammonia solution. The product is then suction filtered and recrystallized from acetone; m.p. 246°-247° C.
Reaction SMILES: C(N1C[C@H](OCC)[C@H](NC2C(CC)=NC(C3C=CC(Cl)=CC=3Cl)=C(CC)N=2)C1)(=O)C.[Cl:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[C:40]1[N:41]=[C:42]([CH2:57][CH3:58])[C:43]([NH:48][C@H:49]2[C@@H:53]([O:54][CH2:55][CH3:56])[CH2:52][NH:51][CH2:50]2)=[N:44][C:45]=1[CH2:46][CH3:47].Cl[C:60]([O:62][CH3:63])=[O:61]>>[Cl:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[C:40]1[N:41]=[C:42]([CH2:57][CH3:58])[C:43]([NH:48][C@H:49]2[C@@H:53]([O:54][CH2:55][CH3:56])[CH2:52][N:51]([C:60]([O:62][CH3:63])=[O:61])[CH2:50]2)=[N:44][C:45]=1[CH2:46][CH3:47]
Reactant: COC(=O)Cl
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC
Agent: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(C(=O)OC)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting 5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine and methyl chloroformate, and making non-critical variations provided the title compound as an oil: 1H NMR (DMSO-d6) δ 1.03–1.09, 1.16, 2.36, 2.67, 3.78, 3.51, 3.60, 3.69, 3.82, 4.15, 4.62, 5.95, 6.98, 7.11, 7.26; IR (diffuse reflectance) 2965 (s,b), 2937, 2351 (w), 2338 (w), 2213 (w), 2158 (w), 2059 (w), 1710 (s), 1568 (s), 1552, 1483 (s), 1456 (s), 1393 (s), 1287 (s), 1228, cm−1 HRMS (FAB) calcd for C23H30ClFN4O4+H 481.2018, found 481.2026. Anal. Calcd for C23H30ClFN4O4: C, 57.44; H, 6.29; N, 11.65; Cl, 7.37; F, 3.95. Found: C, 57.14; H, 6.46; N, 11.37.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[C@@H:17]12[C:26](=[O:27])[O:25][C:23](=[O:24])[C@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22]2>COCCOC>[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:26]([C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[C:23]([OH:25])=[O:24])=[O:27])[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[OH:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Solvent: COCCOC
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCC[C@H]2C(=O)O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 53.3 %

Procedure:
A solution containing 4.00 g (0.022 mole) of 4-amino-2,6-di-t-butylphenol in 50 ml of 1,2-dimethoxyethane was added dropwise over a period of ten minutes to a solution of 3.35 g (0.022 mole) of trans-1,2-cyclohexanedicarboxylic anhydride in 50 ml of 1,2-dimethoxyethane. The reaction mixture was stirred at room temperature for about seventy-two hours. The solvent was removed under vacuum and the residual solid was triturated with a mixture of diethyl ether and hexane. The resulting solid was recrystallized from a mixture of ethyl acetate and hexane to give 4.4 g of white solid 2-[N-(3,5-di-t-butyl-4-hydroxyphenyl) carbamoyl]-trans-cyclohexanecarboxylic acid, m.p. 247°-252° C. Analysis: Calculated for C22H33NO4 : %C, 70.4; %H, 8.9; %N, 3.7; Found: %C, 70.4; %H, 8.9; %N, 3.6.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1[O:7][CH:6]1CO.[C:10](=[O:12])=[O:11]>CO>[C:10](=[O:3])([OH:12])[OH:11].[OH:3][CH2:2][CH:1]([CH2:6][OH:7])[OH:4]
Reactant: OCCO
Reactant: OCC1CO1
Reactant: O=C=O
Solvent: CO
Product: O=C(O)O
Product: OCC(O)CO

Procedure:
Glycerine carbonate is obtained by the transesterification of ethylene carbonate or dimethyl carbonate with glycerine, producing ethylene glycol or methanol as by-products. A further synthesis starts with glycidol (2,3-epoxy-1-propanol), which is reacted under pressure with CO2 in the presence of catalysts to form glycerine carbonate. Glycerine carbonate is a clear liquid of low viscosity with a density of 1.398 g·cm−3 that boils at 125-130° C. (0.15 mbar).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11][C:4]2([NH:8][C:7](=[O:9])[NH:6][C:5]2=[O:10])[CH2:3]1.[O:18]1[CH2:35][CH:19]1[CH2:20][O:21][C:22](=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH:31]1[O:33][CH2:32]1)=[O:28].[OH-:36].[K+]>C(O)(C)(C)C>[OH:18][CH:19]([CH2:35][N:6]1[C:5](=[O:36])[C:4]2([CH2:3][C:2]([CH3:1])([CH3:17])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]2)[NH:8][C:7]1=[O:9])[CH2:20][O:21][C:22](=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH:31]([OH:33])[CH2:32][N:6]1[C:5](=[O:10])[C:4]2([CH2:3][C:2]([CH3:17])([CH3:1])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]2)[NH:8][C:7]1=[O:9])=[O:28]
Reactant: O=C(CCCCC(=O)OCC1CO1)OCC1CO1
Reactant: CN1C(C)(C)CC2(CC1(C)C)NC(=O)NC2=O
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CN1C(C)(C)CC2(CC1(C)C)NC(=O)N(CC(O)COC(=O)CCCCC(=O)OCC(O)CN1C(=O)NC3(CC(C)(C)N(C)C(C)(C)C3)C1=O)C2=O

Procedure:
9.6 g of 7,7,8,9,9-pentamethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione, 5.2 g of bis(2,3-epoxypropyl)adipate and 0.1 g of potassium hydroxide were reacted in 80 ml of t-butanol, following substantially the same procedure as in Example 1. The desired Compound No. 126 was obtained in the form of white crystals, melting at 180°-184° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][NH2:8].Cl[C:10]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.CCN(C(C)C)C(C)C>CO>[NH3:1].[NH2:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][NH:8][C:10]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: NCC1CCCC1N
Reactant: COc1cc(Cl)nc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cc(NCC2CCCC2N)nc2ccccc12
Product: N
Yield: 16 %

Procedure:
(2-Aminocyclopentyl)methylamine (0.50 g, 0.00438 mol), 2-chloro-4-methoxyquinoline (0.85 g, 0.00438 mol) and N,N′-diisopropylethylamine (1 ml) were stirred together at 80° C. in a sealed tube for 16 h. After cooling the mixture was diluted in methanol then concentrated onto silica gel and purified by silica gel chromatography (5%, 10% then 20% (10% 880 aqueous ammonia in methanol) in dichloromethane) to give the title compound as a white gum (50:50 mixture of cis and trans isomers; 0.095 g, 8%). δH (CD3OD) 1.40-2.25 (7H, m, (CH2)3, CHCH2NH), 2.96-3.76 (3H, m, CHNH2, CH2NH), 4.02 (3H, s, OCH3), 6.02-6.23 (1H, 2s, 3-H), 7.13-7.95 (4H, m, ArH). MS (ES+) 272 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>>[CH2:11]1[CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3][CH:2]1[NH:1][C:24]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=1)=[O:25]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: NC1CCN2CCc3ccccc3C2C1
Product: Cc1ccc(NC(=O)NC2CCN3CCc4ccccc4C3C2)cc1

Procedure:
By a procedure analogous to that of Example 1, 2-amino-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine is reacted with p-methylphenyl isocyanate to give the title compound.
Reaction SMILES: [CH2:1]([C:4]1([S:7]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14](=[O:18])[N:13]([CH3:19])[C:12]=2[N:20]([C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=C.CC1C=CC=C(C)N=1.[O:44]1CCOCC1>O.O=[Os](=O)(=O)=O>[CH3:19][N:13]1[C:14](=[O:18])[C:15]([CH3:17])=[CH:16][C:11]([NH:10][S:7]([C:4]2([CH2:1][CH:2]=[O:44])[CH2:6][CH2:5]2)(=[O:8])=[O:9])=[C:12]1[N:20]([C:28]1[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=1[F:35])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25]
Reactant: C1COCCO1
Reactant: C=CCC1(S(=O)(=O)Nc2cc(C)c(=O)n(C)c2N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: Cc1cccc(C)n1
Solvent: O
Product: Cc1cc(NS(=O)(=O)C2(CC=O)CC2)c(N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)n(C)c1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
To a solution of tert-butyl 3-(1-allylcyclopropanesulfonamido)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-2-yl(2-fluoro-4-iodophenyl)carbamate (2.370 g, 3.838 mmol) in dioxane (38.4 ml) under a nitrogen atmosphere was added H2O (7.7 ml). Then NalO4 (4 eq, 3.284 g, 15.353 mmol) and 2,6-dimethyl pyridin (2 eq, 0.894 ml, 7.676 mmol) were added and the mixture was cooled to 0° C. At this temperature OsO4 (4% in t-butanol, 0.04 eq, 1,925 ml, 0.154 mmol) was added. The mixture was allowed to come to room temperature and then stirred for 18 hours. The mixture was diluted with H2O (4 ml) to form a fine suspension. After stirring for 30 min the precipitate was filtered off and washed with water, which dissolved the precipitate. The filtrate was extracted twice with ethyl acetate, washed once with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography (Biotage system) to afford the title compound (1.92 g, 79%) as a mixture of the aldehyde and a cyclised 1,2-thiazolidin-3-ol 1,1-dioxide form.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:13][C:3]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:57][C:58]1[CH:59]=[C:60]([NH:65][C:66](=[O:86])[C:67]2[CH:72]=[CH:71][C:70]([CH2:73][N:74]3[CH2:79][CH2:78][N:77]([CH2:80][CH3:81])[CH2:76][CH2:75]3)=[C:69]([C:82]([F:85])([F:84])[F:83])[CH:68]=2)[CH:61]=[CH:62][C:63]=1[CH3:64]>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([C:8]([NH:57][C:58]2[CH:59]=[C:60]([NH:65][C:66](=[O:86])[C:67]3[CH:72]=[CH:71][C:70]([CH2:73][N:74]4[CH2:79][CH2:78][N:77]([CH2:80][CH3:81])[CH2:76][CH2:75]4)=[C:69]([C:82]([F:85])([F:84])[F:83])[CH:68]=3)[CH:61]=[CH:62][C:63]=2[CH3:64])=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([S:14]([C:17]3[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=3)(=[O:15])=[O:16])[CH:12]=[CH:13][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(C(=O)O)cnc32)cc1
Reactant: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(N)c3)cc2C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(NC(=O)c4cnc5c(ccn5S(=O)(=O)c5ccc(C)cc5)c4Cl)c3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (50 mg, 0.14 mmol) in DMF(1 mL) were added HATU (162 mg, 0.43 mmol), DIEA (0.12 mL, 0.71 mmol) and N-(3-amino-4-methylphenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (60 mg, 0.14 mmol). The reaction mixture was stirred for overnight at room temperature after which, it was poured to water and the produced solid was filtered. The crude solid was dried with nitrogen gas flow. The title compound (85 mg, 0.11 mmol) was used next reaction without further purification. MS m/z: 753 [M+1].
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:17])[C:4]([C:6]1([C:13]([F:16])([F:15])[F:14])[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5].[BH4-].[Na+].O.Cl>C(O)C>[CH3:1][O:2][N:3]([CH3:17])[C:4]([C:6]1([C:13]([F:14])([F:15])[F:16])[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5]
Reactant: CON(C)C(=O)C1(C(F)(F)F)CCC(=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CON(C)C(=O)C1(C(F)(F)F)CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
18.0 g (71.1 mmol) of 4-Oxo-1-trifluoromethyl-cyclohexanecarboxylic acid methoxy-methyl-amide (68) were dissolved in 350 ml of anhydrous ethanol and 2.96 g (78.2 mmol) of NaBH4 were added portionwise at −70° C. The mixture was then stirred for 1 h at ambient temperature, followed by addition of 500 ml of water. Initially, the pH was then adjusted to pH=4-5 using a 10% aqueous HCl-solution to remove remaining NaBH4. Afterwards, the pH was adjusted to pH=8 using saturated aqueous NaHCO3-solution and the ethanol was evaporated. The residual solution was extracted three times using 300 ml of ethyl acetate each. Afterwards, the organic layer was washed using 300 ml of a saturated aqueous NaCl-solution, dried over MgSO4 and evaporated. Chromatography on silica gel using ethyl acetate/n-heptane yielded 6.00 g of 69 as a colourless oil, containing only one cis/trans isomer of unknown configuration. Rt=0.66 min (Method P).
Reaction SMILES: [NH2:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH2:15][CH2:16][OH:17])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.[C:18](OC(=O)C)(=[O:20])[CH3:19].[CH3:25][CH2:26][O:27]CC>>[C:18]([NH:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH2:15][CH2:16][O:17][C:26](=[O:27])[CH3:25])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1)(=[O:20])[CH3:19]
Reactant: NN1NC=C(c2ncc([N+](=O)[O-])n2CCO)S1
Reactant: CCOCC
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NN1NC=C(c2ncc([N+](=O)[O-])n2CCOC(C)=O)S1

Procedure:
The sample (0.1 g.) of 2-amino-5-[1-(2-hydroxyethyl)-5-nitro-2-imidazolyl]thiadiazole is added to 1.5 ml. of acetic anhydride and heated under reflux for 20 minutes. After cooling, the mixture is evaporated to dryness to give a tan solid which is slurried with ether and collected, melting point 258°-265° C.; the yield is 0.11 g. This solid is recrystallized from acetone to give the purified product, melting point 264°-268° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:19]1[CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:21][CH2:20][OH:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(I)ccc2C1
Reactant: C1CO1
Product: CC(C)(C)OC(=O)N1CCc2cc(CCO)ccc2C1

Procedure:
6-(2-Hydroxy-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester is prepared as example 7c from 8.30 g (23.1 mmol) 6-iodo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 10a) and 4.07 g (92.4 mmol) oxirane.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[C:24]([F:27])([F:26])[F:25].Cl>CN(C=O)C>[CH3:13][C:11]1[NH:10][N:9]=[C:8]([O:7][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[C:24]([F:25])([F:26])[F:27])[CH:12]=1
Reactant: Cc1cc(O)n[nH]1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)n[nH]1
Temperature: 60 °C
Yield: 60.6 %

Procedure:
Potassium carbonate (7.60 g, 55.0 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (4.90 g, 50.0 mmol) and 2-fluoro-5-nitrobenzotrifluoride (10.5 g, 50.0 mmol) in DMF (50 ml), and the mixture was stirred under heating at 60° C. for 4 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (100 ml) and extracted with ethyl acetate (50 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellowish viscous substance of 5-methyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole (8.70 g, yield: 60.6%). 1H-NMR (CDCl3, TMS, ppm): δ 2.30 (d, J=0.5 Hz, 3H), 5.78 (d, J=0.5 Hz, 1H), 7.31 (d, J=9.2 Hz, 1H), 8.31 (dd, J=2.7 and 9.2 Hz, 1H), 8.57 (d, J=2.7 Hz, 1H), 10.05-10.50 (br s, 1H).
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[C:13]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C@@H:23]([C:41]([O:43]C)=[O:42])[CH2:24][C:25]3[CH:30]=[C:29]([CH3:31])[C:28]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:27]([CH3:40])[CH:26]=3)=[O:21])[CH2:16][CH2:15]2)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[C:13]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C@@H:23]([C:41]([OH:43])=[O:42])[CH2:24][C:25]3[CH:26]=[C:27]([CH3:40])[C:28]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:29]([CH3:31])[CH:30]=3)=[O:21])[CH2:16][CH2:15]2)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cc(C)c(OCc2ccccc2)c(C)c1)OC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 38 mg (1.60 mmol) LiOH in 50 mL water was added to a solution of 600 mg (1.06 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2-dihydro-quinolin-3-yl)-piperidine-1-carboxylate in 30 mL THF and the reaction mixture was stirred for 1 h at RT. The organic solvent was eliminated i.vac., the aqueous residue was diluted with 50 mL water and acidified with 1 M HCL. The precipitate formed was filtered off, washed with 10 mL water and dried at 50° C.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[OH:9]O>C(O)(=O)C>[CH3:8][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][C:6](=[O:7])[CH:1]=1
Reactant: Cc1cccc(O)c1
Reactant: OO
Solvent: CC(=O)O
Product: CC1=CC(=O)C=CC1=O
Temperature: 55 °C

Procedure:
A mixture of m-cresol (5 mmol) and Ti-superoxide catalyst (125 mg, 20% w/w) in acetic acid (5 ml) was heated with stirring at 50-60° C. under inert atmosphere. To this reaction mixture was added aq. 30% H2O2 (20 mmol) drop wise over 15 min. and heated for 1 h. The catalyst was recovered by simple filtration and 2-methyl-1,4-benzoquinone formed (99%) was separated by chromatographic purification.
Reaction SMILES: [NH2:1][C:2]1[N:19]=[CH:18][C:17](Br)=[CH:16][C:3]=1[C:4]([N:6]=[S@@:7]([CH3:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[OH:21][C:22]1[CH:23]=[C:24]([C:28]#[CH:29])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[N:19]=[CH:18][C:17]([C:29]#[C:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([OH:21])[CH:23]=2)=[CH:16][C:3]=1[C:4]([N:6]=[S@@:7]([CH3:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: C[S@@](=O)(=NC(=O)c1cc(Br)cnc1N)c1ccccc1
Reactant: C#Cc1cccc(O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[S@@](=O)(=NC(=O)c1cc(C#Cc2cccc(O)c2)cnc1N)c1ccccc1
Temperature: 70 °C
Reaction time: 3.3 h
Yield: 4.3 %

Procedure:
To a degassed solution containing (S)-2-amino-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (106 mg, 0.3 mmol) and 3-hydroxyphenylacetylene (50 mg, 0.42 mmol) in 2.0 mL EtOAc at room temperature was added triethylamine (0.13 mL, 0.9 mmol), dichlorobis(triphenylphosphine)palladium(II) (21 mg, 0.03 mmol), and copper(I)iodide (6 mg, 0.03 mmol). The reaction was stirred at 70° C. for 3.3 hours. Additional 3-hydroxyphenylacetylene was added (50 mg, 0.42 mmol) and then again at 5.3 hours (75 mg, 0.63 mmol). The reaction was cooled to room temperature, and after 23 hours additional dichlorobis(triphenylphosphine)palladium(II) (20 mg, 0.03 mmol) was added. The reaction was heated to 60° C. and 3-hydroxyphenylacetylene (120 mg, 1.0 mmol) in 0.7 mL EtOAc (degassed) added dropwise over 7 minutes. The heat was removed after 1 hour and the reaction stirred an additional 22 hours at room temperature. The reaction was dissolved in EtOAc and washed with H2O. The EtOAc layer was extracted with 2% aqueous HCl. The combined acidic aqueous layers were washed with 30% EtOAc/hexane and then made basic with Na2CO3. The basic aqueous layer was extracted with EtOAc. Then the combined organic layers washed with brine, dried with anhydrous Na2SO4 and concentrated. The yellow oil was purified by chromatography (silica gel, CHCl3/EtOAc) to give the title compound as a white solid (5 mg, 4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[C:14]([Cl:15])=[N:13][S:12][N:11]=2)=[C:6]([CH2:8][NH2:9])[CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@H:24]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:25]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29](O)=[O:30])=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:16]([O:20][C:21]([NH:23][C@H:24]([CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[C:25]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([NH:9][CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:10]1[C:14]([Cl:15])=[N:13][S:12][N:11]=1)=[O:30])=[O:26])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)C1CCCCC1
Reactant: NCc1cc(Cl)ccc1-c1nsnc1Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-c1nsnc1Cl)C1CCCCC1

Procedure:
To a stirred solution of 1-[5-chloro-2-(4-chloro-1,2,5-thiadiazol-3-yl)phenyl]methanamine (28.1 mg, 0.11 mmol), 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl}-L-proline (prepared by standard peptide coupling protocols, 38.3 mg, 0.11 mmol) and HOAt (19.1 mg, 0.14 mmol) in DMF (1.0 mL) was added EDC (26.9 g, 0.14 mmol). After 16 h the mixture was partitioned between EtOAc and water. The organic phase was washed with brine dried (Na2SO4) and reduced in vacuo. The residue was purified by HPLC (C18 eluting with an acetonitrile/water/0.1% TFA gradient). 1-{(2R)-2-[(tert-Butoxycarbonyl)amino]-2-cyclohexylethanoyl}-N-[5-chloro-2-(4-chloro-1,2,5-thiadiazol-3-yl)benzyl]-L-prolinamide was obtained as a solid. LCMS m/z=596.5.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:17])[CH2:10][NH:11][C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19].N1C=CC=CC=1.[Cl-:28].[Cl-].IC1C=CC=CC=1>O1CCCC1>[ClH:28].[NH2:2][C:3]1[C:4]([C:18]([F:19])([F:20])[F:21])=[CH:5][C:6]([CH:9]([OH:17])[CH2:10][NH:11][C:12]([CH2:15][CH3:16])([CH3:13])[CH3:14])=[CH:7][C:8]=1[Cl:28]
Reactant: CCC(C)(C)NCC(O)c1ccc(N)c(C(F)(F)F)c1
Reactant: [Cl-]
Agent: Br
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: Ic1ccccc1
Product: CCC(C)(C)NCC(O)c1cc(Cl)c(N)c(C(F)(F)F)c1
Product: Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.37 gm of 1-(4'-amino-3'-trifluoromethyl-phenyl)-2-tert.pentylamino-ethanol hydrobromide and 0.2 ml of pyridine were dissolved in 30 ml of tetrahydrofuran, and the solution was cooled to 0° C. 0.3 gm of iodobenzene dichloride was added, the mixture was held for 2 hours at 0° C., and 0.1 gm of iodobenzene dichloride was again added. After standing for 20 hours at about 4° C., the solution was evaporated, distributed between ethyl acetate and water, the aqueous phase was made alkaline with 2N ammonia, and the solution was again extracted with ethyl acetate. The organic phase was washed with water, dried and a few drops of isopropanolic 4N hydrochloric acid were added. The precipitated hydrochloride of the above-mentioned compound was suction-filtered off and washed with ether. M.p. 176°-178° C. (decomp.).