Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH3:10][O:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].[Cl-].[NH4+]>O1CCCC1>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[CH2:12][O:11][CH3:10])=[CH:4][CH:5]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COCC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCC(O)(c1ccccc1)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
4.4 g of magnesium, 2 cm3 of 4-bromofluorobenzene and 10 cm3 of tetrahydrofuran are heated to a temperature in the region of 60° C. 18 cm3 of 4-bromofluorobenzene in solution in 50 cm3 of tetrahydrofuran are added and the mixture is heated at a temperature in the region of 60° C. for 2 hours. 8.4 cm3 of 2-methoxyacetophenone in solution in 60 cm3 of tetrahydrofuran are added to the solution prepared above, cooled to a temperature in the region of 5° C. After stirring for 24 hours at a temperature in the region of 20° C., the reaction mixture is poured into 200 cm3 of saturated aqueous ammonium chloride solution and extracted with twice 150 cm3 of ethyl ether, and the organic phases are washed with twice 150 cm3 of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue obtained is purified by flash chromatography on silica gel (35–70 μm), eluting with a cyclohexane/ethyl acetate (95/05) mixture; 13.2 g of 1-(4-fluorophenyl)-2-methoxy-1-phenylethanol are thus obtained in the form of a white oil, the characteristics of which are as follows:
Reaction SMILES: C1(OC([N:10]2[CH:15]=[C:14]([CH:16]=[O:17])[CH:13]=[C:12]([Cl:18])[CH2:11]2)=O)C=CC=CC=1.[S].C1C2C(=CC=CC=2)C=CC=1>C(OCC)C>[Cl:18][C:12]1[CH:13]=[C:14]([CH:16]=[O:17])[CH:15]=[N:10][CH:11]=1
Reactant: O=CC1=CN(C(=O)Oc2ccccc2)CC(Cl)=C1
Agent: [S]
Solvent: CCOCC
Solvent: c1ccc2ccccc2c1
Product: O=Cc1cncc(Cl)c1
Temperature: 25 °C

Procedure:
The mixture of 3-chloro-5-formyl-2H-pyridine-1-carboxylic acid phenyl ester (2.3 g, 8.8 mmol), sublimed sulfur (0.29 g, 9 mmol) and naphthalene (6 g) was refluxed under an argon atmosphere for 2 h. After the reaction was complete, the mixture was cooled to r.t., dissolved in ethyl ether (30 mL), and extracted with aqueous 10% HCl. The combined acid extracts were washed with ethyl ether (20 mL) and cooled to 0° C. Dichloromethane (30 mL) was added and “pH” of the mixture was adjusted to be basic with 25% aqueous NaOH, and the mixture was extracted with dichloromethane (20 mL). The combined organic phase was washed with brine, dried over K2CO3, filtered, and concentrated to give a brown solid. (0.8 g, 76%).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:14]([OH:16])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[O:42]=[C:43]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH2:44][NH:45][C:46](=[O:60])[C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:49][CH:48]=1.Cl>CN(C=O)C.O>[Cl:20][C:18]1[CH:17]=[C:13]([CH:12]=[C:11]([Cl:10])[CH:19]=1)[C:14]([N:64]1[CH2:65][CH2:66][N:61]([C:43](=[O:42])[CH2:44][NH:45][C:46](=[O:60])[C:47]2[CH:48]=[CH:49][C:50]([NH:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)=[CH:51][CH:52]=2)[CH2:62][CH2:63]1)=[O:16]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(Cl)cc(Cl)c2)CC1)c1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
DIPEA (125 mg, 0.17 mL, 0.97 mmol) was added drop wise to 3,5-dichloro-benzoic acid (74 mg, 0.389 mmol) in DMF (5 mL). EDCI (74 mg, 0.389 mmol) and HOBT (52 mg, 0.389 mmol) were added consecutively and, after 10 minutes, N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenylamino-benzamide in its HCl salt form (110 mg, 0.32 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in Hexane as eluent) to afford 39 mg (15% yield) of N-{2-[4-(3,5-Dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenylamino-benzamide. LC-MS purity: 95.72%. 1H-NMR (DMSO-d6): δ 8.6 (s, 1H), 8.3 (t, 1H), 7.8 (d, 3H), 7.5 (s, 2H), 7.3 (t, 2H), 7.2 (d, 2H), 7.1 (d, 2H), 6.9 (t, 1H), 4.1 (m, 2H), 3.6 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:16]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:9][CH2:10][O:11][CH3:16])[CH3:12])=[CH:6][CH:7]=1
Reactant: CC(CCO)c1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To the solution of 3-(4-bromophenyl)butan-1-ol (791 mg, 3.47 mmol) in tetrahydrofuran (50 mL) was added sodium hydride (278 mg, 6.94 mmol), the mixture was stirred at room temperature for 30 minutes, then iodomethane (985 mg, 6.94 mmol) was added, the mixture was stirred for 5 hours, then quenched with water (1 mL) concentrated and purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 1-bromo-4-(4-methoxybutan-2-yl)benzene (541 mg, 64%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[C:16]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:17]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[N+]([O-])([O-])=O.[NH4+].[Ce]>C(#N)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:31][CH:32]=2)[C:16]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:15]([CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[N:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1=C(CCCC(C)C)NC([C@@H]2CCCN2C(=O)OC(C)(C)C)=C(C(=O)OCC)C1c1ccc(C(=O)O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1c(CCCC(C)C)nc([C@@H]2CCCN2C(=O)OC(C)(C)C)c(C(=O)OCC)c1-c1ccc(C(=O)O)cc1
Reaction time: 0.75 h

Procedure:
4-[2-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3,5-bis(ethoxycarbonyl)-6-(4-methylpentyl)-1,4-dihydro-4-pyridinyl]benzoic acid was dissolved in a 50:50 mixture of acetonitrile:H2O. To the mixture cerium ammonium nitrate was added (6.65 g, 10.3 mmol) and allowed to stir for 45 minutes. The reaction mixture was dissolved in 100 mL of ethyl acetate and washed with H2O (2×50 mL) and brine. The organics were then dried over sodium sulfate, filtered and concentrated to yield a orange/red oil which was purified by column chromatography (ethyl acetate/hexanes (4:1)) to give 2.0 g of a solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[F:12][C:13]([F:21])([F:20])[C:14]([C:16]([F:19])([F:18])[F:17])=[O:15]>ClCCCl>[F:12][C:13]([F:21])([F:20])[C:14]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])([OH:15])[C:16]([F:19])([F:18])[F:17]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Oc1ccccc1C(O)(C(F)(F)F)C(F)(F)F
Temperature: -35 °C
Reaction time: 36 h
Yield: 82.4 %

Procedure:
94.11 g (1000 mmol) of phenol and 166.02 g (100 mmol) of AlCl3 were initially charged in 1200 ml of 1,2-dichloroethane and cooled to −35° C. At this temperature, the precalculated amount of 166.02 g (1000 mmol) of hexafluoroacetone was metered in from a bomb. Subsequently, the reaction mixture was allowed to come to room temperature (20° C., RT) and stirred at RT for a further 36 h. The reaction flask was subsequently flushed with N2 and the offgas passed into a wash bottle containing water. For workup of the remaining reaction solution, 500 ml of water were added cautiously and the mixture was stirred well. Subsequently, the organic phase was removed, the aqueous phase was extracted with CH2Cl2 and dried over magnesium sulphate, and the solvent was removed on a rotary evaporator. As this was done, the residue crystallized out. For purification, the resulting crystals were slurried in n-hexane and filtered off, and 230 g (842 mmol, yield: 82.4% of theory) of a white, crystalline solid were obtained.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH:7]=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH2:22]([N:24]([CH2:25][CH3:26])[C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH:7]=1)[CH3:23]
Reactant: O=[N+]([O-])c1ccc(F)cc1-c1ccc(OC(F)(F)F)cc1
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN(CC)c1ccc([N+](=O)[O-])c(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 70.6 %

Procedure:
A mixture of 5-fluoro-2-nitro-4′-(trifluoromethoxy)biphenyl (compound of Example 78(1)) (700 mg, 2.32 mmol), diethylamine (339 mg, 4.64 mmol), potassium carbonate (320 mg, 2.32 mmol) and acetonitrile (5 ml) was stirred at 100° for 10 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (580 mg, 70.5%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].[Al+3].[Cl-].[Cl-].[Cl-].[C:13](Cl)([CH3:16])([CH3:15])[CH3:14].Cl>[OH-].[Na+].CCOCC>[C:13]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)Cl
Reactant: Cc1ccccc1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: Cc1ccc(C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 60 h
Yield: 90 %

Procedure:
To o-xylene (Fluka purum, 905 ml, 7.5 mole), kept under stirring, at 0°, there was added AlCl3 (6.7 g, 50 mmole), and then, dropwise, tert-butyl chloride (Fluka puriss., 551 ml, 5 mole), during 1.25 h, while keeping the temperature between 0° and 5° (the evolving HCl was trapped in NaOH 2.5 N). The temperature was allowed to increase to room temperature. After 60 h, the reaction mixture was poured on a mixture of ice and ether, the organic phase was successively washed with brine (2x), H2O, sat. NaHCO3 and brine, dried over Na2SO4 and distilled under vacuum (Vigreux column, 30 cm) to provide 4-tert-butyl-1,2-dimethylbenzene (purity >99%, yield 90%).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15](/[CH:19]=[CH:20]/[C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)=[CH:16][CH:17]=3)[C:12]3[CH:29]=[C:30]([Cl:33])[CH:31]=[N:32][C:11]2=3)(=O)=O)C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:33][C:30]1[CH:31]=[N:32][C:11]2[NH:10][C:18]3[C:13]([C:12]=2[CH:29]=1)=[CH:14][C:15](/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[CH:16][CH:17]=3
Reactant: COc1ccc(/C=C/c2ccc3c(c2)c2cc(Cl)cnc2n3S(=O)(=O)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(/C=C/c2ccc3[nH]c4ncc(Cl)cc4c3c2)cc1
Yield: 16 %

Procedure:
To a Solution of (E)-9-Benzenesulfonyl-3-Chloro-6-(2′-(4-methoxyphenyl)ethenyl)-9H-pyrido[2,3-b]indole (127 mg, 0.25 mmol, 1 equiv.) in anhydrous THF (11 ml) under Argon, TBAF 1M in THF (1.26 ml, 1.26 mmol, 5 equiv.) is added dropwise. The reaction is carried out at reflux for 4 hours and then concentrated under reduced pressure. The crude product is washed with MeOH and then filtered. The product R350 is obtained as a white solid (17 mg, 0.04 mmol) in 21% yield. 1H NMR (300 MHz, DMSO d6) δ 12.05 (br s, 1H), 8.68 (d, 1H, J=2.1 Hz), 8.42 (d, 1H, J=2.3 Hz), 8.41 (s, 1H), 7.74 (d, 1H, J=8.3 Hz), 7.55 (d, 2H, J=8.5 Hz), 7.50 (d, J=8.3 Hz), 7.21 (d, 2H, J=1.5 Hz), 6.97 (d, 2H, J=8.5 Hz), 3.78 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C(N(CC)CC)C.Cl.[CH3:18][C:19]1[NH:23][CH:22]=[N:21][C:20]=1[C:24](Cl)=[O:25]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:24]([C:20]2[N:21]=[CH:22][NH:23][C:19]=2[CH3:18])=[O:25])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1Cl
Reactant: Cc1[nH]cnc1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Cc1ccc(NC(=O)c2nc[nH]c2C)cc1Cl
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 740 g (5.22 moles) of 3-chloro-4-methylaniline and 1054.6 g (10.44 moles) of triethylamine in 10 liters of acetone at room temperature and vigorous stirring, there were added slowly 945 g (5.22 moles) of 5-methyl-4-imidazolecarbonyl chloride hydrochloride. After the addition was ended, the mixture was refluxed for 1 hour and then allowed to cool to room temperature and filtered. The liquid filtrate was evaporated until a slight precipitation appeared, it was then poured over 20 liters of cold water with stirring, filtered and the precipitate was dried to give N-(3-chloro-4-methylphenyl)-5-methyl-4-imidazolecarboxamide, a crude yellowish product. Crystallisation from isopropyl alcohol gave 1108 g (85% yield) of the desired pure product having the same characteristics as the one obtained in Example 1.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.[OH-].[Na+].C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:13])=[CH:6][C:7]=2[N:12]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1

Procedure:
Prepared analogously to Example 113a from 3,4-diamino-benzoic acid ethyl ester and 1,3-dichloro-2-isothiocyanato-benzene with DCC in DMF and NaOH in ethanol.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[O:11]([C:13]1[CH:14]=[C:15]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:16][C:17]1[S:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[C:18]=1[S:26](Cl)(=[O:28])=[O:27])[CH3:12]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:26]([C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:17]=1[CH2:16][C:15]1[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:13]([O:11][CH3:12])[CH:14]=1)(=[O:27])=[O:28]
Reactant: Cc1noc(N)c1Br
Reactant: COc1cc(Cc2sc3ccccc3c2S(=O)(=O)Cl)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cc2sc3ccccc3c2S(=O)(=O)Nc2onc(C)c2Br)cc(OC)c1OC

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4,5-trimethoxybenzyl)-benzo[b]thiophene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 4-bromo-3-methyl-5-aminoisoxazole (0.55 mmoles, 97 mg), NaH (1.4 mmoles, 55 mg), and 2-(3,4,5-trimethoxylbenzyl)-benzo[b]thiophene-3-sulfonyl chloride (0.66 mmoles, 0.27 g) in THF (2 ml) yielded, after flash chromatography using 50% ethyl acetate/hexanes and recrystallization from chloroform and hexanes, 94 mg of a tan solid, m.p. 154-156° C.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][N:12]=[C:11]([C:14](=[N:18][O:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:15]([OH:17])=[O:16])[N:10]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C:9]1[S:13][N:12]=[C:11]([C:14](=[N:18][O:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:15]([OH:17])=[O:16])[N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=NOC2CCCC2)C(=O)O)ns1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(C(=NOC2CCCC2)C(=O)O)ns1
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A solution of 348 mg (0.97 mmoles) of 2-(5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetic acid in 2 ml of trifluoroacetic acid was allowed to stand for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was triturated with 5 ml of isopropyl ether and 10 ml of hexane to give 215 mg (86%) of the title compound. Mp. 162°-165° C. (dec.) [lit(3) : mp. 160°-165° C. (dec.)].
Reaction SMILES: C(C1SC2C=CC(Cl)=CC=2C=1)(=O)C1C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[S:27][C:26](/[C:28](/[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29]\[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][C:24]=2[CH:41]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[S:27][C:26](/[C:28](/[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][C:24]=2[CH:41]=1
Reactant: CCOC(=O)/C=C(/c1ccccc1)c1cc2cc(Cl)ccc2s1
Agent: O=C(c1ccccc1)c1cc2cc(Cl)ccc2s1
Product: CCOC(=O)/C=C(\c1ccccc1)c1cc2cc(Cl)ccc2s1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 2-benzoyl-5-chlorobenzothiophene, (Z)-ethyl 3-(5-chloro-2-benzothiophenyl)-3-phenylacrylate and (E)-ethyl 3-(5-chloro-2-benzothiophenyl)-3-phenylacrylate were obtained as yellowish oils.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11][CH3:12])=[CH:4][N+:3]=1[O-].P(Cl)(Cl)([Cl:16])=O>>[Br:1][C:2]1[N:3]=[C:4]([Cl:16])[C:5]([NH:11][CH3:12])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CNc1c[n+]([O-])c(Br)cc1[N+](=O)[O-]
Product: CNc1c([N+](=O)[O-])cc(Br)nc1Cl
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A suspension of 2-bromo-5-(methylamino)-4-nitropyridine 1-oxide (3.35 g, 13.51 mmol) in phosphorous oxychloride (35 mL, 374 mmol) was heated at 110° C. After 1 h, the reaction mixture was cooled to r.t. and evaporated to dryness in vacuo. The residue was partitioned between EtOAc (100 mL) and saturated sodium hydrogen carbonate, the layers were separated and the organic layer was washed with brine and dried over MgSO4. The residue was purified by flash column chromatography (SiO2, 0% EtOAc/Hexanes to 30% EtOAc/hexanes) to give 6-bromo-2-chloro-N-methyl-4-nitropyridin-3-amine 2.59.
Reaction SMILES: [F:1][CH:2]([F:53])[C:3]1[C:11]2[C:10]([F:13])([F:12])[CH2:9][CH2:8][C:7]([F:15])([F:14])[C:6]=2[N:5]([CH2:16][C:17]([NH:19][C@H:20]([C:30]2[C:35]([C:36]3[CH:37]=[CH:38][C:39]([F:45])=[C:40]([CH:44]=3)[C:41]([NH2:43])=[O:42])=[CH:34][N:33]=[C:32]([N:46]3[CH2:51][CH2:50][C:49](=[O:52])[CH2:48][CH2:47]3)[N:31]=2)[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)=[O:18])[N:4]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>ClCCCl.O>[F:53][CH:2]([F:1])[C:3]1[C:11]2[C:10]([F:12])([F:13])[CH2:9][CH2:8][C:7]([F:14])([F:15])[C:6]=2[N:5]([CH2:16][C:17]([NH:19][C@H:20]([C:30]2[C:35]([C:36]3[CH:37]=[CH:38][C:39]([F:45])=[C:40]([CH:44]=3)[C:41]([NH2:43])=[O:42])=[CH:34][N:33]=[C:32]([N:46]3[CH2:47][CH2:48][CH:49]([OH:52])[CH2:50][CH2:51]3)[N:31]=2)[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)=[O:18])[N:4]=1
Reactant: NC(=O)c1cc(-c2cnc(N3CCC(=O)CC3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: NC(=O)c1cc(-c2cnc(N3CCC(O)CC3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F
Reaction time: 3 h

Procedure:
To a solution of compound 19C (18 mg, 0.023 mmol) in 1,2-dichloroethane (0.5 ml), was added acetic acid (13 μL, 0.23 mmol) and sodium triacetoxyborohydride (9.7 mg, 0.046 mmol) at room temperature. After being stirred for 3 hours, the mixture was treated with EtOAc (10 mL) and water (3 mL). The organic layer was washed with brine (2 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified on reverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford the title product. 1H NMR (400 MHz, CD3OD) δ 8.71 (d, J=8.5 Hz, 1H), 8.09 (s, 1H), 7.41 (dd, J=7.0, 2.3 Hz, 1H), 7.33 (m, 1H), 7.20 (dd, J=10.8, 8.5 Hz, 1H), 6.97-6.61 (m, 3H), 6.42 (d, J=6.2 Hz, 2H), 5.24 (t, J=7.2 Hz, 1H), 5.13-4.96 (m, 2H), 4.51 (m, 2H), 4.01-3.83 (m, 1H), 3.42 (m, 2H), 3.14-2.82 (m, 2H), 2.50 (m, 4H), 2.08-1.84 (m, 2H), 1.68-1.37 (m, 2H); MS (m/z) 756.22 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[C:13](O)(=[O:15])[CH3:14]>>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: N[C@@H]1CCCc2c(Br)cncc21
Reactant: CC(=O)O
Product: CC(=O)N[C@@H]1CCCc2c(Br)cncc21
Yield: 91 %

Procedure:
In analogy to the procedure described for the preparation of intermediate A-4 [D], (+)-(R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (intermediate A-11) and acetic acid gave the title compound as off-white solid in 91% yield. MS: 269.0 (M+H+, 1Br).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]4[C@@H:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][N:21]([C@H:30]([CH:43]5[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]5)[C:31]([O:33]CC5C=CC(OC)=CC=5)=[O:32])[CH2:20]4)[CH2:14][CH2:13]3)=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[C:1]1([C:7]2[S:8][C:9]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]4[C@@H:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][N:21]([C@H:30]([CH:43]5[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]5)[C:31]([OH:33])=[O:32])[CH2:20]4)[CH2:14][CH2:13]3)=[CH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(c4cnc(-c5ccccc5)s4)CC3)[C@@H](c3ccccc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(c3cnc(-c4ccccc4)s3)CC2)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
To 28 mg of α-(R)-(3-(S)-((4-(2-phenyl-thiazol-5-yl)-piperidine -1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxybenzyl ester (from Step C) were added 150 mg of anisole and 3 ml of triflouroacetic acid. The reaction was stirred at room temperature for 1 hr. The trifluoroacetic acid was evaporated under reduced pressure. The residue was purified by flash chromatography with 20% MeOH in EtOAc followed by 20% MeOH+2% NH4OH in EtOAc to give 24 mg of the title compound. LC-MS (Method A): Retention Time: 2.72 min. Mass Spectrum: 544 (M+H).