Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([CH:25]([CH3:27])[CH3:26])=[N:23][CH:24]=[C:18]2[CH:17]1[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(Cl)(Cl)Cl.C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([CH:25]([CH3:27])[CH3:26])=[N:23][C:24]([Cl:1])=[C:18]2[CH:17]1[CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:34][CH:35]=1)=[O:15])([CH3:11])([CH3:12])[CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)c1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Temperature: 70 °C

Procedure:
To a solution of N-chlorosuccinimide (87.3 mg; 0.628 mmol) in chloroform (1 ml) was added a solution of 3-isopropyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (229 mg; 0.523 mmol) in chloroform (2 ml) and the resulting solution was heated to 70° C. for 5 h30. The reaction mixture was allowed to cool to rt, diluted with DCM (20 ml) and washed with water (3×10 ml). The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by preparative HPLC gave the pure product 1-chloro-3-isopropyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (97 mg; 39%). LC-MS: tR=1.04 min.; [M+H]+=472.51 g/mol.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)[CH2:4][CH2:3][C@@H:2]1[CH2:15][OH:16].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:16][CH2:15][C@H:2]2[CH2:3][CH2:4][C:5]3[C:10](=[C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]4=[CH:7][CH:6]=3)[O:1]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1CCc2ccc3ccccc3c2O1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc4ccccc4c3O2)cc1
Temperature: 50 °C
Yield: 77.2 %

Procedure:
To a solution of (2R)-3,4-dihydro-2H-benzo[h]chromen-2-ylmethanol (0.90 g, 4.22 mmol) in dichloromethane (50 mL) was added p-toluenesulfonyl chloride (1.61 g, 8.44 mmol), 4-(dimethylamino)pyridine (0.10 g, 0.84 mmol), and N,N-diisopropylethylamine (1.20 g, 9.28 mmol) and the reaction mixture was heated to 50° C. for 12 h. The reaction mixture was quenched by the addition of water (100 mL). The aqueous layer was separated and extracted with dichloromethane (100 mL). The combined organic extracts were washed with aqueous hydrogen chloride (1.0 M, 100 mL), water (100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:3) gave 1.20 g (77%, 50% ee) of (2R)-3,4-dihydro-2H-benzo[h]chromen-2-ylmethyl 4-methylbenzenesulfonate as a white solid. [α]D25=−10.23 (c 10.16 in chloroform, 50% ee); Rf=0.68 (silica, ethyl acetate:hexanes 2:3); mp 107-111° C.; Anal. Calcd. for C21H20O4S: C, 68.46; H, 5.47. Found: C, 68.10; H, 5.27.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:16](=[O:33])[CH2:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[C:1]([NH:4][CH:5]([CH:16]([OH:33])[CH2:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:20]=1)[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(Cc1csc2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC(=O)NC(Cc1csc2ccccc12)C(O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The compound of Example 4 (1.1 g) was treated with sodium borohydride (100 mg) in the same manner as Example 2 to yield the title compound isomer A as a white solid (0.23 g), mp=70°-71° C.; found: C, 56.43; H, 4.22; N, 2.77; C23H21F6NO2S requires C, 56.44; H, 4.32; N, 2.86%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:13]([C:16]1[CH:17]=[C:18]([C:26](=[O:28])[CH3:27])[CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)(=[O:15])[CH3:14]>C1COCC1>[C:22]([C:20]1[CH:21]=[C:16]([C:13](=[O:15])[CH3:14])[CH:17]=[C:18]([C:26]([OH:28])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:27])[CH:19]=1)([CH3:23])([CH3:25])[CH3:24]
Reactant: Brc1ccccc1
Reactant: CC(=O)c1cc(C(C)=O)cc(C(C)(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(C)(C)C)cc(C(C)(O)c2ccccc2)c1
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To 288.0 mg (1.83 mmol) of bromobenzene in 8 ml of dry THF at -78° C. was added 734 ml (1.83 mmol) of n-BuLi (2.5 M in hexanes). The reaction was stirred for 10 min followed by addition of 400 mg (1.83 mmol) of diketone 14 in 2 ml of dry THF. After stirring for 30 min, the mixture was quenched with saturated aqueous NH4Cl and the products were extracted with EtOAc. The EtOAc extracts were washed with water, brine, dried, filtered, and concentrated to give 420 mg of crude compound 15 which was used in the next step without further purification. TLC (20% EtOAC-80% hexanes) Rf 0.7.
Reaction SMILES: [N:1]1([C:7]([C@@H:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][N:10]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C([O-])(O)=O.[Na+]>O1CCCC1>[N:1]1([CH2:7][C@@H:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][N:10]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C([C@@H]1Cc2ccccc2CN1C(=O)OCc1ccccc1)N1CCOCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1Cc2ccccc2C[C@H]1CN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 5.3 g of the product obtained in Step A (13.9 mmol) in 278 mL of tetrahydrofuran there are added 14 mL of borane-dimethylsulphide complex (BH3Me2S) (27.8 mmol) at ambient temperature. The batch is heated for 4 hours at 80° C. It is allowed to return to ambient temperature and there are then added 7 mL (14 mmol) of BH3Me2S. The reaction mixture is again heated at 80° C. for 2 hours. The tetrahydrofuran is then evaporated off and then there is slowly added methanol and then 5.6 mL of 5N aqueous HCl solution (27.8 mmol). The mixture is stirred at ambient temperature overnight, and then at 80° C. for 1 hour. Saturated aqueous NaHCO3 solution is then added to the reaction mixture placed at 0° C. until a pH of 8 is obtained, and extraction with ethyl acetate is then carried out. The organic phase is then dried over MgSO4, and then filtered and evaporated to dryness. The title product is obtained in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[C:6]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=1.[C:27](=[O:30])([O-])[O-:28].[Na+].[Na+]>COCCOC.O.C1OC2C=CC(B(O)O)=CC=2O1.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>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:5]=[C:6]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[C:8]([C:4]2[CH:9]=[CH:8][C:7]3[O:28][CH2:27][O:30][C:6]=3[CH:5]=2)[CH:9]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OB(O)c1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)cc(-c2ccc3c(c2)OCO3)c1
Yield: 198.6 %

Procedure:
3-Benzyloxy-5-trifluoromethanesulfonyloxy-benzoic acid methyl ester (15.4 g) was dissolved in 1,2-dimethoxyethane (250 mL), followed by addition of Pd(PPh3)4 (2.5 g), solution of sodium carbonate (12 g) in water (120 mL) and 3,4-methylenedioxyphenylboronic acid (8.4 g). The resulting reaction mixture was refluxed under the flow of nitrogen for 5 h. After cooling the organic layer was separated and washed with water and then dried over magnesium sulfate. The crude material was purified on a silica gel column using ethyl acetate and hexanes to yield 14.2 g (99% yield) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:21]=[N:20][C:19]2[NH:18][C:17](=[O:22])[N:16]3[N:23]=[CH:24][N:25]=[C:15]3[C:14]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Br:11][C:12]1[CH:21]=[N:20][C:19]2[N:18]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=3)[C:17](=[O:22])[N:16]3[N:23]=[CH:24][N:25]=[C:15]3[C:14]=2[CH:13]=1
Reactant: O=c1[nH]c2ncc(Br)cc2c2ncnn12
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(Br)cnc32)cc1
Temperature: 40 °C
Yield: 70 %

Procedure:
1-(Chloromethyl)-4-methoxybenzene (3.10 ml, 22.9 mmol) was added to a stirred solution of 9-bromopyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (3.02 g, 11.35 mmol) and potassium carbonate (4.71 g, 34.1 mmol) in 1-methylpyrrolidinone (60 ml) and the mixture was heated at 40° C. for 14 hours. The mixture was filtered, and the resulting solid was washed liberally with dichloromethane. The combined organics were concentrated under vacuum and the residue was triturated with ethyl acetate (40 mL) to afford 3.07 g (70%) of the benzylated product as a brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].[CH2:35]([O:37][C:38](=[O:49])[C:39]([C:42]1[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=1)([CH3:41])[CH3:40])[CH3:36]>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>[CH2:35]([O:37][C:38](=[O:49])[C:39]([C:42]1[CH:47]=[CH:46][C:45]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:33])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:34])=[CH:19][CH:20]=2)=[CH:44][CH:43]=1)([CH3:41])[CH3:40])[CH3:36]
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Reactant: CCOC(=O)C(C)(C)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C(C)(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)cc1

Procedure:
Following the procedure described in Example 17, Step 2, {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester, 2-(4-bromo-phenyl)-2-methyl-propionic acid ethyl ester, and bis(triphenylphosphine)palladium(II) dichloride were reacted to provide 2-(4′-{-4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-2-methyl-propionic acid ethyl ester; further purification by preparative HPLC was required. The ester was hydrolyzed to the acid as described in Example 17, Step 3; purification by preparative HPLC was utilized.
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH2:6][C:7]2[NH:11][C:10](C=O)=[CH:9][CH:8]=2)[NH:3][CH:2]=1.C12C=C3N=C(C=C3)C=C3NC(C=C3)=CC3=NC(C=C3)=CC(N1)=CC=2>>[CH:9]1[CH:8]=[C:7]([CH2:6][C:4]2[NH:3][CH:2]=[CH:1][CH:5]=2)[NH:11][CH:10]=1
Reactant: O=Cc1ccc(Cc2ccc[nH]2)[nH]1
Agent: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Product: c1c[nH]c(Cc2ccc[nH]2)c1
Yield: 46 %

Procedure:
1-Formyldipyrromethane 2 is the key precursor for the porphine synthesis described herein. Formylation of dipyrromethane via Vilsmeier or Grignard reagent mediated syntheses21 results in multiple byproducts, requiring tedious chromatographic separation for the purification of 1-formyldipyrromethane (2). The TLC and 1H NMR analyses of the crude reaction mixture obtained from Vilsmeier formylation of dipyrromethane showed the presence of three components: starting dipyrromethane (3), 1-formyldipyrromethane (2), 1,9-diformyldipyrromethane (4), and an unknown byproduct (tentatively assigned as a 2-formyldipyrromethane) in a ratio of 7:20:4:1. We were able to separate the desired 2 in 46% yield (without using a tin complexation strategy); however, the purification required lengthy column chromatography.
Reaction SMILES: [CH2:1]([C:3]1([CH3:19])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[O:4]1)[CH3:2].FC(F)(F)C(O[I:25](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.II>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([C:3]1([CH3:19])[C:7](=[O:8])[C:6]([I:25])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[O:4]1)[CH3:2]
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=CC1=O
Agent: II
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(I)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 135 %

Procedure:
To 8.88 g of 2-ethyl-2-methyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone in 50 ml carbon tetrachloride and 50 ml chloroform, were added [bis(trifluoroacetoxy)iodo]benzene (6.82 g) and iodine (4 g). The reaction solution was stirred at room temperature for 4 hours. Then the reaction was quenched by adding saturated aqueous sodium thiosulfate until the characteristic color of iodine disappeared. The solution was extracted with 50 ml water and dichloromethane (100 ml×3). The organic layer was concentrated in vacuo and the resulting residue was purified by lo column chromatographic separation (hexane/ethylacetate=1:1) to yield 8.7 g of 2-ethyl-4-iodo-2-methyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone. NMR: δ0.89 (t, J=7.5 Hz, 3H), 1.51 (s, 3H), 1.93 (q, J=7.5 Hz, 2H), 3.11 (s, 3H), 8.11 (d, J=8.7 Hz, 2H), 8.34 (d, J=8.7 Hz, 2H). IR (cm−1): 2928, 1701, 1552, 1314, 1148, 747, 551.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:29])=[O:28])([CH3:26])[CH3:25])[N:21]=[C:20]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[N:19]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:29])=[O:28])([CH3:25])[CH3:26])[N:21]=[C:20]([C:34]2[CH:40]=[CH:39][C:37]([NH:38][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:36][CH:35]=2)[N:19]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C(C)(C)C)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C(C)(C)C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
Phenyl chloroformate (0.368 mL, 2.93 mmol) was added to 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-tert-butylsulfonylpropan-2-yl)pyrimidin-2-yl]aniline (1.153 g, 2.67 mmol) and sodium hydrogen carbonate (0.336 g, 4.00 mmol) in dioxane (20 mL) at RT. The resulting slurry was stirred at RT for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 20%-70% ethyl acetate in isohexane, to give the desired material as a near colourless solid (1.42 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15](F)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH3:22]>O1CCCC1>[NH2:22][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)=[CH:13][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: N
Reactant: O=[N+]([O-])c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1F
Solvent: C1CCOC1
Product: Nc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 72 h

Procedure:
A solution of 50.0 g of 3-chloro-2-(4-fluoro-3-nitrophenyl)-5-trifluoromethylpyridine in 200 ml of tetrahydrofuran was treated with 200 g of a 25% strength by weight aqueous ammonia solution. After stirring at 23° C. for three days, the tetrahydrofuran was removed by distillation, whereupon the product crystallized. The crystals were separated off, washed with water and dried in a vacuum drying oven. Yield: 48.7 g (98%) of colorless crystals; m.p.: 126-127° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][CH:44]=[CH:45][C:46]=2[CH3:47])[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][CH:44]=[CH:45][C:46]=2[CH3:47])[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: Cc1ccncc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: Cc1ccncc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(OCC(F)(F)F)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K30) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (380 mg, 83%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32][CH2:33][N:34]=[N+]=[N-])=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N>N1C=CC=CC=1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32][CH2:33][NH2:34])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CCN=[N+]=[N-]
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CCN
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of (2R,4S)-1-allyloxycarbonyl-2-(2-azidoethyl)-4-(triphenylmethylthio) pyrrolidine (10.1 g) in pyridine (30 ml) was added triphenylphosphine at ambient temperature. The mixture was stirred at the same temperature for 1 hour, and then 28% aqueous ammonia was added. After stirring at ambient temperature overnight, the mixture was evaporated under reduced pressure, and co-evaporated with toluene. The residue was column chromatographed on silica gel (chloroform:methanol=9:1) to give (2R,4S)-1-allyloxycarbonyl-2-(2-aminoethyl)-4(triphenylmethylthio)pyrrolidine (9.0 g).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[C:7]([Cl:8])=[N:6][C:5](=[C:9]([Cl:11])[Cl:10])[N:4]=1>C1(C)C=CC=CC=1>[Cl:2][C:3]1[N:4]=[C:5]([C:9]([Cl:1])([Cl:11])[Cl:10])[NH:6][C:7]=1[Cl:8]
Reactant: ClC1=NC(=C(Cl)Cl)N=C1Cl
Reactant: Cl
Solvent: Cc1ccccc1
Product: Clc1nc(C(Cl)(Cl)Cl)[nH]c1Cl
Yield: 89 %

Procedure:
Dry hydrogen chloride was passed into a solution of 218 g (1.0 mol) of 4,5-dichloro-2-dichloromethylene-imidazole in about 2 liters of dry toluene until the formation of the precipitate had ceased (at least 1 mol). After cooling (the addition reaction with HCl proceeded exothermically), filtering off the product and drying, 235 g (89% of theory) of 4,5-dichloro-2-trichloromethylimidazole with a melting point of 210° C. (with decomposition) were obtained.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[CH:14]1[CH:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[C:23]([SH:24])[C:17]2=[CH:16][CH:15]=1.C(O)CO>C(O)(C)C.CO.C(Cl)Cl.[Cu]I>[C:23]1([S:24][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=3)[NH:4][N:3]=2)[C:17]2[C:18](=[CH:19][CH:14]=[CH:15][CH:16]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Reactant: Sc1cccc2ccccc12
Agent: [Cu]I
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2[nH]nc(Sc3cccc4ccccc34)c2c1
Temperature: 90 °C
Yield: 49 %

Procedure:
A mixture of 3-iodo-5-nitro-1H-indazole (10.00 g, 34.60 mmol), 1-naphthylthiol (5.54 g, 34.60 mmol), CuI (0.659 g, 3.46 mmol) and ethylene glycol (4.30 g, 69.20 mmol) in isopropanol was heated at 90° C. under nitrogen overnight, cooled, diluted with 30% MeOH in CH2Cl2, and filtered through a pad of silica gel. The filtrate was concentrated in vacuo. The concentrate was purified by chromatography with 1% MeOH in CH2Cl2 to provide the title compound, 5.5 g (49% yield), characterized by NMR and mass spectral analyses.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[N:19]=[CH:18][CH:17]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.C(O)C.[OH-].[Pd+2].[OH-]>[N:16]1[N:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[N:19]=[CH:18][CH:17]=1
Reactant: c1ccc(COc2ccc(-n3nccn3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1ccc(-n2nccn2)cc1

Procedure:
2-[4-(benzyloxy)phenyl]-2H-1,2,3-triazole (400 mg, 1.6 mmol) was dissolved in 3.2 mL of a mixture of ethyl acetate and ethanol (1:1). The solution was degassed and purged with nitrogen. Palladium hydroxide (20% w/w on carbon, 110 mg, 0.16 mmol) was added and the reaction was degassed and purged with hydrogen three times. The hydrogenation was continued at room temperature under a hydrogen balloon for 1 hour. The catalyst was removed by filtration through a plug of silica gel, which was washed thoroughly with acetone. Concentration afforded the product as white solid. LRMS calc: 161.1; obs: 162.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12]C[CH:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.C1(C(=NC2C=CC([C@H]3CCC(=CC(OCC)=O)C3)=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:13][CH2:12][C:10](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1CCCC(c2ccc(N)cc2)C1
Agent: CCOC(=O)C=C1CC[C@H](c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)C1
Product: CCOC(=O)C=C1CC[C@H](c2ccc(N)cc2)C1

Procedure:
Following the procedure described for ethyl [3-(4-aminophenyl)cyclohexyl]acetate (Intermediate 89(iv)), replacing ethyl (3-{4-[(diphenylmethylene)amino]phenyl}cyclohexyl)acetate with ethyl ((3S)-3-{4-[(diphenylmethylene)amino]phenyl}cyclopentylidene)acetate the title compound was obtained; 1H NMR δ 1.17-1.22 (3H, m), 1.57-1.68 (1H, m), 2.27-2.48 (2H, m), 2.53 (OH, s), 2.56-2.68 (1H, m), 2.74-2.76 (1H, m), 2.93-3.00 (1H, m), 3.15-3.24 (0.5H, m), 3.69-3.71 (0.5H, m), 4.01-4.12 (2H, m), 4.79-4.83 (2H, m), 5.49-5.53 (1H, m), 5.78-5.82 (1H, m), 6.47-6.52 (2H, m), 6.80-6.93 (2H, m); MS m/e M+MeCN 287.