Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]1[CH3:26]>ClC(Cl)C>[CH3:15][N:16]1[C:20]([C:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)=[O:8])=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]1[CH3:26]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)c1ccn(C)c1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)c2ccc(C)cc2)n(C)c1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Thirty-seven grams of p-toluoyl chloride (0.243 mole) is added to a suspension of 32.4 g. (0.243 mole) of aluminum chloride in 80 ml of dichloroethane. The resulting solution is then added dropwise to a solution of 40.7 g. (0.243 mole) of ethyl 1,2-dimethylpyrrole-3-carboxylate in 80 ml of dichloroethane cooled in an ice bath. After the addition is complete, the resulting solution is stirred at room temperature for 20 minutes, is refluxed for 20 minutes, and is then poured into an ice-3N hydrochlorice acid mixture. The organic phase is separated and is washed twice with concentrated sodium chloride solution, after which it is dried over magnesium sulfate. Evaporation of the solvent yields a residue from which the desired product crystallized. Further product is obtained by chromatography of the mother liquor over acid-washed alumina in hexane using benzene as the eluant. Evaporation of the first compound-bearing fractions yields the desired product. Recrystallization of the combined yields of product from 95% ethanol and then methanol gives as pure product ethyl 1,2-dimethyl-5-(p-toluoyl)pyrrole-3 -carboxylate; m.p. 98°-100° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1([C:27]2[O:28][C:29]([C:35]([F:38])([F:37])[F:36])=[C:30]([C:32](O)=[O:33])[N:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:32]([C:30]3[N:31]=[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:28][C:29]=3[C:35]([F:37])([F:38])[F:36])=[O:33])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(5-Amino-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester described above was mixed with 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid (771 mg, 3.0 mmol) and bromotrispyrrolidinophosphonium hexafluorophosphate (1.40 g, 3.0 mmol) in N,N-dimethylformamide (20 mL) and methylene chloride (5 mL) containing triethylamine (0.85 mL). The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and solvent was evaporated. The residue was triturated with ethyl acetate and the solid was filtered to give 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (1.09 g). LC-MS calcd for C25H26F3N5O4 (m/e) 517.5, obsd 518.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccncc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2ccncc2c1
Temperature: -75 °C
Yield: 80.6 %

Procedure:
To a 2-liter, 3-necked round bottom flask equipped with a magnetic stir bar and addition funnel is added 19.7 g (0.124 mole) of 7-methoxyisoquinoline and 800 ml of dry dichloromethane. This solution is stirred and cooled to -75° C. with a dry ice/acetone bath, 628 ml (0.628 mole) of 1.0M boron tribromide in dichloromethane is added dropwise maintaining the temperature at -75° C. Thereafter the slurry is stirred for 18 hours allowing the temperature to rise to room temperature. The reaction slurry is poured into 1 liter of ice water and stirred for an hour. The layers are separated and the aqueous layer is then adjusted from acidic to neutral (pH 7) with 1N NaOH. A yellow solid precipitates and is filtered off, then air dried to yield 14.5 g of a yellow solid, 81%.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[CH2:3][CH:4]([C:9](=[O:32])[NH:10][C@H:11]1[CH2:29][C:28]2=[CH:30][N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=32)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:31])[CH2:5][C:6]([OH:8])=O.O.OC1C=CC2NN=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:56]([O:63][NH2:64])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>CN(C=O)C>[CH2:56]([O:63][NH:64][C:6](=[O:8])[CH2:5][CH:4]([C:9](=[O:32])[NH:10][C@H:11]1[CH2:29][C:28]2=[CH:30][N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=32)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:31])[CH2:3][CH:2]([CH3:1])[CH3:33])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)CC(CC(=O)O)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCCNC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Oc1ccc2[nH]nnc2c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(CC(=O)NOCc1ccccc1)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCCNC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the less polar stereoisomer of (11S)-5-methyl-3-(10-oxo-1,9-diazatricyclo[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanoic acid (210 mg) and 5-hydroxybenzotriazole monohydrate (109 mg) in anhydrous DMF (20 mL) under argon was cooled to 0° C. (ice bath). To this mixture was added EDCI (282 mg) and stirring was continued for 0.5 hours. O-benzylhydroxylamine (0.27 mL) was added to the solution and the reaction mixture was left to warm to room temperature overnight. All volatiles were removed under reduced pressure. The residue was taken up in CH2 Cl2 (100 mL) and 20% HCl (100 mL) and transferred to a separatory funnel. The organic phase was isolated and the aqueous phase washed (2×100 mL) with CH2Cl2. The organic materials were then washed consecutively with 5% NaHCO3, brine, dried (MgSO4), filtered and concentrated to provide (11S)-N-benzyloxy-5-methyl-3-(10-oxo-1,9-diazatricyclo[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl) hexanamide as a crystalline product. The product was further purified by column chromatography on silica gel followed by crystallization from hot ethyl acetate/CH2Cl2, to provide the more polar stereoisomer of the compound having a melting point at 232°-233° C. m.p., and the less polar stereoisomer of the compound having a melting point at 251°-253° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:24][C@H:25]([C:31]([OH:33])=[O:32])[CH2:26][CH2:27][C:28](=[O:30])[NH2:29])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>>[NH2:1][C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:24][C@H:25]([C:31]([OH:33])=[O:32])[CH2:26][CH2:27][C:28](=[O:30])[NH2:29])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: Cl
Product: CC(C)C[C@H](NC(=O)CNC(=O)[C@@H](N)Cc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)O

Procedure:
Boc-Phe-Gly-Leu-Gln-NA (0.90 g) was deblocked by treatment with ethanolic HCl to yield 0.79 g of H-Phe-Gly-Leu-Gln-NA HCl. TLC in 1-butanol:acetic acid:water (4:1:1) indicated a major spot, Rf 0.61, and two trace spots, Rf 0.71 and Rf 0.51.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([NH:14][CH2:15][CH3:16])=O)[CH2:8][CH2:7]1)[CH3:2].[BH4-].[Na+].C(O)(=O)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][NH:14][CH2:15][CH3:16])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCNC(=O)[C@H]1CC[C@H](CC(=O)OCC)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCNC[C@H]1CC[C@H](CC(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A stirred suspension of ethyl{trans-4-[(ethylamino)carbonyl]cyclohexyl}acetate (Step A; 740 mg; 3.07 mmol) and sodium borohydride (558 mg; 14.74 mmol) in THF (6 mL) was heated at reflux. Acetic acid (845 mL) was added dropwise over 1 h and the resultant mixture was heated at reflux for 2 h more. The reaction was cooled in an ice bath and carefully quenched with H2O (1.5 mL). 1.5NNaOH (10 mL) was added and the reaction was extracted with EtOAc (3×50 mL). The combined extracts were washed with H2O and brine (25 mL each), dried (Na2SO4), filtered and concentrated in vacuo. The residue was redissolved in EtOH (4 mL) and 4N HCl(EtOAc) (0.9 mL) was added dropwise. The reaction stirred at room temperature for 14 h. The reaction was diluted with EtOAc (30 mL) and washed successively with 2N NaOH, H2O, and brine (15 mL each). The aqueous layers were re-extracted with EtOAc (2×25 mL) and the extracts were washed with brine (15 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford ethyl{trans-4-[(ethylamino)methyl]cyclohexyl}acetate as a yellow oil. LCMS=228.3 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 4.14 (q, J=7.1 Hz, 2 H), 2.66 (q, J=7.2 Hz, 2 H), 2.47 (d, J=6.9 Hz, 2 H), 2.19 (d, J=6.8 Hz, 2 H), 1.83-1.78 (m, 4 H), 1.59-1.52 (m, 2H), 1.44-1.36 (m, 2 H), 1.27 (t, J=7.1 Hz, 3 H), 1.13 (t, J=7.2 Hz, 3 H), 1.03-0.97 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([S:11]([NH:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])(=[O:13])=[O:12])[N:10]=[C:4]2[N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([S:11]([N:14]([C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:15]3[C:16]([Cl:22])=[CH:17][CH:18]=[CH:19][C:20]=3[Cl:21])(=[O:13])=[O:12])[N:10]=[C:4]2[N:3]=1
Reactant: Cc1ccn2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccn2nc(S(=O)(=O)N(C(=O)c3ccccc3)c3c(Cl)cccc3Cl)nc2n1
Yield: 71.1 %

Procedure:
A mixture of 3.00 g (8.37 mmol) of 5-methyl-N-(2,6-dichlorophenyl)-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide and 1.16 g (8.37 mmol) of anhydrous powdered K2CO3 in 100 ml of acetone was heated at reflux for 30 minutes. A solution of 1.18 g (8.37 mmol) of benzoyl chloride in 10 ml of acetone was added, and the reaction was heated at reflux for 115 min. The reaction was filtered, and the filtrate was evaporated at reduced pressure. The solid residue was collected by filtration, washed thoroughly with aqueous NaHCO3 and H2O and dried to yield 2.75 g (72%) of the desired product as a solid, mp 187°-189° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2ccccc2nc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc2ccccc2nc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-3-formylquinoline (6 g; 21.3 mmol) in 150 mL of methanol was added sodium borohydride (1.8 g; 46.97 mmol) and was stirred at room temperature for 16 hours. Methanol was removed by rotary evaporation. The residue was re-suspended in chloroform, washed with water and dried over potassium carbonate. After filtration through a silica gel pad, the product, 2-chloro-3-hydroxymethylquinoline was present as a white solid (4.3 g), which was used for the next synthesis step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)([CH:9]=[O:10])[CH2:5][CH2:4]1.[BH4-].[Na+].O>CCCC>[CH3:26][O:25][C:3]1([O:2][CH3:1])[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:12]=2)([CH2:9][OH:10])[CH2:5][CH2:4]1
Reactant: COc1ccc(C2(C=O)CCC(OC)(OC)CC2)cc1OC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCC
Solvent: O
Product: COc1ccc(C2(CO)CCC(OC)(OC)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-1-one dimethyl ketal (0.24 g, 0.66 mmol) in 1,2-dimethyl-ethane (5 mL) under an argon atmosphere was added sodium borohydride (0.05 g, 1.3 mmol) and the mixture was stirred at room temperature for 0.75 h. Water was added, the mixture was partitioned between ether and water, was extracted twice with ether, the organic extract was dried (potassium carbonate) and evaporated to an oil (0.19 g, 79%).
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15](OC)=[O:16])=[CH:12][CH:13]=3)[N:8]([CH3:19])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][CH:21]([CH3:23])[O-:22].[Li+].O>CC(O)C>[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]([O:22][CH:21]([CH3:23])[CH3:20])=[O:16])=[CH:12][CH:13]=3)[N:8]([CH3:19])[CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)[O-]
Reactant: COC(=O)c1ccc2c(C3CCCC3)cn(C)c2c1
Agent: [Li+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)OC(=O)c1ccc2c(C3CCCC3)cn(C)c2c1
Temperature: 65 °C
Yield: 95.2 %

Procedure:
The mixture of methyl 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate (50.0 g, 0.194 mol) and lithium isopropoxide (16.2 g, 95%, 0.233 mol) in 2-propanol was stirred at 65±5° C. for at least 30 min for complete trans-esterification. The batch was cooled to 40±5° C. and water (600 g) was added at a rate to maintain the batch temperature at 40±5° C. After addition, the mixture was cooled to 20-25° C. over 2±0.5 h and held at 20-25° C. for at least 1 h. The batch was filtered and rinsed with 28 wt % 2-propanol in water (186 g), and water (500 g). The wet cake was dried in vacuo (≦200 Torr) at 40-45° C. until the water content was ≦0.5% to give isopropyl 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate (52.7 g, 95% yield) in 99.2 A % (240 nm).
Reaction SMILES: O1CCCC1.O.O.[NH2:8][CH:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]([NH:12][CH:13]1[C:28](=[O:29])[N:15]2[C:16]([C:25]([OH:27])=[O:26])=[C:17]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH2:18][S:19][C@H:14]12)=[O:11].[CH3:36][N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]([C:46](Cl)=[O:47])[C:38]1=[O:49]>CO>[CH3:36][N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]([C:46]([NH:8][CH:9]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:10]([NH:12][CH:13]2[C:28](=[O:29])[N:15]3[C:16]([C:25]([OH:27])=[O:26])=[C:17]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH2:18][S:19][C@H:14]23)=[O:11])=[O:47])[C:38]1=[O:49]
Reactant: Cn1c(=O)n(C(=O)Cl)c2ccccc21
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccccc3)[C@H]2SC1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)n3c(=O)n(C)c4ccccc43)c3ccccc3)[C@H]2SC1

Procedure:
To 30 ml. of dry tetrahydrofuran (THF) were added 441 mg. (1 mmole) of 7-(α-aminophenylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid dihydrate and 0.97 ml. (4 mmoles) of N,O-bis-trimethylsilylacetamide. The mixture was stirred until solution was complete, and then a solution of 210 mg. (1 mmole) of 3-methyl-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylcarbonyl chloride in 5 ml. of THF was added at room temperature. The reaction mixture was stirred for 50 minutes. Methanol (5 ml.) was added to the mixture; however, no precipitation occurred. The mixture then was evaporated to a volume of about 10 ml., and the resulting precipitate was filtered. A mixture of 50 ml. of ethyl acetate and 50 ml. of water was added to the filtrate, and the pH of the mixture was adjusted to 7.5 by addition of sodium bicarbonate. The layers were separated, and the aqueous layer was acidified to pH 2.0 by addition of 1N hydrochloric acid. The acidic mixture then was extracted twice with 50 ml. of a 6:1 mixture of ethyl acetate and tetrahydrofuran. The organic extract was dried over magnesium sulfate, filtered, and evaporated slowly to a volume of about 10 ml. The concentrate was cooled overnight, and the resulting crystalline precipitate was filtered and dried to obtain 275 mg. of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:11])=[N:4][C:5]([S:9][CH3:10])=[N:6][C:7]=1[Cl:8].ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[Br:1][C:2]1[C:3]([NH2:11])=[N:4][C:5]([S:9]([CH3:10])=[O:20])=[N:6][C:7]=1[Cl:8]
Reactant: CSc1nc(N)c(Br)c(Cl)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc(N)c(Br)c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a stirring solution of 5-bromo-6-chloro-2-(methylthio)pyrimidine-4-amine (intermediate 1) (52.2 mmol) in 450 ml of DCM, a solution of 12.9 g (57.4 mmol) of m-chloroperbenzoic acid (77%) (Sigma-Aldrich) in 100 ml of DCM was slowly added. The reaction mixture was stirred at room temperature for 1 hour. The formed white precipitate was filtered, washed several times with DCM and dried. 13.96 g of 5-bromo-6-chloro-2-(methylsulfinyl)pyrimidine-4-amine were obtained (98.9%).
Reaction SMILES: [CH:1]12[C:9](=[C:10]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21]C(C)(C)C)=[O:20])=[CH:13][CH:12]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[CH:5]12[C:9](=[C:10]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)[CH:1]([CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2C3CCCC2CCC3)c2ccc(O)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(O)/C=C/c1ccc(C(=C2C3CCCC2CCC3)c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
To an ice-cooled solution of 44 (0.32 g, 0.755 mmol) in CH2Cl2 (4 mL) was added TFA (4 mL) slowly. The stirred reaction mixture was allowed to warm to RT over a period of 3 h. The reaction mixture was concentrated to give a yellow solid. The solid was dissolved in toluene, and the solution was concentrated to give a powder. The powder was triturated with CH2Cl2 and dried to give compound 45 as a tan powder (0.21 g, 74%). 1H NMR (400 MHz, DMSO-d6): δ 1.50-1.53 (m, 2H), 1.72 (s, 8H), 1.93-2.01 (m, 2H), 2.53-2.60 (m, 2), 6.43 (d, J=16.1 Hz, 1H), 6.66 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.3 Hz, 2H), 7.09 (d, J=7.8 Hz, 2H), 7.52 (d, J=16.0 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 9.30 (s, 1H), 12.33 (s, 1H). The compound was silated prior to EI analysis. HRMS (EI) Calcd for C31H42O3Si2: 518.2673 (M+). Found: 518.2685.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:29]2([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[Cl:56])[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36](OC)[CH:35]=3)[C:31]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44](OC)[CH:43]=3)=[N:30]2)[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](OC)[CH:14]=2)[C:10]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](OC)[CH:22]=2)=[N:9]1.COC1C=CC=CC=1C1(C2(C3C=CC=CC=3OC)N=C(C3C=CC=CC=3)C=N2)N=C(C2C=CC=CC=2)C(C2C=CC=CC=2)(C2C=CC=CC=2)N1>>[Cl:56][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[C:29]1([C:8]2([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:9]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:12]2)[N:30]=[C:31]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:33]1
Reactant: COc1cccc(C2=NC(c3ccccc3Cl)(C3(c4ccccc4Cl)N=C(c4cccc(OC)c4)C(c4cccc(OC)c4)=N3)N=C2c2cccc(OC)c2)c1
Agent: COc1ccccc1C1(C2(c3ccccc3OC)N=C(c3ccccc3)C(c3ccccc3)(c3ccccc3)N2)N=CC(c2ccccc2)=N1
Product: Clc1ccccc1C1(C2(c3ccccc3Cl)N=C(c3ccccc3)C(c3ccccc3)=N2)N=C(c2ccccc2)C(c2ccccc2)=N1

Procedure:
2,2'-bis(2-chlorophenyl)-4,4',5,5'-tetrakis(3-methoxyphenyl)biimidazole; 2,2'-bis(2-methoxyphenyl)-4,4',5,5-tetraphenylbiimidazole; etc.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][CH:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]I.[CH3:29][NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39].[Cl-].[Na+]>CN1CCCC1=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:30]([CH3:29])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([F:42])([F:43])[C:38]([F:39])([F:40])[F:41]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCI)[C@H]3[C@@H]1CCC2O
Reactant: CNCCCCCCC(F)(F)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(CCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F)CCCCCCC(F)(F)C(F)(F)F
Yield: 69 %

Procedure:
A solution of 690 mg of 11β-fluor-7α-(6-iodohexyl)-estra-1,3,5(10)-triene-3,17-diol in 15 ml of 1-methyl-2-pyrrolidinone is stirred with 810 mg of methyl-(7,7,8,8,8-pentafluor-octyl)-amine for 3 hours at a bath temperature of 80° C. For working-up, the batch is added to saturated sodium chloride solution, extracted with ether, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol/ammonia (25%). 576 mg of 11β-fluoro-7α-{6-[methyl-(7,7,8,8,8-pentafluor-octyl)-amino]-hexyl}-estra-1,3,5(10)-triene-3,17β-diol is obtained as a foam, [α]D=+42° (c=0.5 in CHCl3).
Reaction SMILES: [CH2:1]1[C:13]2[C:12]3[CH:11]=[C:10]([C:14]([NH:16][CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[O:15])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][NH:2]1.Br[CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:36]([C:35]1[CH:39]=[CH:40][C:32]([CH2:31][N:2]2[CH2:3][CH2:4][C:5]3[NH:6][C:7]4[CH:8]=[CH:9][C:10]([C:14]([NH:16][CH:17]5[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]5)=[O:15])=[CH:11][C:12]=4[C:13]=3[CH2:1]2)=[CH:33][CH:34]=1)(=[O:37])[NH2:38]
Reactant: NC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CNCC4)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CN(Cc2ccc(C(N)=O)cc2)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a solution of tert-butyl 4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate (0.745 g, 1.9 mmol) in DMF (10 mL), 4-bromomethylbenzamide (0.44 g, 2.1 mmol) and TEA (1.2 mL, 0.857 g, 8.5 mmol) were added. The resulting dark yellow reaction mixture was allowed to stir at room temperature under N2 atmosphere overnight and then poured into saturated sodium bicarbonate solution (100 mL). The resulting precipitate was collected and dried under vacuum overnight to provide tert-butyl 4-(2-(4-carbamoylbenzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate (28 in Scheme 1(m)) as a white solid (0.75 g, 75%). 1H NMR (DMSO-d6, 300 MHZ) 10.80 (s, 1H), 7.86-7.79 (m, 4H), 7.55 (d, J=8.5 Hz, 1H), 7.45 (d, J=8.3 Hz, 3H), 7.26 (d, J=8.5 Hz, 2H), 4.00-3.88 (m, 3H), 3.82 (s, 2H), 3.65 (s, 2H), 2.92-2.80 (m, 6H), 1.80 (d, J=9.9 Hz, 2H), 1.54-1.47 (m, 2H), 1.43 (s, 9H) ppm; MS (ES) 532 (M+H).