Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17](B(O)O)=[C:12]2[CH:11]=[N:10]1.Br[C:22]1[C:23]([CH3:28])=[N:24][CH:25]=[N:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCO.COCCOC.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17]([C:22]3[C:23]([CH3:28])=[N:24][CH:25]=[N:26][CH:27]=3)=[C:12]2[CH:11]=[N:10]1
Reactant: OB(O)c1ccnc2c1cnn2-c1ccc(F)cc1F
Reactant: Cc1ncncc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: Cc1ncncc1-c1ccnc2c1cnn2-c1ccc(F)cc1F
Temperature: 90 °C
Yield: 61.1 %

Procedure:
Example 64 was prepared according to the general procedure in Example 1, except heating at 90° C. for 18 h, and using the following materials: Intermediate 63A (35.0 mg, 0.127 mmol), 5-bromo-4-methylpyrimidine (41.2 mg, 0.238 mmol), sodium carbonate (58.9 mg, 0.556 mmol), EtOH:DME:H2O (1.2:2.5:1.0 ratio) (1.0 mL) and tetrakis(triphenylphosphine) palladium(0) (17.5 mg, 0.0151 mmol). Example 64 was isolated as a white solid (25.1 mg, 60.7%). Purification was done by preparative HPLC (Condition A) using a Phenomenex Luna Axia 30×100 mm S10 column from 18% Solvent B to 100% Solvent B over 12 min, ret. T=9.2 min, followed by Biotage Silica gel chromatography on a 4 g Thompson Single Step™ silica cartridge using a linear gradient from 100% hexanes to 100% (1:1 acetone/hexanes) over 10 column volumes. 1H NMR (500 MHz, CCl3D) δ ppm 9.27 (1 H, s), 8.68-8.79 (2 H, m), 8.09 (1 H, s), 7.71 (1 H, td, J=8.62, 5.95 Hz), 7.21 (1 H, d, J=4.58 Hz), 7.13 (2 H, td, J=7.86, 5.65 Hz), 2.58 (3 H, s). LC/MS (Condition B): ret. T=3.22 min, (M+H)+ 324.13. Analytical HPLC: (Condition A): >99%, ret. T=18.26 min, (Condition B): >99%, ret. T=18.09 min, (Condition C): >99%, ret. T=12.33 min, (Condition D): >99%, ret. T=10.15 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:25][CH2:24][C:5]2([C:9](=[O:10])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3]1>CCOCC.CCCCCCC>[F:22][C:19]([F:20])([F:21])[CH:18]([CH3:23])[O:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:4][CH2:3][C:2](=[O:1])[CH2:25][CH2:24]3)[C:9]2=[O:10])=[CH:12][CH:13]=1
Reactant: CC(Oc1ccc(N2CCC3(CCC(O)CC3)C2=O)cc1)C(F)(F)F
Solvent: CCCCCCC
Solvent: CCOCC
Product: CC(Oc1ccc(N2CCC3(CCC(=O)CC3)C2=O)cc1)C(F)(F)F

Procedure:
This material was obtained in analogy to example 108, step 4 by Swern oxidation of 8-hydroxy-2-[4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-2-aza-spiro[4.5]decan-1-one (230 mg, obtained in example 162, step 3) as a colorless solid (230 mg). Rf: 0.3 (silica gel, ether/heptane 1:1).
Reaction SMILES: Cl.[C:2]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1)#[N:3].C(O)(=[O:30])C>>[C:2]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1)(=[O:30])[NH2:3]
Reactant: CC(=O)O
Reactant: CS(=O)(=O)Nc1cc2occ(C#N)c(=O)c2cc1Oc1ccccc1F
Agent: Cl
Product: CS(=O)(=O)Nc1cc2occ(C(N)=O)c(=O)c2cc1Oc1ccccc1F
Yield: 42.1 %

Procedure:
30 ml of concentrated hydrochloric acid and 60 ml of acetic acid were added to 3.74 g of 3-cyano-6-(2-fluorophenoxy)-7-methylsulfonylamino-4H-1-benzopyran-4-one. The mixture was refluxed for 30 minutes. After the completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was washed with water and then recrystallized from acetic acid to obtain 1.65% (yield: 42.1%) of 3-carbamoyl-6-(2-fluorophenoxy)-7-methylsulfonylamino-4H-1-benzopyran-4-one having a melting point of 249°-251° C.
Reaction SMILES: [BrH:1].[CH:2]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH:17]=[CH2:18])([CH3:4])[CH3:3]>C(O)C.[Pd]>[BrH:1].[CH:2]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][CH3:18])([CH3:3])[CH3:4]
Reactant: C=CCc1ccccc1OCCCNC(C)C
Agent: [Pd]
Agent: Br
Solvent: CCO
Product: CCCc1ccccc1OCCCNC(C)C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
A solution of N-isopropyl-3-(2-allylphenoxy)propylamine hydrobromide (313 mg) in ethanol was hydrogenated at ambient temperature and pressure for 3 hours using a catalyst of palladium on carbon (10% w/w, 30 mg). The catalyst was removed by filtration and the filtrate evaporated to give a solid which was crystallised from a mixture of propan-2-ol and diethyl ether to give N-isopropyl-3-(2-propylphenoxy)propylamine hydrogen bromide as a colourless solid (204 mg), m.p. 89°-90°; microanalysis, found: C, 56.6; H, 8.2; N, 4.43%; C15H25NO.HBr requires: C,57.0; H, 8.3; N, 4.70%; NMR([CD3 ]2SO): 0.92(3H,t), 1.25(6H,d), 1.55(2H,m), 2.10(2H,m), 2.51(2H,m), 3.10(2H,t), 3.31(1H,m), 4.05(2H,t), 6.90(2H,m), 7.13(1H,m) and 8.46(2H,m); m/z 236(M+H).
Reaction SMILES: [C:1](=[O:14])([O:6][CH:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[O:2][CH:3](Cl)[CH3:4].[I-:15].[Na+]>C(#N)C>[C:1](=[O:14])([O:6][CH:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[O:2][CH:3]([I:15])[CH3:4]
Reactant: CC(Cl)OC(=O)OC(C(C)C)C(C)C
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(I)OC(=O)OC(C(C)C)C(C)C

Procedure:
A mixture of 1.78 g of 1-chloroethyl 2,4-dimethyl-3-pentyl carbonate and 5 g of sodium iodide is stirred in 30 ml of acetonitrile at 70° C. for 4 hours and concentrated. The residue is extracted with ether and concentrated to give crude 1-iodoethyl 2,4-dimethyl-3-pentyl carbonate. In 30 ml of dimethylformamide is dissolved 3.6 g of potassium 7β-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylate, and with ice-cooling and stirring, the above 1-iodoethyl 2,4-dimethyl-3-pentyl carbonate is added thereto at one stroke, followed by stirring for 5 minutes. The reaction mixture is poured into a mixture of 150 ml of ethyl acetate and 150 ml of ice-cooled 20% aqueous sodium chloride. The organic layer is separated, washed with two 150-ml portions of saturated aqueous sodium chloride and extracted with 40 ml of 1N hydrochloric acid. The extract is subjected to column chromatography using Diaion MCI® GEL CHP-20P (Mitsubishi Chemical Industries Limited, Japan), elution being carried out with acetonitrile-0.01N hydrochloric acid. The fractions containing the desired product are combined and lyophilized to give 940 mg of the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([O:11]C)[C:8]([OH:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:4]=2[S:5][CH:6]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([OH:11])[C:8]([OH:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:4]=2[S:5][CH:6]=1
Reactant: COc1cc2c(Cl)csc2c([N+](=O)[O-])c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1c(O)c(O)cc2c(Cl)csc12
Temperature: 90 °C

Procedure:
To the solution of 3-chloro-6-hydroxy-5-methoxy-7-nitro-benzo[b]thiophene (0.13 g) and pyridine (3.3 ml) was gradually added aluminum trichloride (0.09 g). The reaction mixture was heated at 90° C. for 2 hours. To the warm reaction (60° C.) mixture was added the mixture of ice and concentrated hydrochloric acid (1:1). The product was filtered, washed with 1M hydrochloric acid and water and dried under vacuum.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([OH:16])=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:4]=2.[C:25](Cl)(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[C:25]([O:16][C:12]1[CH:11]=[CH:10][C:9]2[C:8]3[C:3](=[CH:4][C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:6][CH:7]=3)[C:2]([F:1])=[CH:15][C:14]=2[CH:13]=1)(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCc1ccc2c(c1)c(F)cc1cc(O)ccc12
Reactant: CCCCCC(=O)Cl
Product: CCCCCCCCc1ccc2c(c1)c(F)cc1cc(OC(=O)CCCCC)ccc12

Procedure:
From 9-fluoro-7-octylphenanthren-2-ol by reaction with hexanoyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=O)/[CH:6]=[C:7](/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1)\[O-])[CH3:2].[Li+].Cl.[Cl:24][C:25]1[CH:26]=[C:27]([NH:31][NH2:32])[CH:28]=[CH:29][CH:30]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([N:31]2[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=3)=[CH:6][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:21])=[N:32]2)[CH:28]=[CH:29][CH:30]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)C(=O)/C=C(\[O-])c1cccc(OC(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Product: CCOC(=O)c1cc(-c2cccc(OC(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Yield: 33 %

Procedure:
Starting from 4.53 g (14.6 mmol) of lithium (1Z)-4-ethoxy-3,4-dioxo-1-[3-(trifluoro-methoxy)phenyl]but-1-en-1-olate from example 3A and 3.56 g (19.8 mmol) of 3-chloro-phenylhydrazine hydrochloride, 1.98 g (4.8 mmol, 33% yield of theory) of product are obtained according to the method described in example 4A.
Reaction SMILES: [OH2:1].[ClH:2].Cl.[CH3:4][N:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)[CH:6]1[CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8][CH2:7]1.CN(C1C=CC=C(C)C=1)C1CCN(CC2C=CC=CC=2)CC1.Cl.Cl.[H][H]>[Pd].CO>[OH2:1].[ClH:2].[ClH:2].[CH3:4][N:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)[CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: Cc1cccc(N(C)C2CCN(Cc3ccccc3)CC2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cccc(N(C)C2CCNCC2)c1
Yield: 60.9 %

Procedure:
A mixture of 9 parts of N-methyl-N-(3-methylphenyl)-1-(phenylmethyl)-4-piperidinamine dihydrochloride hemihydrate and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over Hyflo and the filtrate was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and dried, yielding 1.5 parts (60.9%) of N-methyl-N-(3-methylphenyl)-4-piperidinamine dihydrochloride monohydrate; mp. 209.1° C. (intermediate 97).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:46])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[CH:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:46])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:42][CH2:43][CH2:44][CH2:45]3)[CH:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(N3CCCC3)c2)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(N4CCCC4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-oxo-3-[3-(2-pyrrolidin-1-yl-pyridin-4-yl)-phenyl]-propionic acid tert-butyl ester (Example K63) (275 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white amorphous substance (348 mg, 80%).
Reaction SMILES: [Br:1][C:2]1[C:14]([F:15])=[CH:13][C:5]2[S:6][C:7]([C:9]([O:11]C)=[O:10])=[CH:8][C:4]=2[CH:3]=1.[Li+].[OH-].O>C1COCC1>[Br:1][C:2]1[C:14]([F:15])=[CH:13][C:5]2[S:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc2cc(Br)c(F)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2cc(Br)c(F)cc2s1
Yield: 84 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 25 for the preparation of I-25b above, methyl 5-bromo-6-fluorobenzo[b]thiophene-2-carboxylate (I-28b: 0.3 g, 1.038 mmol) in THF (10 mL) was hydrolyzed with LiOH (300 mg, 1.038 mmol) and water (2 mL) to afford 240 mg of the product (85% yield)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30][C:31]([O:33]CC)=[O:32])=[O:24])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6].[OH-].[Li+].CO.ClCl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30][C:31]([OH:33])=[O:32])=[O:24])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6]
Reactant: CCOC(=O)C[C@H]1CCCN1C(=O)c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Agent: ClCl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CC(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 74 %

Procedure:
Prepared analogously to Example 19b from 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-4-[(2R)-2-(ethoxycarbonylmethyl)pyrrolidin-1-ylcarbonyl]benzamide and lithium hydroxide in tetrahydrofuran. Yield: 74%; Rf value: 0.32 (Reversed phase RP 8: methanol/5% sodium chloride solution=6:4); C23H22Cl2N4O4 (489.357); mass spectrum: (M+H)+=489/491/493 (chlorine isotope).
Reaction SMILES: C(Cl)Cl.[C:4](Cl)(=[O:8])[C:5]([CH3:7])=[CH2:6].[CH2:10]([N:17]([CH2:24][CH2:25][OH:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C>[CH2:10]([N:17]([CH2:24][CH2:25][O:26][C:4](=[O:8])[C:5]([CH3:7])=[CH2:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=C(C)C(=O)Cl
Reactant: OCCN(Cc1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCN(Cc1ccccc1)c1ccccc1

Procedure:
1000 ml of dried methylene chloride are placed in a 4 l sulfonating vessel at 0° C. together with 334 g of methacrylic acid chloride. A mixture of 500 ml of dried methylene chloride, 323 of dried triethylamine and 454 of N-benzyl-N(β-hydroxyethyl)aniline, (the compound of formula 1a) are added drop by drop to this mixture at 0°-10° C. The reaction mixture is allowed to rise to room temperature slowly and is controlled on a thin layer chromatograph (silica gel) solvent: toluene/acetic acid ester 2:1. After the end of the reaction (after standing overnight), the reaction mixture is filtered and washed three times with one liter of a 10% aqueous NaOH solution and finally four times each time with 1 l of water. The organic phase is then dried over sodium sulphate and the solvent is removed in a rotary evaporator. 482 g of the product of formula 1d ##STR15## results.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[S:24][C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:38])=[C:26]([C:28]([F:31])([F:30])[F:29])[N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:22][C:23]3[S:24][C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:38])=[C:26]([C:28]([F:31])([F:29])[F:30])[N:27]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: FC(F)(F)c1nc(CBr)sc1-c1ccccc1Cl
Product: O=c1n(Cc2nc(C(F)(F)F)c(-c3ccccc3Cl)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
40 mg (0.13 mmol) of the compound from Example 5A were reacted with 46 mg (0.13 mmol) of the compound from Example 92A analogously to the preparation of the compound in Example 77. This gave 58 mg (76% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([O:12][C:13]([C:15]1([CH2:28][CH2:29][CH:30]=O)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])[CH3:11].C(OC(=O)C)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:10]([O:12][C:13]([C:15]1([CH2:28][CH2:29][CH2:30][NH:4][C:3]2[CH:5]=[CH:6][C:7]([Br:9])=[CH:8][C:2]=2[CH3:1])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])[CH3:11]
Reactant: Cc1cc(Br)ccc1N
Reactant: CCOC(=O)C1(CCC=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)C1(CCCNc2ccc(Br)cc2C)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 48 h

Procedure:
2-Methyl-4-bromo-aniline (1.68 g, 9.05 mmol, 1 eq) was dissolved in 1,2-dichloroethane (95 mL). A solution of 4-(3-Oxo-propyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (2.8 g, 9.05 mmol, 1 eq) in 95 mL of 1,2-dichloroethane was added to the previous solution followed by glacial acetic anhydride (1.74 g, 28.05 mol, 3.1 eq) and NaBH(OAc)3 (5.76 g, 27.15 mmol, 3 eq). The reaction mixture was stirred for 48 h, quenched with 200 mL of water, transferred to a separatory funnel and extracted with dichloromethane (2×100 mL). The combined organics were dried over Na2SO4 and purified by column chromatography on silica gel (200 g column, 25% EtOAc in heptanes; 50 mL/min). This gave 3.78 g (86%) of the title compound as a beige gum.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:17]I>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (939 mg) in dimethylformamide (30 ml) was added 1-t-butoxycarbonyl-4-hydroxypiperidine (3.15 g) under ice-water cooling and the mixture was stirred at 0° C. for 0.5 hour. To the solution was added methyl iodide (1.17 ml) under ice-water cooling and the mixture was stirred at 0° C. for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (3:1) to give 1-t-butoxycarbonyl-4-methoxypiperidine as colorless oil (2.84 g).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:31]=[N:30][CH:29]=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Clc1cnccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4cnccn4)cc3CC[C@@H]12
Yield: 48.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloropyrazine (53 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80%ethyl acetate/hexanes eluent) to give 63 mg (49%) of the title compound as an off white solid. mp 94°-95°. FDMS: m/e=339. α[D]589 =+88.14 (c=0.92, chloroform).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][CH:8]([Cl:12])[C:9](Cl)=[O:10].[NH2:13][C:14]1[N:18]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[C:21]([Cl:30])[C:20]=2[Cl:31])[N:17]=[CH:16][CH:15]=1>ClCCl>[Cl:7][CH:8]([Cl:12])[C:9]([NH:13][C:14]1[N:18]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:27])[F:28])=[C:21]([Cl:30])[C:20]=2[Cl:31])[N:17]=[CH:16][CH:15]=1)=[O:10]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl)C(Cl)Cl
Temperature: 25 °C
Reaction time: 13 h
Yield: 93.5 %

Procedure:
15.3 g (0.145 mol) of anhydrous sodium carbonate and 4.76 ml (0.048 mol) of 98% strength dichloroacetyl chloride are added in succession, at 5° C. to 10° C., to 8.0 g (0.024 mol) of 5-amino-1-(2,3,6-trichloro-4-trifluoromethyl-phenyl)-pyrazole in 80 ml of dichloromethane. The mixture is stirred for 4 hours at 5° C.-10° C. and for 13 hours at room temperature. The mixture is diluted with 80 ml of dichloromethane, filtered, and washed in succession with water and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and freed from the solvent in vacuo. 10.0 g (93.5% of theory) of 5-dichloroacetamido-1-(2,3,6-trichloro-4-trifluoromethyl-phenyl)-pyrazole of melting point 156° C.-161° C. are obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])[S:8][C:6]=2[N:7]=1.[CH3:17][NH:18][CH3:19].CO>>[CH3:17][N:18]([CH3:19])[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])[S:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)Nc1nc2cnc(Cl)nc2s1
Reactant: CNC
Solvent: CO
Product: CCOC(=O)Nc1nc2cnc(N(C)C)nc2s1
Temperature: 75 °C
Yield: 99 %

Procedure:
Ethyl 5-chlorothiazolo[5,4-d]pyrimidin-2-ylcarbamate (300 mg, 1.16 mmol) was suspended in a 2.0 M solution of dimethylamine in methanol (5.0 mL, 10.00 mmol) in a pressure vessel, which was sealed and heated overnight on a 75° C. oil bath. The mixture was cooled to ambient temperature, the solvent was evaporated and the residue was partitioned between aqueous bicarbonate and chloroform and extracted 3 times. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford ethyl 5-(dimethylamino)thiazolo[5,4-d]pyrimidin-2-ylcarbamate (236 mg, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (s, 1H) 8.67 (s, 1H) 4.26 (q, J=7.03 Hz, 2H) 3.17 (s, 6H) 1.16-1.40 (m, 3H). MS (LC/MS) R.T.=1.88; [M+H]+=268.09.
Reaction SMILES: [CH2:1]([C@H:3]1[C:7](=[O:8])[NH:6][C:5]2([CH2:13][CH2:12][N:11](C)[CH2:10][CH2:9]2)[S:4]1)[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.C(N)CN.[OH-].[Na+]>ClCCl.[Fe](Cl)Cl>[CH2:1]([C@H:3]1[C:7](=[O:8])[NH:6][C:5]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[S:4]1)[CH3:2]
Reactant: CC[C@@H]1SC2(CCN(C)CC2)NC1=O
Agent: Cl[Fe]Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: NCCN
Solvent: ClCCl
Product: CC[C@@H]1SC2(CCNCC2)NC1=O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a cooled (ice-salt bath) stirred solution of AF267B (6.1 gr, 0.028 mol) in dichloromethane (60 ml) was added m-chloroperbenzoic acid (mCPBA) in small portions over a period of 15 min mCPBA (70%, 7.02 gr, 0.028 mol total). The mixture was stirred for 1 hr and then treated with iron (II) chloride (2.14 ml of 1M solution in water). Stirring and cooling (−10 ° C.) were continued for 1 hr and then stirring continued for 2 hrs at room temperature. Ethylene diamine (1.9 ml, 0.285 mol), sodium hydroxide (30.5 ml of 2N aqueous solution), and petroleum ether 40-60° C. (60 ml) were added. After vigorous shaking the layers were separated, the aqueous layer was extracted with mixture of dichloromethane/petroleum ether 1:1 (600 ml) followed by dichloromethane (first 600 ml then 300 ml). The combined extracts were dried (Na2SO4), filtered and the solvents were removed under reduced pressure. Flash chromatography (silica-gel 60, 230-400 mesh, Merck 1.09385, elution with methanol/chloroform/ammonium hydroxide 10:89:1 v/v) of the residue gave AF292. 1H NMR (CDCl3) δ 1.02 (t, j=7 Hz, 3H), 1.76 1.92 and 2.07 (3xm, 6H), 2.84 (m, 2H), 3.04 (m, 2H), 3.83 (dd, j=8.8, 4 Hz, 1H), 7.66 (NH) ppm; 13C NMR (CDCl3) δ 11.50, 27.24, 42.87, 43.95, 44.10, 48.80, 64.22, 175.22 ppm: MS m/e 200(M+). The compound was >99.9% purity by HPLC, GC.