Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[CH2:10][CH2:11][C:12]2[CH:33]=[CH:32][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[NH:24][CH2:25][CH:26]([C:28](OC)=[O:29])[N:27]=4)[CH:18]=3)=[CH:14][CH:13]=2)=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].[BH4-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[NH:24][CH2:25][CH:26]([CH2:28][OH:29])[N:27]=4)[CH:18]=3)=[CH:32][CH:33]=2)=[CH:4][C:3]=1[C:35]([F:36])([F:37])[F:38]
Reactant: COC(=O)C1CNC(c2cc(Oc3ccc(CCC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)cc3)ccn2)=N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(CCc1ccc(Oc2ccnc(C3=NC(CO)CN3)c2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of methyl 2-{4-[4-(3-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-3-oxopropyl)phenoxy]pyridin-2-yl}-4,5-dihydro-1H-imidazole-4-carboxylate (107 mg, 0.20 mmol) in MeOH (2 mL), at 0° C., was added sodium borohydride (8.0 mg, 0.22 mmol) portionwise. The reaction mixture was stirred at 0° C. for 45 min, and then warmed to rt and stirred for 18 h. After this time additional sodium borohydride (8.0 mg, 0.22 mmol) was added and the mixture was heated at 60° C. for 18 h. The reaction was then cooled to rt, and 1N HCl was added. The solvents were evaporated and the residue was purified by HPLC (250 mm C18 column) eluting with ACN containing 30% to 100% of 0.1% FA in water (20 min gradient) to give A-243 (6.0 mg, 5.8%). 1H NMR (300 MHz, CD3OD) δ: 8.55 (d, 1H), 8.08 (d, 1H), 7.76-7.72 (m, 1H), 7.61 (d, 1H), 7.53 (d, 1H), 7.41-7.38 (m, 2H), 7.11-7.08 (m, 3H), 4.45-4.35 (m, 1H), 4.06 (t, 1H), 3.90-3.83 (m, 1H), 3.74-3.61 (m, 2H), 3.06 (t, 2H), and 2.73 (t, 2H). LCMS: (FA) ES+ 519.1 (M+1).
Reaction SMILES: Cl.[C:2]1([C:8]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@H:16]3[C@H:12]([CH2:13][NH:14][CH2:15]3)[C:11](=[O:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:31][C@@H:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33](Cl)=[O:34].FF>ClCCl.N1C=CC=CC=1>[F:31][C@@H:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33]([N:14]1[CH2:13][C@H:12]2[C@H:16]([C:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9][CH2:10][C:11]2=[O:17])[CH2:15]1)=[O:34]
Reactant: O=C(Cl)[C@@H](F)c1ccccc1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Agent: FF
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CN(C(=O)[C@@H](F)c3ccccc3)C[C@H]12
Reaction time: 2 h

Procedure:
A solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.12 g), triethylamine (0.9 cc) and pyridine (0.5 cc) in dichloromethane (30 cc) is added, at 0° C., to a solution of (S)-α-fluorophenylacetyl chloride [prepared from acid (1 g) by the method described by S. Hamman et al., J. Fluorine Chem., 37, 85 (1987)] in dichloromethane (20 cc). The reaction mixture is stirred for 2 hours allowing the temperature to return to 20° C. and is then concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in ethyl acetate (100 cc). The solution is washed with water (2×100 cc) and then with saturated sodium bicarbonate solution (50 cc) and with saturated sodium chloride solution (50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.2-0.063 mm, diameter 3 cm, height 40 cm), eluting under a nitrogen pressure of 0.7 bar with ethyl acetate and collecting 100 cc fractions to give (3aR,7aR)-2-[(S)-α-fluorophenylacetyl]-7,7-diphenyl-4-perhydroisoindolone (1 g) in the form of a white meringue.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[I-]>C(C(C)=O)C>[CH2:2]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: O=Cc1ccc(O)cc1
Reactant: C=CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCCCCCCCCCOc1ccc(C=O)cc1

Procedure:
A mixture of 11-bromoundec-1-ene (2.02 g), 4-hydroxy-benzaldehyde (1.06 g, 8.6 mmol), potassium carbonate, potassium iodide and tetra-n-butylamomnium iodide was heated at reflux in methyl ethyl ketone (10 ml) for 16 hours. After cooling, the solids were filtered off and washed with acetone. The combined organic fractions were evaporated to dryness. The crude product obtained was filtered through a pad of silica gel which was eluted with petroleum ether (b.p. 40-60° C.) to remove the excess of bromoundecene. The silica gel was then eluted with acetone and the acetone fractions evaporated under reduced pressure to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[N:37][C:5]2[N:6](S(C3C=CC=CC=3)(=O)=O)[C:7]3[C:12]([C:4]=2[CH:3]=1)=[CH:11][C:10]([C:13]1[CH:27]=[CH:26][C:16]([O:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:15][CH:14]=1)=[CH:9][CH:8]=3>CO>[Cl:1][C:2]1[CH:38]=[N:37][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[CH:11][C:10]([C:13]1[CH:27]=[CH:26][C:16]([O:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[CH:15][CH:14]=1)=[CH:9][CH:8]=3
Reactant: CCN(CC)CCCOc1ccc(-c2ccc3c(c2)c2cc(Cl)cnc2n3S(=O)(=O)c2ccccc2)cc1
Solvent: CO
Product: CCN(CC)CCCOc1ccc(-c2ccc3[nH]c4ncc(Cl)cc4c3c2)cc1
Reaction time: 2 h
Yield: 70 %

Procedure:
3-(4-(3-chloro-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indol-6-yl)phenoxy)-N,N-diethylpropan-1-amine (57 mg, 0.10 mmol) is added to a solution of Na° (23 mg, 1 mmol, 10 eq) in methanol (0.1 ml). The reaction is carried out at 65° C. for 2 hours, the mixture is then hydrolysed with ethanol and H2O and extracted with ethyl acetate (3×20 ml). The organic layers are dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue (orange solid) is purified over flash chromatography (eluted with THF/MeOH 9:1) to give the product R337 as a white solid (29 mg, 0.07 mmol) with a 70% yield. 1H NMR (CDCl3 300 MHz) δ ppm 8.42 (br s, 1H), 8.28 (br. s, 1H), 8.14 (br.s, 1H), 7.70 (dd, 1H, J=1.7, 8.5 Hz); 7.60-7.45 (m, 3H), 7.57 (d, 21-1, J=8.6 Hz), 7.01 (d, 21-1, J=8.7 Hz), 4.08 (t, 2H, J=6.3 Hz), 2.67 (t, 2H, J=7.3 Hz), 2.59 (q, 4H, J=7.1 Hz), 1.98 (p, 2H, J=6.8 Hz), 1.07 (t, 6H, J=7.1 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[C:9]([C:4]1[CH:3]=[C:2]([Br:1])[CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])(=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.3 %

Procedure:
To a solution of 4-bromophthalic anhydride (50 g, 220 mmol) in benzene (500 mL) was added aluminum chloride (60 g, 450 mmol) by small portions under ice-cooling. The obtained mixture was stirred at room temperature for 24 h. The reaction mixture was poured into ice water and extracted with a mixed solvent of ethyl acetate-tetrahydrofuran (1/1). The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized from ethyl acetate-diisopropyl ether. The precipitated crystals were collected by filtration to give 2-benzoyl-4-bromobenzoic acid (33 g, 49%)as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:18]2[CH:23]=[CH:22][C:21](F)=[CH:20][C:19]=2Cl)[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11][Br:12])=[O:4].[Cl:26]C1C=CC(C=O)=CC=1>>[Br:12][CH2:11][C:10]1[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7][CH:6]([C:18]2[CH:23]=[CH:22][C:21]([Cl:26])=[CH:20][CH:19]=2)[C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Product: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1

Procedure:
Compound C-4 was prepared in analogy to compound C by using 4-chlorobenzaldehyde instead of 2-chloro-4-fluorobenzaldehyde without chiral SFC separation of dihydropyrimidine intermediate in Scheme 1-1.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][C@H:7]1[CH2:24][C@@:23]2([CH3:25])[C@@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][C@H:16]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:17]2=[O:26])[CH2:9][CH2:8]1)(=[O:5])[CH3:4].O>CO>[C:3]([O:6][C@H:7]1[CH2:24][C@@:23]2([CH3:25])[C@@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][C@H:16]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C@@H:17]2[OH:26])[CH2:9][CH2:8]1)(=[O:5])[CH3:4]
Reactant: CC(=O)O[C@@H]1CC[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)[C@@H](N5CCCCC5)C[C@@H]34)[C@@]2(C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)O[C@@H]1CC[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](O)[C@@H](N5CCCCC5)C[C@@H]34)[C@@]2(C)C1
Reaction time: 1 h
Yield: 54 %

Procedure:
Sodium borohydride (9.40 g) was added portionwise to a stirred solution of 2β-acetyloxy-16β-(1-piperidinyl)-5α-androstan-17-one (46.99 g) in methanol (235 ml). After 1 h, water (300 ml) was added to precipitate the product as a gum, which was extracted into diethyl ether (300 ml). The extract was washed neutral with water (3×300 ml), dried (MgSO4) and evaporated to dryness. Crystallisation of the residue from methanol afforded 16β-(1-piperidinyl)-5α-androstane-2β,17β-diol 2-acetate (25.49 g), m.p. 162°-166° C., [α]D +29.1° (c 0.45 in CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>>[CH3:1][O:2][C:3]([C:5]1([C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ncnc3cc(OC)c(OC)cc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.04 h

Procedure:
To a mixture of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (17.1 g, 70.5 mmol), as prepared in the previous step, and 4-chloro-6,7-dimethoxyquinazoline (15.0 g, 67.0 mmol) (Oakwood Products, Inc.) immersed in a −78° C. bath was added 1.08 M LiHMDS/THF (71 mL, 77 mmol) in ˜20 mL portions under argon via syringe along the sides of the flask (to allow cooling of the hindered base before reaction with the ester). Following completion of LiHMDS/THF addition, the reaction was allowed to sit in the −78° C. bath for 2-3 min before removing the cold bath and allowing the mixture to stir with gradual warming to rt. After 18 h stirring at rt, and an additional 2 d sitting at rt, the mixture was quenched with 0.5 M NaH2PO4 (150 mL) and extracted with DCM (1×150 mL and 1×100 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure to provide the crude title compound as a translucent yellow oil that was used in the next step without further purification (33g). A small sample was purified by flash chromatography (1:1 hex/EtOAc) for characterization. 1H-NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.34 (s, 1H), 7.29 (s, 1H), 4.05 (s, 3H), 3.96 (s, 3H), 3.76-3.67 (m, 2H), 3.62-3.49 (m, 2H), 3.61 (s, 3H), 2.50-2.36 (br s, 4H), 1.46 (s, 9H). LC/MS (ESI): calcd mass 431.2, found 432.2 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-:3])=[O:2].[CH2:16]=[CH:17][CH:18]=[CH2:19]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[C:5]2[C:6](=[O:15])[C:7]3[C:8](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9](=[O:14])[C:10]=2[CH:11]=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: C=CC=C
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A 1 liter glass pressure reactor is charged with 600 parts of toluene and 122 parts of technical 5-nitro-1,4-naphthoquinone (100%) as ca. 93% product. The reactor is blanketed with nitrogen and 57.6 parts of butadiene are introduced under pressure. The mixture is then heated in the closed system to 80° C. and stirred for 4 hours at this temperature. The pressure falls from a maximum of 3.5 to 4 bar to ca. 3 bar at the conclusion of the reaction. The mixture is cooled, the pressure in the reactor removed over a cooling trap, and excess butadiene is distilled at 400 mbar from the autoclave into the cooling trap. At a distillation temperature of 80° C., a total amount of 336 parts of butadiene/toluene is present in the cooling trap, with a butadiene content of ca. 6%. Then the residual toluene is removed with steam, such that at the conclusion of the steam distillation the suspension of 1-nitro-5,8,11,12-tetrahydroanthraquinone in 750 parts of water is free from toluene. The suspension is then run at 10° C. into a mixture of 160 parts of 50% aqueous sodium hydroxide and 50% aqueous potassium hydroxide. Further processing as described in Example 11 gives 138 parts of pure (99%) 1-nitroanthraquinone, i.e. 90% of theory, based on 5-nitro-1,4-naphthoquinone.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[BrH:21]>[Cu]Br>[Br:21][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Product: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1

Procedure:
3-Amino-5-(pentafluorosulfanyl)benzoic acid (1.1 g; example 2a) was dissolved in 24% hydrogen bromide solution (40 ml). While stirring and cooling, sodium nitrite solution (290 mg dissolved in 20 ml of water) was added dropwise, in the course of which the temperature was not to exceed 5° C. On completion of formation of the diazonium salt, copper(I) bromide solution (720 mg dissolved in 15 ml of 48% hydrobromic acid) was cooled to 0° C. while stirring and the above diazonium salt solution was slowly added dropwise. Then the cooling bath was removed and the mixture was stirred at RT for 3 h. Thereafter, the reaction mixture was diluted with water and extracted repeatedly with EA. The combined EA phases were dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in 500 ml of EA and filtered through a glass frit filled with a 10 cm silica gel layer. The filter layer was washed thoroughly with EA. The clear filtrate was concentrated, and solvent residues were drawn off under high vacuum. 800 mg of the title compound were obtained.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=1.N1C=CC=CC=1>ClCCl>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[C:17]([C:22]([F:23])([F:24])[F:25])[CH:16]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(F)cc1C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)cc1
Temperature: -5 °C
Reaction time: 12 h

Procedure:
2.21 g (10 mmol) of 4-chlorosulfonylbenzoic acid is suspended under exclusion of moisture in 30 ml of dichloromethane, the suspension is cooled to -5° C. and, at this temperature, a solution of 1.79 g (10 mmol) of 4-fluoro-2-(trifluoromethyl)aniline and 1 ml of pyridine in 20 ml of dichloromethane is added dropwise thereto. After this dropwise addition has been completed, the mixture is allowed to warm up to room temperature and is agitated for another 12 hours. The thus-produced precipitate is suctioned off and extracted with ether. This ether extract and the filtrate are evaporated together, and the residue is dissolved in dichloroethane. The solution is extracted three times with respectively 10 ml of saturated sodium bicarbonate solution. The combined aqueous extracts are acidified with 2N hydrochloric acid and the thus-precipitated product is removed by filtration. The filter residue is dried under vacuum at 50° C., thus obtaining 3.3 g (9.08 mmol)=90.84% of theory.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[C:15]([O:17][CH:18]([CH3:20])[CH3:19])[C:14]([NH:21][C:22]3[N:27]=[C:26]4[NH:28][N:29]=[C:30]([CH3:31])[C:25]4=[C:24]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[S:39]([CH:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])[N:23]=3)=[CH:13][C:12]=2[CH3:45])[CH2:7][CH2:6]1)=[O:4].[NH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[CH:18]([O:17][C:15]1[C:14]([NH:21][C:22]2[N:27]=[C:26]3[NH:28][N:29]=[C:30]([CH3:31])[C:25]3=[C:24]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[S:39]([CH:42]([CH3:43])[CH3:44])(=[O:41])=[O:40])[N:23]=2)=[CH:13][C:12]([CH3:45])=[C:11]([CH:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:46]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)[CH2:10][CH2:9]2)[CH:16]=1)([CH3:19])[CH3:20]
Reactant: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCN(C(=O)CBr)CC1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCN(C(=O)CN2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromo-1-(4-(5-isopropoxy-4-(4-(2-(isopropylsulfonyl)phenylamino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-methylphenyl)piperidin-1-yl)ethanone from Example 8 (10 mg, 0.014 mmol), and piperidine (3 uL, 0.031 mmol) in DMF was stirred at rt overnight. The crude mixture was directly purified by reverse phase HPLC to give 1-(4-(5-isopropoxy-4-(4-(2-(isopropylsulfonyl)phenylamino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-methylphenyl)piperidin-1-yl)-2-(piperidin-1-yl)ethanone. MS: m/z=703.4 (M+1), 352.2 (M/2+1). 1H-NMR (400 MHz, CD3OD): δ=8.39 (brs, 1H), 7.98 (dd, 1H, J=1.6, 8.0 Hz), 7.70 (t, 1H, J=7.6 Hz), 7.53-7.49 (m, 2H), 6.88 (s, 1H), 4.73-4.69 (m, 1H), 4.62 (sept, 1H, J=6.0 Hz), 4.31 (d, 1H, J=16.4 Hz), 4.22 (d, 1H, J=16.4 Hz), 3.85-3.82 (m, 1H), 3.60 (t, 2H, J=12.0 Hz), 3.41-3.25 (m, 2H), 3.11-3.00 (m, 3H), 2.90-2.84 (m, 1H), 2.79 (s, 3H), 2.22 (s, 3H), 1.99-1.85 (m, 7H), 1.80-1.54 (m, 3H), 1.27 (d, 6H, J=6.0 Hz), 1.24 (d, 6H, J=6.8 Hz).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:35][CH2:36][O:37][CH2:38][CH2:39][CH3:40]>CN(C=O)C>[CH2:38]([O:37][CH2:36][CH2:35][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH2:39][CH3:40]
Reactant: O=C(Nc1ccc2c(c1)NCCC2)c1ccc(-c2ccccc2)cc1
Reactant: CCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOCCN1CCCc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-(1,2,3,4-Tetrahydroquinolin-7-yl)-1,1′-biphenyl-4-carboxamide (Example 24) (66 mg, 0.2 mmol), potassium carbonate (41 mg, 0.3 mmol), potassium iodide (100 mg, 0.6 mmol) and 2-chloroethyl-n-propyl ether (38 ul, 0.3 mmol) in DMF (1 ml) were heated at 60° C. for 17 h then 100° C. for 48 h. After cooling to ambient temperature the reaction mixture was purified on a silica SPE column. Elution with 8% EtOAc/60-80° C. petroleum ether gave the title compound as a yellow solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.93 (d, 2H), 7.72 (br, 1H), 7.70 (d, 2H), 7.63 (d, 2H), 7.48 (t, 2H), 7.40 (t, 1H), 7.03 (d, 1H), 6.92 (d, 1H), 6.74 (dd, 1H), 3.66 (t, 2H), 3.50 (t, 2H), 3.40 (m, 4H), 2.73 (t, 2H), 1.93 (qn, 2H), 1.58 (sx, 2H), 0.91 (t, 3H).
Reaction SMILES: [OH-].[Na+].CO.C[O:6][C:7](=[O:23])[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O>[C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:7]([OH:23])=[O:6])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)C=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1CCCN1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
5N sodium hydroxide (18.58 ml) was added dropwise to a methanol solution (100 ml) of N-cinnamoyl-L-proline methyl ester (20.07 g) under ice cooling, and the mixture was stirred at room temperature for three hours. The pH value of the obtained reaction solution was adjusted to 5 with 5N hydrochloric acid, and the resultant solution was poured into 1 l of water. The precipitate was filtered out and dried to obtain 16.84 g of N-cinnamoyl-L-proline.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:12])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:13]([O-])=O)[C:3]=1[OH:16].Cl.CO>CC(O)=O.[Pd]>[Cl:1][C:2]1[C:3]([OH:16])=[C:4]([NH2:13])[C:5](=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:6]([OH:8])=[O:7]
Reactant: Cc1c(Cl)c(O)c([N+](=O)[O-])c(C(=O)O)c1Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(Cl)c(O)c(N)c(C(=O)O)c1Cl
Yield: 89.6 %

Procedure:
4,6-Dichloro-3-hydroxy-5-methyl-2nitrobenzoic acid (69 mg, 0.26 mmol) was dissolved in HOAc (10 mL), 10% Pd/C (10 mg) and concentrated HCl (33μ, 0.39 mmol) were added. Hydrogenation at room temperature and at atmospheric pressure for 2 h gave a slurry to which methanol (5 mL) was added and the catalyst was filtered off. Evaporation of the solvent, co-evaporation with toluene (10 mL) followed by vacuum-drying over KOH gave 63 mg of a crude product. Purification by flash column chromatography (SiO2), EtOAc-HOAc 45:1) yielded 55 mg of the title compound. Mp: 192° C. (dec); 1H NMR (DMSO-d6): δ 2.27 (s, 3H); 13C NMR (DMSO-d6): δ 167.43, 139.25, 136.01, 122.90, 121.26, 120.37, 116.89, 16.96; MS (EI, 70 eV): m/z (rel.int.) 237/235 (M+, 45/79), 219/217 (37/64), 191/189 (60/100).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH2:18][CH2:19][C:20]3=[O:25])[CH:13]=[CH:14][CH:15]=1.Br[CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1>C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH2:18][CH:19]([CH2:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[C:20]3=[O:25])[CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C1CCc2c1cccc2-c1cccc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2Cc3c(cccc3-c3cccc(Cl)c3)C2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 5.3 %

Procedure:
A solution of lithium diisopropylamide (2.0 M in THF, 0.49 mL, 0.98 mmol) was added to a solution of 4-(3-chlorophenyl)-2,3-dihydro-1H-inden-1-one (235 mg, 0.97 mmol) in THF (3.3 mL) at −78° C. After 1 h at −78° C., a solution of methyl 4-(bromomethyl)benzoate (229 mg, 1.0 mmol) in THF (1.7 mL) was added via cannula. After 1 h at −78° C., the mixture was allowed to slowly warm to 0° C. After 1 h at 0° C., the reaction was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (40 g column, hexanes→30% EtOAc/hexanes, gradient) to afford 20 mg (5%) of methyl 4-((4-(3-chlorophenyl)-1-oxo-2,3-dihydro-1H-inden-2-yl)methyl)benzoate.