Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]3[C:14](=[CH:15][C:5]=2[N:4]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.SC[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.O>C(O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:1][S:2][C:3]1[NH:4][C:5]2[CH:15]=[C:14]3[C:9](=[CH:8][C:6]=2[N:7]=1)[CH:10]=[CH:11][CH:12]=[CH:13]3
Reactant: SCc1ccccn1
Reactant: CSc1nc2cc3ccccc3cc2[nH]1
Solvent: O
Solvent: CCO
Product: c1ccc(CSc2nc3cc4ccccc4cc3[nH]2)nc1
Yield: 81.7 %

Procedure:
0.45 g of 2-methylthio-1H-naphth[2,3-d]imidazole and 0.64 g of 2-mercaptomethylpyridine were heated for 40 hours under reflux in 10 ml of ethanol. 10 ml of water were added to the homogeneous solution and the precipitate formed was filtered off. 0.50 g of 2-[(2-pyridylmethyl)thio]-1H-naphth[2,3-d]imidazole having a m.p. of 170° was obtained.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][N:35]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[F:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([F:12])[C:5]=1[C:4]1[N:30]=[C:29]([C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[C:26]([O:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][N:35]=3)[CH:27]=2)[N:2]([CH3:1])[N:3]=1
Reactant: COc1ccc(C#N)cc1Oc1ccc(C(F)(F)F)cn1
Reactant: CN(N=C(Cl)c1c(F)cccc1F)S(=O)(=O)c1ccccc1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: COc1ccc(-c2nc(-c3c(F)cccc3F)nn2C)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2,6-difluorobenzohydrazonoyl chloride (0.70 g), 4-methoxy-3-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (0.80 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.30 g of desired compound.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:17][C:18](=[O:21])[NH:19][OH:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O1CCOCC1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[CH2:8]([O:17][C:18](=[O:21])[NH:19][O:20][S:34]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:36])=[O:35])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCOC(=O)NO
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCCOC(=O)NOS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
20.4 Parts of triethylamine are added to a stirred mixture of 40.6 parts of nonyl-N-hydroxycarbamate, 100 parts of dioxan and 35.3 parts of benzene sulphonyl chloride at 0° C keeping the pH in the range 2 to 5. The mixture is stirred for 18 hours at 25° C then added to 500 parts of water. The oily product is separated into 300 parts of toluene and the solution is washed with water, dried and evaporated at 40° l C under reduced pressure to give 72 parts of nonyl-N-benzenesulphonyloxycarbamate as a colourless oil.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[CH:5][S:4][CH:3]=1.C([Li:12])CCC.[S:13](=[O:15])=[O:14]>C(OCC)C.CCCCCC>[CH3:7][C:6]1[C:2]([S:13]([O-:15])=[O:14])=[CH:3][S:4][CH:5]=1.[Li+:12]
Reactant: O=S=O
Reactant: Cc1cscc1Br
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cscc1S(=O)[O-]
Product: [Li+]
Reaction time: 8 h

Procedure:
To 30 g of 3-bromo-4-methylthiophene in 150 ml of anhydrous ethyl ether under nitrogen at -70° to -75° C. was added, cautiously, during 30 minutes 111 ml of 1.6 M butyl lithium in hexane. The mixture was stirred for an additional thirty minutes and then 30 ml of liquified sulfur dioxide was added at such a rate that the temperature of the reaction mixture was maintained below -70° C. Upon completion of the addition, the mixture was stirred for an additional 90 minutes at -75° C. and then allowed to stand overnight at room temperature. The resulting precipitate was filtered and washed with ethyl ether, dried in air and in vacuo under nitrogen to yield 30 g of the desired salt, m.p. >250° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][N:17](C(OC(C)(C)C)=O)[CH:18]=3)[CH2:11][C@@H:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:9]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:8][C:7]=2[CH:37]=1)#[N:2].O(C)S([C:42](F)(F)F)(=O)=O.CCN(C(C)C)C(C)C.C(Cl)(Cl)[Cl:57]>C(Cl)Cl>[ClH:57].[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]([CH3:42])[CH:16]=[N:17][CH:18]=3)[CH2:11][C@@H:10]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:9]([S:33]([CH3:36])(=[O:34])=[O:35])[CH2:8][C:7]=2[CH:37]=1)#[N:2]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)n1cnc(CN2C[C@@H](Cc3ccccc3)N(S(C)(=O)=O)Cc3cc(C#N)ccc32)c1
Reactant: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cl
Product: Cn1cncc1CN1C[C@@H](Cc2ccccc2)N(S(C)(=O)=O)Cc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To a solution of 200 mg (0.38 mmol) of (R)-7-cyano-2,3,4,5-tetrahydro-1-[(((1,1-dimethylethoxy)-carbonyl)-1H-imidazol-4-yl)methyl]-4-(methylsulfonyl)-3-(phenylmethyl)-1H-1,4-benzodiazepine (prepared from Example 224 as described for Compound A of Example 225) in 2 mL of methylene chloride, at -78° C. and under argon, was added dropwise 59 μL (0.48 mmol) of methyl triflate. The reaction was allowed to warm to rt, during which time a white precipitate was obtained. Stirring was continued at rt for 3 hr, after which time 140 μL (0.8 mmol) of DIEA was added and stirring continued overnight at rt. The mixture, without workup, was subjected to flash chromatography on a 30 cc column of silica gel. Elution with 2% MeOH--CHCl3 afforded 122 mg (0.28 mmol, 74%) of a clear colorless oil which crystallized on standing. This material was converted to its hydrochloride by the addition of 0.28 mL of 1M HCl in ether to a methylene chloride solution (2 mL) of the free base. A white precipitate was obtained which on filtration afforded 90 mg of Example 235 as a white powder.
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][C:10]([C:15]([OH:17])=O)([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH2:24]([O:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([NH:38][NH2:39])=[O:37])=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:24]([O:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([NH:38][NH:39][C:15]([C:10]23[CH2:9][CH2:8][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([CH2:14][CH2:13]2)[CH2:12][CH2:11]3)=[O:17])=[O:37])=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)C12CCC(c3ccccc3)(CC1)CC2
Reactant: NNC(=O)c1ccc(OCc2ccccc2)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NNC(=O)C12CCC(c3ccccc3)(CC1)CC2)c1ccc(OCc2ccccc2)cc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a magnetically stirred solution of 4-phenylbicyclo[2.2.2]octane-1-carboxylic acid (8-A) (70 mg, 0.30 mmol) in methylene chloride (1 mL) at room temperature was added 2 M oxalyl chloride in methylene chloride (0.61 mL, 1.22 mmol). Two drops of catalytic DMF were added to catalyze the reaction. The reaction was stirred for 30 min and solvent and reagent removed in vacuo. Methylene chloride (1 mL) was added to the residue, followed by 4-(benzyloxy)-2-(trifluoromethyl)benzoic hydrazide (8-B) (141 mg, 0.46 mmol) and triethylamine (0.07 mL, 0.46 mmol). The reaction was stirred at room temperature overnight to afford intermediate 8-C, N′-[4-(benzyloxy)-2-(trifluoromethyl)benzoyl]-4-phenylbicyclo[2.2.2]octane-1-carbohydrazide, which was not isolated. To the crude product (8-C) were then added 2-chloro-1,3-dimethylimidazolinium chloride (257 mg, 1.52 mmol), more triethylamine (0.42 mL, 3.04 mmol), and methylene chloride (2 mL). The reaction was stirred at room temperature for 4 h. The reaction mixture was then diluted with methylene chloride (30 mL) and washed with water (30 mL) two times and with brine (30 mL) once. The combined aqueous layers were extracted with methylene chloride (25 mL) once. The combined organic layers were dried (MgSO4) and the solvent removed in vacuo. The residue was chromatographed on silica with 10% ethyl acetate in hexanes as eluant to give 2-[4-(benzyloxy)-2-(trifluoromethyl)pheny ]-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole (8-D). MS: m/z 505 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](O)(=[O:11])[CH:9]=[CH2:10]>>[N:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8](=[O:11])[CH2:9][CH:10]=1
Reactant: Nc1ccccc1
Reactant: C=CC(=O)O
Product: O=C1CC=Nc2ccccc21

Procedure:
The process of Scheme IX begins with the reaction of an aniline (structure 37) with an unsaturated acid, for example acrylic acid, followed by a cyclization reaction mediated by, for example, polyphosphoric acid to afford a 4-quinolinone. The nitrogen atom is then protected by treatment with a base, for example, 4-dimethylaminopyridine, followed by the addition of an acylating agent such as di-tert-butyldicarbonate, to afford a compound of structure 38. Addition of an organomagnesium or organolithium reagent, with, for example, ethyl magnesium bromide, affords an alcohol. Reduction of the alcohol with, for example hydrogen over palladium on carbon, followed by deprotection of the nitrogen atom, affords a compound of structure 39. Nitration of a compound of structure 39 by the action of nitric acid in the presence of, for example, sulfuric acid, followed by reduction of the nitro group with, for example, hydrogen over palladium on carbon, affords a 7-amino-1,2,3,4-tetrahydroquinoline of structure 40. A Knorr cyclization with a β-keto ester effected by, for example, zinc chloride, affords a compound of structure 41. A compound of structure 41 may be further transformed into a compound of structure 42 by acylation of the quinoline nitrogen, which may be accomplished in one of two ways. Treatment of structure 41 with an acid chloride, for example, acetyl chloride, followed by treatment with a base, for example, potassium carbonate, to afford a compound of structure 42. Alternatively, treatment of structure 41 may be treated with an anhydride, for example, trifluoroacetic anhyride, likewise to afford a compound of structure 42. ##STR16##
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:22])C(=O)C1.CCOC(C)=O.O>C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>[Br:22][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=1)[C:12]([OH:14])=[O:13]
Reactant: CC(C)(C)c1ccc(CC(=O)O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)c1ccc(C(Br)C(=O)O)cc1
Temperature: 70 °C
Yield: 99.3 %

Procedure:
To a stirring solution of (4-tert-butyl-phenyl)-acetic acid (1.5 g, 7.8 mmol) in benzene (30 mL) at room temperature was added NBS (1.39 g, 7.8 mmol) and AIBN (15 mg, 0.08 mmol). The mixture was heated at 70° C. for 16 hrs, added EtOAc and water. The organic layer was collected and dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude bromo-(4-tert-butyl-phenyl)-acetic acid as a light yellow solid (2.1 g, 99%): 1H NMR (300 MHz, DMSO-d6): 7.46 (m, 4H), 5.74 (s, 1H), 1.29 (s, 9H).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.C1COC2C=CC(NC3N=C(NC4C=CC5OCCOC=5C=4)C(Br)=CN=3)=CC=2O1.[Cl:64]C1C=C(B(O)O)C=CC=1>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:64])[CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Brc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2
Product: Clc1cccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)c1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine, N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and 3-chlorophenylboronic acid were reacted to yield N2,N4-bis(3,4-ethylenedioxyphenyl)-5-(3-chlorophenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.77 (s, 1H), 7.45-7.41 (m, 2H), 7.38-7.33 (m, 2H), 7.09 (d, 1H, J=2.4 Hz), 7.01 (d, 1H, J=2.4 Hz), 6.92 (dd, 1H, J=2.4 and 9.0 Hz), 6.86 (dd, 1H, J=2.4 and 8.7 Hz), 6.74 (d, 1H, J=8.7 Hz), 6.67 (d, 1H, J=8.7 Hz), 4.21 (s, 4H), 4.19 (s, 4H); LCMS: ret. time: 27.18 min.; purity: 95%; MS (m/e): 490 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([CH2:25][OH:26])[CH:24]=1)[O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:34][S:35]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])[CH:24]=1)[O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])(=[O:37])=[O:36]
Reactant: COC(=O)CCOCCOCCOCCOc1cc(CO)cc(CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCOCCOCCOCCOc1cc(COS(C)(=O)=O)cc(COS(C)(=O)=O)c1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 3-(2-(2-(2-(3,5-bis(hydroxymethyl)phenoxy)ethoxy)ethoxy)ethoxy)propanoate (263b) (145 mg, 0.389 mmol) in anhydrous dichloromethane (5.5 ml) was added triethylamine (0.163 ml, 1.168 mmol). The mixture was cooled to −5° C. and methanesulfonyl chloride (0.076 ml, 0.973 mmol) was added slowly. After stirring for one hour at −5° C. the reaction was quenched with cold water and extracted with cold ethyl acetate. The organic extracts were washed with cold water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 3-(2-(2-(2-(3,5-bis((methylsulfonyloxy)methyl)phenoxy)ethoxy)ethoxy)ethoxy)propanoate. MS (m/z). found 551.1 (M+Na)+. To a stirred mixture of methyl 3-(2-(2-(2-(3,5-bis((methylsulfonyloxy)methyl)phenoxy)ethoxy)ethoxy)ethoxy)propanoate (206 mg, 0.390 mmol) and compound 8 (287 mg, 0.974 mmol) in anhydrous DMF (3.9 ml) was added potassium carbonate (269 mg, 1.949 mmol). The reaction was allowed to stir at room temperature for 18 hours. The mixture was quenched with water and extracted three times with dichloromethane. The organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash silica gel chromatography (5% MeOH/CH2Cl2) followed by preparative reverse phase HPLC (C18 column, eluted with CH3CN/H2O) gave compound 263c (110 mg, 30%) as a white solid. 1H NMR (400 Hz, CDCl3): δ 8.18 (d, J=8.0 Hz, 2H), 7.77 (m, 2H), 7.49 (s, 2H), 7.19 (m, 4H), 7.02 (m, 2H), 6.89 (s, 2H), 6.87 (s, 1H), 6.75 (s, 2H), 5.10 (m, 4H), 4.39 (m, 2H), 4.05 (m, 2H), 3.90 (s, 6H), 3.77 (m, 2H), 3.67 (t, J=6.4 Hz, 2H), 3.64 (m, 2H), 3.59 (s, 3H), 3.70-3.54 (m, 8H), 3.40 (m, 2H), 2.51 (t, J=6.4 Hz, 2H); MS (m/z). found 965.3 (M+H2O+Na)+, 983.3 (M+2H2O+Na)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[S:19]C5CCCC=5[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12.[C:39]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=O)[CH2:40][CH2:41][CH2:42][CH3:43]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18]4[S:19][C:40]([CH2:41][CH2:42][CH3:43])=[C:39]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)[N:22]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: CCCCC(=O)c1ccccc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6c(s5)CCC6)cc4)c4c(N)ncnc43)CC2)CC1
Product: CCCc1sc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)nc1-c1ccccc1

Procedure:
The procedure described for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-amine was used to convert valerophenone (0.488 g, 3.01 mmol) to the title compound. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 9.6-11.8 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-phenyl-5-propyl-1,3-thiazol-2-amine as a yellow powder (0.135 g, 0.222 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 10.08 min;
Reaction SMILES: C(=[N:8][C:9]([CH2:19][CH3:20])([CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])C1C=CC=CC=1.Cl>>[NH2:8][C:9]([CH2:19][CH3:20])([CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCCCC(CC)(N=Cc1ccccc1)C(=O)OCC
Agent: Cl
Product: CCCCC(N)(CC)C(=O)OCC
Temperature: 10 °C
Yield: 70 %

Procedure:
A solution of the product from step (c) (1mole) in 1N aqu. HCl (1.2 moles) was stirred for 10 minutes at room temperature, then washed with toluene. The pH of the remaining aqueous phase was adjusted to 7 using 12.5% w/v sodium hydroxide, then cooled to 10° C., further basified to pH 12 and extracted with toluene. The extracts were combined, washed with brine, dried and evaporated in vacuo. The residue was distilled to give the desired product as an oil (70-80% yield).
Reaction SMILES: [C-:1]#[N:2].C([Al+]CC)C.[CH3:8][CH:9]([CH2:11][CH2:12][CH2:13][C@H:14]([C@@H:16]1[C@:33]2([CH3:34])[C@H:19]([C:20]3[CH2:21][CH2:22][C:23]4[C@:28]([C:30]=3[CH2:31][CH2:32]2)([CH3:29])[CH2:27][CH2:26][C:25](=[O:35])[CH:24]=4)[CH2:18][CH2:17]1)[CH3:15])[CH3:10].[OH-].[Na+]>O1CCCC1>[C:1]([C@@:23]12[CH2:24][C:25](=[O:35])[CH2:26][CH2:27][C@:28]1([CH3:29])[C:30]1[CH2:31][CH2:32][C@@:33]3([CH3:34])[C@@H:19]([CH2:18][CH2:17][C@@H:16]3[C@H:14]([CH3:15])[CH2:13][CH2:12][CH2:11][CH:9]([CH3:8])[CH3:10])[C:20]=1[CH2:21][CH2:22]2)#[N:2].[C:1]([C@:23]12[CH2:24][C:25](=[O:35])[CH2:26][CH2:27][C@:28]1([CH3:29])[C:30]1[CH2:31][CH2:32][C@@:33]3([CH3:34])[C@@H:19]([CH2:18][CH2:17][C@@H:16]3[C@H:14]([CH3:15])[CH2:13][CH2:12][CH2:11][CH:9]([CH3:8])[CH3:10])[C:20]=1[CH2:21][CH2:22]2)#[N:2]
Reactant: [C-]#N
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C=C1CC3
Agent: CC[Al+]CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C[C@@]1(C#N)CC3
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C[C@]1(C#N)CC3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
30 ml of a diethylaluminum cyanide solution (1 N, in toluene) are added to a solution of 3.82 g cholesta-4,8-dien-3-one in 60 ml tetrahydrofuran at 0° C. The reaction mixture is warmed to room temperature and stirred for 4 hours. 20 ml of a sodium hydroxide solution (1 N) are added before the mixture is extracted with diethyl ether. The organic layer is separated, dried over anhydrous sodium sulphate and filtered. After evaporation of the solvent the residue is chromatographed with a mixture of hexane and ethyl acetate to give 1.46 g 5-cyano-5β-cholest-8-en-3-one and 1.76 g 5-cyano-5α-cholest-8-en-3-one as pale yellow crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[N+](C1C=CC([O:26][C:27](=O)[NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=2)=CC=1)([O-])=O.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:35]([C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:27]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][CH:8]=3)[CH2:5][CH2:6]2)=[O:26])=[CH:30][CH:31]=1)([CH3:37])[CH3:36]
Reactant: CC(C)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: c1ccc2c(C3CCNCC3)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)c1ccc(NC(=O)N2CCC(c3ccnc4ccccc34)CC2)cc1
Temperature: 100 °C
Reaction time: 14 h
Yield: 32.3 %

Procedure:
A solution of 4-piperidin-4-yl-quinoline (21.1 mg, 99.5 μmol), as prepared in the previous step, (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester (33.2 mg, 111 μmol), as prepared in Example 4a, and DIEA (18 μL, 109 μmol) in DMSO (100 μL) was stirred at 100° C. for 14 h. The reaction was then allowed to cool to rt, shaken with 2 M K2CO3 (aq) (2 mL), and extracted with DCM (2×2 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. Flash chromatography of the residue (3:4 hex/acetone) provided the title compound (12 mg, 32%). 1H-NMR (300 MHz, CDCl3) δ 8.88 (d, 1H), 8.14 (m, 2H), 7.74 (m, 1H), 7.61 (m, 1H), 7.30 (m, 2H), 7.28 (d, 1H), 7.17 (m, 2H), 6.38 (br s, 1H), 4.36-4.26 (m, 2H), 3.58 (m, 1H), 3.16 (td, 2H), 2.87 (heptet, 1H), 2.13-2.03 (m, 2H), 1.95-1.79 (m, 2H), 1.23 (d, 6H). LC/MS (ESI): calcd mass 373.2, found 374.2 (MH)+.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:14])([F:13])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:10]1[CH:9]=[CH:8][C:7]([OH:12])=[C:6]([O:5][C:4]([F:13])([F:14])[F:3])[CH:11]=1
Reactant: Oc1ccccc1OC(F)(F)F
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(Br)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.55 mL (30.3 mmol) bromine in 50 mL DCM is added dropwise to a solution of 5.0 g (28.1 mmol) 2-trifluoromethoxy-phenol in 70 mL DCM at −78° C. The reaction solution is heated to RT and stirred for a further 48 h. Then 70 mL Na2SO3 solution are added and the mixture is stirred until the orange colour has disappeared. The solution is diluted with DCM, the organic phase is washed with NaCl solution, dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (gradient: PE to PE:EtOAc 4:1).