Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:12]2=[O:18])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C(=O)NCCn2ccnn2)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.1 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (61 mg, 52%).
Reaction SMILES: C[O:2][C:3](=[O:25])[C@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[C:12]([CH:20]2[S:24][CH2:23][CH2:22][S:21]2)[CH:11]=1)[NH:5][C:6](=[O:8])[CH3:7].O.[OH-].[Li+].Cl>C1COCC1.O>[S:21]1[CH2:22][CH2:23][S:24][CH:20]1[C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[CH2:16][C:17]([OH:19])=[O:18])[CH2:9][C@@H:4]([C:3]([OH:25])=[O:2])[NH:5][C:6](=[O:8])[CH3:7]
Reactant: COC(=O)[C@H](Cc1ccc(CC(=O)O)c(C2SCCS2)c1)NC(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1ccc(CC(=O)O)c(C2SCCS2)c1)C(=O)O
Reaction time: 0.75 h

Procedure:
To 3-(1,3-dithiolan-2-yl)4-(carboxymethyl)-N-acetyl-L-phenylalanine methyl ester (0.22 g, 0.57 mmol) in THF (10 mL) at 0° C. was added lithium hydroxide monohydrate (0.025 g, 0.60 mmol, 1 mL water). The mixture was stirred for 45 min., diluted with water, made acidic with 1 N HCl, and extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and concentrated to a glassy solid which was homogeneous by RP HPLC (0.18 g, 86%). MS [M−H]− 368.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([OH:14])=O)[S:5][N:4]=1)[CH3:2].S(Cl)([Cl:17])=O.CN(C)C=O.C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:17])=[O:14])[S:5][N:4]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1nsc(C(=O)O)c1C(=O)OC
Agent: O=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCc1nsc(C(=O)Cl)c1C(=O)OC

Procedure:
73 g of the carboxylic acid from Example c and 80 g of thionyl chloride in 200 ml of toluene are refluxed in the presence of a little dimethylformamide until the evolution of gas is complete. The crude carbonyl chloride which remains in quantitative yield after evaporation is directly reacted further.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1)[CH3:2].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:22][CH2:23][C:24](Cl)=[O:25]>O>[CH2:1]([N:3]([CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1)[C:24](=[O:25])[CH2:23][Cl:22])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCNCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCN(CC1OCCO1)C(=O)CCl

Procedure:
N-Ethyl-N-(1,3-dioxolan-2-ylmethyl)amine (50 grams), benzene (100 ml), water (100 ml) and sodium carbonate (5.0 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (3 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-ethyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([OH:15])[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:16](OC=C)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[C:16]([O:15][C@@H:13]([C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[O:12][N:11]=1)[CH3:14])(=[O:18])[CH3:17]
Reactant: CC(O)c1cc(-c2cccc(Cl)c2)on1
Reactant: C=COC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H](C)c1cc(-c2cccc(Cl)c2)on1
Yield: 39.5 %

Procedure:
The title compound of Example 7.1 (106.5 g, 476 mmol) and Novozyme 435® (13 g) are taken up under Ar in dry toluene (1.5 L). After addition of vinyl acetate (66 mL, 716 mmol) the reaction was run at RT over night, followed by filtration over diatomaceous earth and washing with DCM. The solvent was evaporated in vacuo and the crude product was subjected to column chromatography on silica using dichloromethane/methanol (20:1) to give the title compound (50 g, 47%).
Reaction SMILES: [C:1]1([C:9]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=2)=[O:10])[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.[C:20](Cl)(=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:6][O:5][C:4]1[CH:3]=[CH:2][C:1]([C:9](=[O:10])[CH:11]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[CH:18][CH:19]=2)[C:20]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[O:29])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C(C(=O)c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of desoxyanisoin (1.0 equiv.) in THF at −78° C. was added dropwise 1.5 equiv. of [(CH3)2Si]2NLi. The solution was stirred for 1 h at −78° C., followed by addition of 1.2 equiv. of p-anisoyl chloride. The reaction mixture was stirred for 10 min at −78° C. and then for 22 h at rt, acidified with 10% citric acid, and extracted with EtOAc. The combined organic layers were washed with water and dried over Na2SO4. Removal of solvent in vacuo provided a crude solid which was purified by flash chromatography (CH2Cl2) to give 1,2,3-tris(4-methoxyphenyl)propane-1,3-dione.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]O)=[CH:8][C:7]=1[O:14][CH3:15])(=[O:5])=[O:4].S(Cl)([Cl:19])=O>C(Cl)Cl>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][Cl:19])=[CH:8][C:7]=1[O:14][CH3:15])(=[O:5])=[O:4]
Reactant: COc1cc(CO)ccc1S(=O)(=O)N(C)C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(CCl)ccc1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.6 %

Procedure:
To a solution of OBS02014 (2.76 g, 10.55 mmol) in anhydrous DCM (50 mL) was added thionyl chloride (1.15 mL, 15.82 mmol). The mixture was stirred at room temperature for 2 h and the volatiles removed in vacuo. The residue was re-dissolved and co-evaporated three times with DCM (3×20 mL) to give OBS02016 as a brown oil (2.91 g, 99%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.84; 1H-NMR (270 MHz, CDCl3)=2.96 (6H, s), 3.90 (3H, s), 4.55 (2H, s), 6.95 (1H, dd, J=1.8, 8.0), 7.01 (1H, d, J=1.8), 7.32 (1H, d, J=8.0). Dimethylsulfamic Acid 4-{[(4-cyano-phenyl)-[1,2,4]triazol-4-ylamino]methyl}-2-methoxyphenyl ester (OBS02017, STX739)
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:34])[C:5](=O)[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[NH:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH:9]=1.[NH3:35]>C(O)C>[NH2:35][C:5]1[C:4](=[O:34])[C:3](=[O:2])[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[NH:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH:9]=1
Reactant: N
Reactant: COc1ccc(C(NCC(C)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Solvent: CCO
Product: COc1ccc(C(NCC(C)c2ccccc2)c2cccc(Nc3c(N)c(=O)c3=O)c2)cc1

Procedure:
In a similar manner to that described in Example (1d), 3-methoxy-4-{3-[(4-methoxyphenyl)-(2-phenylpropylamino)methyl]phenylamino}-3-cyclobutene-1,2-dione (2.35 g) [prepared as described in step (c) above] and a solution of ammonia in ethanol (2N, 10.2 ml) were reacted, to give the title compound (1.87 g) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[C:13](=[O:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Br:23]N1C(=O)CCC1=O>CN(C=O)C.CCOCC>[Br:23][C:7]1[CH:6]=[C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:4]=[C:3]([C:13](=[O:22])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:2]=1[OH:1]
Reactant: O=C(O)CCc1ccc(O)c(C(=O)CCc2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(O)CCc1cc(Br)c(O)c(C(=O)CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The carboxylic acid 209, for example 3-[4-Hydroxy-3-(3-phenyl-propionyl)-phenyl]-propionic acid, (1.04 gm, 3.4 g mmol) was dissolved in DMF (7 mL) and N-bromosuccinimide (0.65 g, 3.66 mmol) was added to the solution. The mixture was stirred at ambient temperature for 2.5 h, diluted with ether and the organic layer was separated and washed with water and brine and then filtered through a pad of magnesium sulfate and concentrated. The residue was purified by flash chromatography (3.5:1.5:0.1 of hexane:ethyl acetate:acetic acid) to give 0.5 g of 3-[3-bromo-4-hydroxy-5-(3-phenyl-propionyl)-phenyl]-propionic acid 210 as a yellow-brown oil.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12]O)[CH:4]=1)=[O:2].S(Cl)([Cl:16])=O>ClCCl>[Cl:16][CH2:12][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([CH:1]=[O:2])=[CH:4]1
Reactant: O=Cc1cn(CO)c2ccccc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=Cc1cn(CCl)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.08 g of 3-formyl-1H-indole-1-ylmethanol was dissolved to 60 ml of dichloromethane. 2.5 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain 3.02 g of 1-(chloromethyl)-3-formyl-1H-indole.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@@H:5]([NH2:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:9][CH:8]=1.[Br:28][C:29]1[CH:30]=[CH:31][C:32]([NH2:38])=[C:33]([CH:37]=1)[C:34](O)=[O:35]>>[CH3:2][O:3][C:4](=[O:27])[C@@H:5]([NH:26][C:34](=[O:35])[C:33]1[CH:37]=[C:29]([Br:28])[CH:30]=[CH:31][C:32]=1[NH2:38])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2Oc2ccccc2)cc1
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Br)ccc1N
Yield: 80 %

Procedure:
(S)-(2-Amino-5-bromo-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (1.53 g, 80%) was prepared from (2S)-Amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester HCl salt (1.0 g, 2.6 mmol, 5-bromo-2-amino-benzoic acid (0.5 g, 2.9 mmol) as described in general procedure A.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7](S(C)(=O)=O)[CH:8]=[C:9]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH:10]=1)=[O:5])C.CO.CC1C=CC(S([CH2:37][N+:38]#[C-:39])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>COCCOC>[F:20][C:14]1[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:11]([C:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[NH:7][CH:8]=2)[CH:39]=[N:38][CH:37]=1
Reactant: CCOC(=O)c1cc(N=Cc2cccc(F)c2F)cn1S(C)(=O)=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: O=C(O)c1cc(-n2cncc2-c2cccc(F)c2F)c[nH]1
Yield: 12.3 %

Procedure:
To a solution of 4-[(2,3-difluoro-benzylidene)-amino]-1-methanesulfonyl-1H-pyrrole-2-carboxylic acid ethyl ester (500 mg, 1.40 mmol) in co-solvents of MeOH (10 mL) and DME (5 mL) was added TosMIC (410 mg, 2.10 mmol) and K2CO3 (390 mg, 2,82 mmol). The reaction mixture was heated under reflux for 2 hours and the solvents were removed by evaporation. The residue was treated with LiOH in THF/H2O at room temperature for 14 hours. After removal of the solvents by evaporation, the residue was acidified by 2N HCl solution. The crude product was then purified by HPLC to afford 50 mg desired product (12%). MS (ES−): m/e=288.0 (M−H); LC/Method A/2.45 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:11]([N:12]=[C:13]3[C:18]=1[CH:17]=[CH:16][C:15]([OH:19])=[CH:14]3)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4].C(=O)([O-])[O-].[K+].[K+].[N+:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br)([O-:28])=[O:27]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:11]([N:12]=[C:13]3[C:18]=1[CH:17]=[CH:16][C:15]([O:19][CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=1)=[CH:14]3)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: COC(=O)c1c2ccccc2nc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c2ccccc2nc2cc(OCc3cccc([N+](=O)[O-])c3)ccc12
Temperature: 25 °C

Procedure:
3-Hydroxyacridine-9-carboxylic acid methyl ester (14.6 g; 57.7 mmol) was dissolved in 500 ml DMF, then potassium carbonate (25.0 g; 181 mmol) and m-nitrobenzylbromide (15.0 g; 69.4 mmol) were added and stirred at room temperature. After 4 hours the mixture was filtered and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in CH2Cl2 and washed with HCl 1N, NaOH 1N and sodium chloride solution (10%). After drying with sodium sulfate and evaporating to dryness the residue was flash chromatographed (column: 10 cm diameter) in CH2Cl2 +1% methanol (fractions of 200 ml). Fractions 7-23 were combined, evaporated and the residue was collected on a Buchner funnel and washed with diethylether. Yield 8.7 g (39%), Fp.>250° C. 1H-NMR(CDCl3): 5,35(2H, s, CH2) and 4,22 ppm (3H, s, CH3). MS: M+ =388.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.CCN(CC)CC.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]>C(Cl)Cl>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([N:1]2[CH2:6][CH2:5][S:4][CH2:3][CH2:2]2)=[O:22])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C1CSCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCSCC1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a stirred solution of thiomorpholine (2.00 mL, 20 mmol) and Et3N (5.0 mL) in CH2Cl2 (60 mL) was added drop wise a solution of 4-nitrobenzoyl chloride (3.71 g, 20 mmol) in CH2Cl2 (50 mL) at 0° C. The reaction was allowed to stir at room temperature for over night and then washed with a saturated NaHCO3 solution (2×75 mL), and water (2×75 mL). The CH2Cl2 layer was dried (Na2SO4) and filtered and concentrated. Finally dried under high vacuum to afford 5.027 g (99%) of the 4-(4-nitrobenzoyl)thiomorpholine. 1H NMR (CDCl3, 300 MHz): δ 8.28 (d, 2H, J=9.0 Hz), 7.54 (d, 2H, J=8.7 Hz), 4.04 (br s, 2H), 3.61 (br s, 2H), 2.75 (br s, 2H), 2.57 (br s, 2H); LCMS (m/z): 253 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:7][CH:8]=1.[CH2:17](Br)[CH2:18][CH2:19][CH3:20].[OH-].[K+]>CS(C)=O.CCOCC>[CH2:17]([N:7]1[CH:8]=[C:4]([CH:3]([O:2][CH3:1])[O:15][CH3:16])[N:5]=[C:6]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:18][CH2:19][CH3:20]
Reactant: COC(OC)c1c[nH]c(-c2ccccc2)n1
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCCCn1cc(C(OC)OC)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-dimethoxymethyl-2-phenyl-1H-imidazole 208 (2.18 g, 10 mmol) and n-butyl bromide (2.74 g, 20 mmol) in anhydrous DMSO (15 mL) is added to a suspension of powdered potassium hydroxide (0.96 mg, 15 mmol) in DMSO (20 mL) at room temperature over 3 h. The mixture is then stirred at rt for 16 h. The mixture is diluted with ether and washed with water (three times), brine, and dried over anhydrous sodium sulfate. Removal of the solvent and purification of the residue affords the desired product. Yield: 2.5 g; LC-MS (MH+): 275.
Reaction SMILES: [OH:1][C@H:2]([CH3:9])[CH2:3][NH:4][C@H:5]([CH3:8])[CH2:6][OH:7].C(=O)(O)[O-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>ClCCl>[OH:7][CH2:6][C@H:5]([N:4]([CH2:3][C@H:2]([OH:1])[CH3:9])[C:16](=[O:17])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:8]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](CO)NC[C@@H](C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](CO)N(C[C@@H](C)O)C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a mixture of (R)-2-((R)-2-hydroxypropylamino)propan-1-ol (11 g, 83 mmol) in 200 mL dichloromethane stirred at 0° C. was added a sat. solution of sodium bicarbonate (8.3 g, 99 mmol), then added dropwise benzyl chloroformate (15 g, 91 mmol). The mixture was stirred from 0° C. warming to RT over 4 h. The mixture was extracted with dichloromethane (3×100 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by column eluting with 20-70% ethyl acetate in hexane to give the benzyl (R)-1-hydroxypropan-2-yl((R)-2-hydroxypropyl)carbamate as a colorless oil.
Reaction SMILES: [I-].[K+].CS(O[CH2:8][CH2:9][O:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[C:23]([F:35])[CH:22]=2)[NH:13][N:12]=1)(=O)=O.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[F:35][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([O:10][CH2:9][CH2:8][N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)[C:19]=23)[CH:26]=[CH:25][C:24]=1[O:27][C:28]1[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCOS(C)(=O)=O)c34)cc2F)cn1
Agent: [I-]
Agent: [K+]
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCN(C)CC5)c34)cc2F)cn1
Yield: 54 %

Procedure:
The procedure described in Example 23 was repeated (except that potassium iodide was not used) using 2-{[4-({3-fluoro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate and N-methylpiperazine to give the title compound in 54% yield; NMR Spectrum: 2.11 (s, 3H), 2.44 (s, 8H), 2.08 (t, 2H), 3.31 (hidden by water, 3H), 4.46 (t, 2H), 7.26 (m, 3H), 7.55 (dd, 1H), 8.01 (dd, 1H), 8.24 (d, 1H), 8.36 (s, 1H), 8.60 (br s, 1H); Mass Spectrum: 479 (MH+).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[N:8]1([C@H:14]2[CH2:31][C@@:30]3([CH3:32])[C@@H:17]([CH2:18][CH2:19][C@@H:20]4[C@@H:29]3[CH2:28][CH2:27][C@@:25]3([CH3:26])[C@H:21]4[CH2:22][C@H:23]([N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[C@@H:24]3[OH:33])[CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[C:1]([O:33][C@H:24]1[C@@H:23]([N:34]2[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]2)[CH2:22][C@H:21]2[C@H:20]3[C@H:29]([CH2:28][CH2:27][C@:25]12[CH3:26])[C@:30]1([CH3:32])[C@H:17]([CH2:16][CH2:15][C@@H:14]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:31]1)[CH2:18][CH2:19]3)(=[O:3])[CH3:2]
Reactant: C[C@]12C[C@H](N3CCCCC3)CC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCCC3)C[C@@H]12
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@@H](N2CCCCC2)C[C@H]2[C@@H]3CC[C@H]4CC[C@@H](N5CCCCC5)C[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 19 h

Procedure:
Acetic anhydride (1.21 ml) was added to a solution of 2β,16β-di-(1-piperidinyl)-5α-androstan-17β-ol (3.77 g) in dry pyridine (75 ml) at 0°-5° C. and the solution was set aside at room temperature for 19 h. Saturated sodium carbonate solution (40 ml) was added to precipitate the product, which was filtered off and washed well with water (200 ml). A solution of the crude product in diethyl ether (50 ml) was washed with water (2×100 ml), dried (MgSO4) and concentrated to afford 2β,16β-di-(1-piperidinyl)-5α-androstan-17β-ol acetate (3.91 g), m.p. 156°-161° C.; [α]D +28.7° (c 0.47 in CHCl3).
Reaction SMILES: [OH:1][C@H:2]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:27])[CH2:13][CH2:14][CH2:15][C@@H:16]([CH3:26])[CH2:17][O:18][Si](C(C)(C)C)(C)C)[C:3]1([CH3:38])[CH3:37].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CO>[CH3:38][C:3]1([CH3:37])[C@@H:2]([OH:1])[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:4]1=[CH:5][CH2:6][C@@H:7]1[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:27])[CH2:13][CH2:14][CH2:15][C@@H:16]([CH3:26])[CH2:17][OH:18]
Reactant: C[C@H](CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Product: C[C@@H](CO)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 63.3 %

Procedure:
Silyl deprotection of 3β-hydroxy-4,4-dimethyl-(25R)-26-(tert-butyldimethylsilyloxy)cholest-5-ene (60 mg, 0.11 mmol) with tetrabutyl ammonium fluoride and recrystallisation from methanol to give 4,4-dimethyl-(25R)-cholest-5-ene-3β,26-diol (30 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[CH:5][O:6][CH:7]([F:9])[F:8].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][Br:36])=[CH:5][O:6][CH:7]([F:8])[F:9]
Reactant: COC(=O)C(=COC(F)F)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=COC(F)F)c1ccccc1CBr
Temperature: 25 °C

Procedure:
A solution of 14.2 g of 3-difluoromethoxy-2-(o-tolyl)-acrylic acid methyl ester and 0.15 g of dibenzoyl peroxide in 85 ml of carbon tetrachloride is heated to reflux. With radiation from a lamp, 10.44 g of N-bromosuccinimide are then added in several small portions and the reaction mixture is left to react for 1.5 hours. After cooling to room temperature, the reaction mixture is filtered and concentrated by evaporation in vacuo. The pale red crude product is purified by chromatography on silica gel with hexane/ethyl acetate and crystallised from hexane. Pure 2-(2-bromomethylphenyl)-3-difluoromethoxy-acrylic acid methyl ester is obtained; m.p. 63°-67° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([Br:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C([O-])([O-])=O.[K+].[K+].Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Cl)[CH:33]=1>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([Br:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:38][C:34]1[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)c1cc(C)cc(Br)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C)cc(Br)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 48 h
Yield: 82 %

Procedure:
To a sired solution of 2.0 g (4.8 nmnol) of the product of Example 135 in 20 mL of DMF was added 1.0 g (10 mmol) of K2CO3 and 1.1 g (7.2 mmol) of 3-picolyl chloride hydrochloride. The reaction niixture was stirred for 48 h at room tempera and then diluted with water. The resulting mixture was extracted with chloroform and the combined organic layers were washed with water, dried over MgSO4, filtered and concentraed in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate. hexane (1:1) to provide 2.90 g (82%) of the desired product as a brown oil. Electrospray Mass Spec: 508 (M+H).