Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@@:4]1([OH:37])[C@@:9](C(=O)C)([OH:10])[C@@:8](C(=O)C)([OH:14])[C@@H:7]([CH:18](C(=O)C)[OH:19])[O:6][C@H:5]1[O:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=1[N+:34]([O-:36])=[O:35])[C:27]([O:29][CH3:30])=[O:28])(=O)C.CO>C(N(CC)CC)C>[C@@H:5]1([O:23][C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=2[N+:34]([O-:36])=[O:35])[C:27]([O:29][CH3:30])=[O:28])[O:6][C@H:7]([CH2:18][OH:19])[C@H:8]([OH:14])[C@H:9]([OH:10])[C@H:4]1[OH:37]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O[C@@H]2O[C@H](C(O)C(C)=O)[C@@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@]2(O)C(C)=O)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1

Procedure:
The tetracetate IV (119 g, 0.226 mole) was added to methanol (1000 ml). The mixture was heated at 60° until the solid dissolved. Triethylamine (25 ml) was then added, and the solution was heated at 60° for an additional two hours. The crude solid product was obtained in several crops by evaporation of the solution, the final crop being taken from a 20 ml volume. The crude material was used in the next reaction without further purification.
Reaction SMILES: ClC1C=[CH:9][C:5]([C:6](O)=O)=[C:4]([N+]([O-])=O)C=1.[CH2:14]([O:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24]([O:26][C:5]([CH3:9])([CH3:6])[CH3:4])=[O:25])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C(O)c1ccc(Cl)cc1OCc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(Cl)cc1OCc1ccccc1

Procedure:
Instead of the starting material, that is, 4-chloro-2-nitrobenzoic acid, of Reference Example 6, 2-(benzyloxy)-4-chlorobenzoic acid was used for a similar procedure as in Reference Example 6 to obtain tert-butyl 2-(benzyloxy)-4-chlorobenzoate (compound S12a).
Reaction SMILES: [NH2:1][NH2:2].[F:3][C:4]([F:15])([F:14])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1>C(O)C>[F:3][C:4]([F:15])([F:14])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[N:1][NH2:2])=[CH:8][CH:7]=1
Reactant: NN
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Solvent: CCO
Product: NN=Cc1ccc(OC(F)(F)F)cc1
Reaction time: 0.75 h
Yield: 91 %

Procedure:
Hydrazine (3.3 mL, 105 mmol) was dissolved in ethanol (10 mL) at room temperature. To this solution was added 4-trifluoromethoxybenzaldehyde (5.0 mL, 35 mmol) dropwise over 25 min. The reaction mixture was stirred an additional 45 min and concentrated under vacuum. The residue was dissolved in ethyl ether (20 mL) and washed with water (10 mL). The water layers were extracted with ethyl ether (3×15 mL), and the combined organic layer was dried over magnesium sulfate, filtered and concentrated to give [4-(trifluoromethoxy)benzylidene]hydrazine (XX) as a yellow oil (6.5 g, 91% yield). 1H NMR (DMSO-d6): δ 7.69 (s, 1H); δ 7.56 (d, J=8.7 Hz, 2H) δ 7.30 (d, J=7.8 Hz, 2H); δ 6.94 (bs, 2H); GC-MS m/z 204 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:22]=[O:23]>CN(C=O)C>[C:24]1([NH:21][C:22]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:23])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccccc4)CC3)c2cc1OC
Yield: 26.4 %

Procedure:
A solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (30 mg, 0.110 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with isocyanato-benzene (19.6 mg, 0.165 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a yellow solid (11.4 mg, 27%). 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 7.37 (m, 6H), 7.06 (m, 1H), 6.42 (br s, NH), 4.31-4.27 (m, 2H), 4.08 (s, 6H), 3.62 (m, 1H), 3.19 (m, 2H), 2.17 (m, 2H), 2.04-1.98 (m, 2H); LC/MS (ESI): calcd mass 392.2, found 393.3 [M+1]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:7][CH2:6][N:5]2[CH2:8][CH2:9][CH2:10][C@@H:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[C:4]2=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]([F:33])([F:32])[S:28](Cl)(=[O:30])=[O:29].O>CN(C=O)C>[F:26][C:27]([F:33])([F:32])[S:28]([O:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:11]2[C:4]3=[N:3][S:2](=[O:1])(=[O:19])[CH2:7][CH2:6][N:5]3[CH2:8][CH2:9][CH2:10]2)=[CH:13][CH:14]=1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)C2=N1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (1.00 g) and potassium carbonate (1.23 g) in DMF (dry) (30 ml) was added trifluoromethanesulfonyl chloride (0.939 mL) at 0° C. The mixture was stirred at 0° C. for 5 min then at room temperature for 2 hr. The mixture was added with water. The resulting precipitate was collected, washed with water, and dried at 60° C. in vacuo to give the title compound (1.27 g) as a white solid.
Reaction SMILES: [CH:1]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:6]2[CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][C:12]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:30])=[CH:32][CH:33]=1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Reactant: c1ccc2c(c1)CCc1ccccc1NC2
Product: O=C(c1ccccc1)c1ccc(C(=O)N2Cc3ccccc3CCc3ccccc32)cc1

Procedure:
As described for Example 26, 5,6,11,12-tetrahydrodibenz[b,f]azocine is reacted with 4-(benzoyl)benzoyl chloride to give the product as a solid, m.p. 89°-92° C., Mass spectrum (CI), 418(MH+)
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].CN(C)CC[N:11]1[C:19]2[CH:18]=[CH:17][C:16](Cl)=[C:15]3[C:21](=[O:28])[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][C:27]=4[C:13]([C:14]=23)=[N:12]1>N1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:16]1[CH:17]=[CH:18][C:19]2[NH:11][N:12]=[C:13]3[C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[C:21](=[O:28])[C:15]=1[C:14]=23
Reactant: CN(C)CCN
Reactant: CN(C)CCn1nc2c3c(c(Cl)ccc31)C(=O)c1cnccc1-2
Solvent: c1ccncc1
Product: CN(C)CCNc1ccc2[nH]nc3c2c1C(=O)c1cnccc1-3
Temperature: 80 °C

Procedure:
Under a nitrogen atmosphere N,N-dimethylethylenediamine (1.79 mL) is added to a stirred solution of 2-[2-(dimethylamino)ethyl]-5-chloroisoquino[5,6,7-cd]indazole-6(2H)-one (0.539 g) in pyridine (6.80 mL) and the resulting solution is heated at 80° C. for 12 hours. The pyridine and excess N,N-dimethylethylenediamine are removed by roto-evaporation and the obtained residue is purified by silica gel column chromatography eluting first with methylene chloride, then with methylene chloride/methanol 95/5 and finally with methylene chloride/methanol/concd. ammonia from 95/5/0.5 to 95/5/1 v/v/v. The fractions containing the yellow desired product are pooled and the solvents roto-evaporated. The obtained residue (0.529 g) is crystallized from diisopropylether to give 2-[2-(dimethylamino)ethyl)]-5-[[2-(dimethylamino)ethyl]amino]isoquino[5,6,7-cd]indazole-6(2H)-one as a yellow powder (0.291 g).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([SH:12])[CH:9]=[C:8]([CH3:13])[C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][N:15]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]1=[O:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:14][N:15]1[C:19](=[O:20])[CH2:18][CH:17]([S:12][C:10]2[CH:9]=[C:8]([CH3:13])[C:6]([NH2:7])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=2)[C:16]1=[O:21]
Reactant: Cc1cc(S)cc(C(C)(C)C)c1N
Reactant: CN1C(=O)C=CC1=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(SC2CC(=O)N(C)C2=O)cc(C(C)(C)C)c1N
Yield: 52.2 %

Procedure:
A stirred solution of 1.0 g (5 mmol) of 2-tert-butyl-4-mercapto-6-methylaniline, 0.6 g (5 mmol) of N-methylmaleimide and 0.1 g (1 mmol) of triethylamine in 10 mL of toluene is heated at 50° C. for 18 hours. The solvent is removed in vacuo and the residue is purified by flash chromatography (silica gel, 3:2, heptane:ethyl acetate eluent) followed by recrystallization from a heptane:toluene solvent mixture to give 0.8 g (51%) of the title compound as a white solid melting at 92°-94° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.CO>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1
Reactant: N#Cc1ncc(CO)cc1Cl
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ncc(C=O)cc1Cl
Temperature: 40 °C
Yield: 59.3 %

Procedure:
CrO2 (Magtrieve) (335 mg, 3.99 mmol) was added to a solution of 3-chloro-5-(hydroxymethyl)-2-pyridinecarbonitrile (33.6 mg, 0.199 mmol) in DCM (2.5 ml) and the mixture was stirred at 40° C. TLC (5% MeOH in DCM) after 3 h showed some starting material. It was heated at 40° C. overnight and full conversion was observed by TLC. The solids were filtered off and the solvent evaporated, yielding 3-chloro-5-formyl-2-pyridinecarbonitrile (19.7 mg, 0.118 mmol, 59% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH2:21]>>[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cc1ccc(C)c(N)c1
Product: Cc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2,5-dimethylaniline (48 μl, 0.386 mmol) similar to Example 58 and isolated as a light tan solid (14mg, 21%). 1H NMR (CDCl3): 9.70 (dd, J=0.8, 2.0 Hz, 1H), 8.74-8.70 (m, 1H), 8.67 (dd, J=1.8, 4.8 Hz, 1H), 7.75 (s, 1H), 7.43-7.38 (m, 1H), 7.24 (d, J=7.5 Hz, 1H), 7.19 (s, 1H), 7.10 (d, J=7.8 Hz, 1H), 6.56 (s, 1H), 2.38 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24](Cl)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:27]1CCO[CH:28]1[C:32]1[O:36][C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:34][CH:33]=1>Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([C:35]4[O:36][C:32]([CH:28]=[O:27])=[CH:33][CH:34]=4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Agent: Cl
Product: O=Cc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cn2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.9 %

Procedure:
(4-Benzyloxyphenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (4.0 g, 11.0 mmol), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (J. Chem. Soc., Chem. Commun., (1988), 560) (6.0 g, 14.0 mmol) were reacted together in a procedure analogous to Procedure B above for 20 hrs. The reaction mixture was allowed to cool, 1N HCl (50 ml) added and stirred at room temperature for 15 minutes. The reaction was filtered and the residue washed with dioxane (20 ml) and 2N HCl (20 ml). The combined filtrate and washings were stirred at room temperature for a further hour. The dioxane was removed under vacuum, the reaction diluted with water and the solid which precipitated was collected by filtration, and washed with water, iso-hexane and acetone. This precipitate was converted to the free base by partitioning into a mixture of triethylamine, ethyl acetate and water. The organic phase was washed with water, dried (magnesium sulphate) and the solvent removed under vacuum. The residue was triturated with iso-hexanelethyl acetate to give the product (2.41 g, 52%) as a yellow solid; δH [2H6]-DMSO 10.60 (1H, b, NH), 9.83 (1H, s, CHO), 9.30 (1H, s, 2-H), 9.08 (1H, s, 5-H or 8-H), 8.76 (1H, s, 5-H or 8-H), 7.89 (1H, d, furan-H), 7.82 (2H, d, 2′-H, 6′-H), 7.65-7.42 (6H, m, 5× Ph-H, furan-H), 7.21 (2H, d, 3′-H, 5′-H), 5.26 (2H, s, OCH2); m/z (M+1)+ 423.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:5])[NH2:4].[CH2:6]([O:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>O>[CH2:6]([O:13][C:14]([NH:5][C:3](=[NH:4])[S:2][CH3:1])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CSC(=N)N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSC(=N)NC(=O)OCc1ccccc1

Procedure:
13.9 g (0.1 mole) of S-methyl-isothiourea are dissolved in 50 ml of water, cooled to a temperature of 0° to 5° C., and at this temperature and with constant stirring 15 ml (0.1 mole) of chloroformic acid benzyl ester and 50 ml of 4 N sodium hydroxide are added in about 20 minutes. The precipitate formed is filtered, washed three times with 50 ml of cold water, then three times with 50 ml of n-hexane, and finally dried over phosphorpentoxide in vacuo. Yield 15.7 g (70 percent) of the named compound. M.p.: 74° to 75° C.; RF1 0.70 to 0.75.
Reaction SMILES: [C:1]1([CH:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)(Cl)Cl>[C:28]([N:12]1[CH2:11][CH2:10][C:9]2([C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8]2)[CH2:14][CH2:13]1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: c1ccc(C2OC3(CCNCC3)c3ccccc32)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC2(CC1)OC(c1ccccc1)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold stirred solution of 6.0 g. of 1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine] (Example 65), 2.4 g. of triethylamine, and 50 ml. of chloroform is added dropwise a solution of 2.0 g. of acetyl chloride and 50 ml. of chloroform. The mixture is stirred for 2 hours at room temperature, washed with water, dried over sodium sulfate, and concentrated. The residue is recrystallized from chloroform to provide colorless crystals, m.p. 128°-130°.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:24][NH2:25])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:17]([O:16][C:14](=[O:15])[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:24][NH2:25])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CN)CCCCNC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC[C@@H](N)CCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of ((S)-1-aminomethyl-5-benzyloxycarbonylamino-pentyl)-carbamic acid tert-butyl ester (0.24 g, 0.657 mmol) in DCM (2.4 ml) is treated dropwise with TFA (0.6 ml) and stirred at room temperature for 3 days. The solvent is removed in vacuo to afford ((S)-5,6-Diamino-hexyl)-carbamic acid benzyl ester as a yellow oil; [M+H]+ 266
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:30]1[C:38]2[C:33](=[CH:34][C:35]([NH2:39])=[CH:36][CH:37]=2)[CH:32]=[N:31]1.CCN=C=NCCCN(C)C.CN1C=CN=C1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:39][C:35]3[CH:34]=[C:33]4[C:38](=[CH:37][CH:36]=3)[NH:30][N:31]=[CH:32]4)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc5[nH]ncc5c4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.1 %

Procedure:
To a mixture of 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (82 mg, 0.2 mmol) and 1H-indazol-5-amine (27 mg, 0.2 mmol) in 5 mL of DCM was added EDCI (80 mg, 0.6 mmol) followed by N-methylimidazole (50 mg, 0.6 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc to give 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(1H-indazol-5-yl)benzamide (20 mg, 19%) as white solid. 1H NMR (300 MHz, DMSO): δ 13.01 (s, 1H), 10.46 (s, 1H), 10.14 (s, 1H), 9.42 (s, 1H), 8.99 (s, 1H), 8.62 (d, 1H, J=7.8 Hz), 8.29 (s, 1H), 8.13-8.10 (m, 2H), 7.88 (s, 1H), 7.74-7.69 (m, 2H), 7.58-7.55 (m, 2H), 7.01 (d, 1H, J=8.7 Hz), 3.84 (s, 3H), 3.75 (s, 3H). LC-MS: 524 [M+H]+, tR=1.50 min. HPLC: 95.85% at 214 nm, 95.63% at 254 nm, tR=4.60 min.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([O:39][CH3:40])=[C:29]([C:31]([C:33]2[S:34][C:35]([CH3:38])=[CH:36][N:37]=2)=O)[CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C1COCC1.O>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([O:39][CH3:40])=[C:29](/[C:31](/[C:33]2[S:34][C:35]([CH3:38])=[CH:36][N:37]=2)=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1ccc(OCc2ccccc2)cc1C(=O)c1ncc(C)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\c1ncc(C)s1)c1cc(OCc2ccccc2)ccc1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a suspension of NaH (60%, 884 mg, 22.1 mmol) in dry THF (120 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (4.96 g, 22.1 mmol) at −78° C. After being stirred at −78° C. for 1 hour, a solution of (5-(benzyloxy)-2-methoxyphenyl)(5-methylthiazol-2-yl)methanone (2.50 g, 7.37 mmol) in THF (30 mL) was added drop wise over 30 min. The mixture was stirred at −78° C. for 30 min and then warmed to room temperature with stirring overnight. The mixture was cooled to 0° C. and treated with water (50 mL), pH value was adjusted to 6 with HCl (0.5N). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether/EtOAc (3:1) to afford (Z)-ethyl 3-(5-(benzyloxy)-2-methoxyphenyl)-3-(5-methylthiazol-2-yl)acrylate (1.75 g, 58.0%) as yellow gel.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:32]=[C:31]([F:33])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:20]([OH:30])=[CH:19][N:18]=3)=[N:10]2)=[C:6]([F:34])[CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][CH2:43][N:44]([CH3:46])[CH3:45]>CN(C=O)C>[CH3:45][N:44]([CH3:46])[CH2:43][CH2:42][O:30][C:20]1[C:21]([NH:23][C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)=[N:22][C:17]([C:11]2[C:12]3[CH2:16][CH2:15][CH2:14][C:13]=3[N:9]([CH2:8][C:7]3[C:6]([F:34])=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:32][C:31]=3[F:33])[N:10]=2)=[N:18][CH:19]=1
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(O)c(Nc4ccncc4)n3)c3c2CCC3)c(F)c1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCN(C)C)c(Nc4ccncc4)n3)c3c2CCC3)c(F)c1
Temperature: 50 °C

Procedure:
100 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]-pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-ol 2-2-1 (0.215 mmol, 1.00 eq.) were dissolved in 8 mL of dry DMF and 149 mg potassium carbonate (1.08 mmol, 5.00 eq.) and 47 mg 2-chloro-N,N-dimethylethanamine (0.323 mmol, 1.50 eq.) were added. The reaction mixture was stirred over night at 50° C. The reaction mixture was partitioned between aqueous half saturated sodium chloride solution and DCM/isopropanol (4:1). The separated aqueous layer was extracted with DCM/isopropanol (4:1). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The purification of the residue by flash chromatography provided 51 mg (0.09 mmol, 42%) of analytically pure target compound.
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][C:18]([OH:20])=O)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]>C1C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][C:18]([C:2]2[CH:1]=[CH:13][CH:14]=[CH:9][CH:10]=2)=[O:20])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: COc1ccc(CC(=O)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.8 %

Procedure:
Combine 3.9 g of oxalyl chloride, 2.0 g of 3,4-dimethoxyphenylacetic acid and 50 mL of benzene and stir the mixture at 60° C. for 2.5 h. Remove the excess oxalyl chloride by distillation and concentrate the solution to a volume of 20 mL. Cool the solution to room temperature and add slowly to a suspension of anhydrous aluminium chloride (1.6 g) in 300 mL of benzene over 12 h. Stir the reaction mixture for 6 h., pour into a mixture of ice and conc. hydrochloric acid, then extract with ethyl acetate. Dry the organic extract over Na2SO4, filter and concentrate the filtrate to a residue. Chromatograph the residue on silica gel using 3:7 ethyl acetate/hexane to give 847 mg of α-(3,4-dimethoxyphenyl)-acetophenone. 1H NMR (CDCl3): δ8.1-7.98 (2H, m); 7.62-7.4 (3H, m); 6.76-6.9 (3H, m); 4.24 (2H, s); 3.85 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]([OH:22])[CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=1>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:21][CH2:20][CH:19]([OH:22])[C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=2)[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1ccc(C)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Solvent: c1ccccc1
Product: Cc1ccc(CC(C)NCC(O)c2cccc(Cl)c2)cc1
Yield: 56.3 %

Procedure:
A mixture of 4-methylphenylacetone (1.56 g) and 2-(3-chlorophenyl)-2-hydroxyethanamine (1.81 g) was refluxed in benzene (70 ml) under Dean & Stark conditions for 4 h. The solvent was removed under reduced pressure, replaced with ethanol (100 ml) and the solution hydrogenated using Pt as catalyst. The filtered solution was evaported and the residual oil chromatographed on Kieselgel 60 (150 g). Elution with 1% methanol-chloroform gave the title compound (1.8 g) as an oil. Crystallisation from hexane gave 1.26 g as a 56:44 mixture of diastereoisomers, mp 76-78.
Reaction SMILES: [C:1]([O:4][C@@:5]1([CH2:26][CH2:27][CH3:28])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C@@H:16]([OH:25])[CH2:17][C@@H:18]1[CH3:24])[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[CH3:29][O:30][CH2:31]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[C:1]([O:4][C@@:5]1([CH2:26][CH2:27][CH3:28])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C@@H:16]([O:25][CH2:29][O:30][CH3:31])[CH2:17][C@@H:18]1[CH3:24])[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CCC[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)C[C@H](C)[C@]4(C)[C@H]3CC[C@@]21C
Reactant: COCOC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CCC[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OCOC)C[C@H](C)[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
400 mg of 17β-acetoxy-1α-methyl-17α-n-propyl-5α-androstan-3β-ol is combined in 2.8 ml of absolute dichloromethane and 1.8 ml of formaldehyde dimethylacetal with a mixture of 600 mg of kieselguhr W 20 and 300 mg of phosphorus pentoxide and stirred for 45 minutes at room temperature. The mixture is vacuum-filtered from the insoluble components and washed with dichloromethane containing 3-5% triethylamine. The crude product obtained after evaporation is chromatographed on silica gel, thus producing 280 mg of 17β-acetoxy-3β-methoxymethoxy-1α-methyl-17α-n-propyl-5α-androstane.