Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([C:33](=[O:35])[CH3:34])[CH:23]=2)[C:10]=1[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])C>[OH-].[Na+]>[C:33]([C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[CH:25]=1)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]1[C:10]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:43])=[O:3])(=[O:35])[CH3:34]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(C)=O)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccsc2)c1
Yield: 67 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[3-[6-(3-acetyl-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (272 mg, 0.44 mmol) and 1.0 N aqueous sodium hydroxide (10 mL) to afford 4-[3-[6-(3-acetyl-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (163 mg, 66%) as a light brown solid: ES(+)-HRMS m/e calcd for C31H36O7S (M+Na)+ 575.2074. found 575.2074.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][N:5]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:6]1[C:7]2[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][CH:22]=[N:21][CH:20]=3)=[CH:15][CH:14]=2)[N:11]=1.O>CO>[O:23]1[C:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10]3[N:11]=[C:6]([N:5]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:4][CH2:3][OH:2])[C:7]4[CH2:27][NH:26][CH2:25][CH2:24][C:8]=4[N:9]=3)=[CH:14][CH:15]=2)=[CH:20][N:21]=[CH:22]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Agent: Cl
Solvent: O
Solvent: CO
Product: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Hydrochloric acid (2 M, 2 ml) was added to a solution of tert-butyl 4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (150 mg, 0.28 mmol, Example 1a) in methanol (4 mL). Water (2 mL) was added and the solution was stirred at 70° C. for 30 min. The residual solvent was evaporated under reduced pressure and the crude product dissolved in DMSO. Purification by preparative HPLC afforded 2-((2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (72 mg, 54.8%). MS (ESI+)/(ESI−) m/z 429/427
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O.[C:12](=[O:15])([O-])[O-:13].[K+].[K+]>O1CCCC1.CN(C1C=CN=CC=1)C>[C:2]([O:13][C:12]([NH:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:15])([CH3:8])([CH3:7])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: NC1(C(=O)O)CCCCC1
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a slurry of 1-amino-1-cyclohexane-carboxylic acid, 5.0 g (35.0 mmol) in 50 mL of tetrahydrofuran and 50 mL of water was added 14.5 g (105.0 mmol) of potassium carbonate, 7.7 g (35.0 mmol) of BOC-anhydride and 5 mg of DMAP. The mixture was stirred overnight at rt. and the organics were evaporated off in vacuo. The aqueous layer was acidified to pH=1 with 5 N HCl and extracted with 20% isopropanol/chloroform. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to dryness to yield 1.83 g (21%) of the desired product as a white oil that solidifies upon standing. MS (IS) 244.2 (M+).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[C:10](/[CH:12]=[C:13](\[CH3:19])/[C:14]([O:16]CC)=[O:15])[CH:9]=[CH:8][C:7]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:37])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:28])[CH:21]=1)[CH3:4]>C(O)C.C(OCC)C.CCCCC>[CH2:3]([O:5][C:6]1[CH:11]=[C:10](/[CH:12]=[C:13](\[CH3:19])/[C:14]([OH:16])=[O:15])[CH:9]=[CH:8][C:7]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:37])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:28])[CH:21]=1)[CH3:4]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)OCC)cc2OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: CCCCC
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)O)cc2OCC)c1
Temperature: 50 °C
Yield: 74.6 %

Procedure:
297 mg (7.4 mmol) of sodium hydroxide are added to a solution of 357 mg (0.74 mmol) of ethyl (E)-3-[2-ethoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-methylacrylate in 15 mL of ethanol. The reaction mixture is heated at 50° C. for 3 hours. After cooling, the medium is evaporated to dryness, taken up in water, acidified with 2 N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water, dried over magnesium sulfate and filtered. The solvent is evaporated off and the solid obtained is taken up in a mixture of ethyl ether and pentane, filtered and dried. 250 mg (75%) of (E)-3-[2-ethoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-methylacrylic acid are obtained in the form of a white powder with a melting point of 123° C.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[NH:23]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:24]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl.C(N=C=NCCCN(C)C)C>O1CCCC1>[CH2:28]([O:27][C:25]([CH:24]1[CH2:30][CH2:31][CH2:32][CH2:33][N:23]1[C:14]([C:12]1[O:13][C:9]([CH2:8][O:7][C:4]2[CH:3]=[CH:2][C:1]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:6][CH:5]=2)=[CH:10][CH:11]=1)=[O:16])=[O:26])[CH3:29]
Reactant: O=C(O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Reactant: CCOC(=O)C1CCCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCCN1C(=O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Yield: 59.4 %

Procedure:
A solution of 5-(biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (of Intermediate 8; 0.098 g, 0.33 mmol), ethyl pipecolinate (Aldrich; 0.139 g, 0.88 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (Avocado; 0.13 g, 0.68 mmol), and N,N-dimethylaminopyridine (0.083 g, 0.68 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 16 h. The solvents were evaporated under reduced pressure, and water and ethyl acetate were added. The aqueous phase was extracted three times with ethyl acetate, and the combined organic layers were dried (sodium sulfate), filtered, evaporated, and purified using a Biotage Flash 40 purification system, eluting with methylene chloride/acetone 9:1, to give (rac)-1-[5-(biphenyl-4-yloxymethyl)-furan-2-carbonyl]-piperidine-2-carboxylic acid ethyl ester as a colorless oil (0.085 g, 59%).
Reaction SMILES: [C:1]([C:3]1[N:7]=[CH:6][N:5]([C@@H:8]2[O:20][C@H:19]([CH2:21][O:22]C(=O)C)[C@@H:14]([O:15]C(=O)C)[C@H:9]2[O:10]C(=O)C)[N:4]=1)#[N:2].C(N(CC)CC)C.S.C(N)=[S:35]>C(O)C>[C@@H:8]1([N:5]2[CH:6]=[N:7][C:3]([C:1](=[S:35])[NH2:2])=[N:4]2)[O:20][C@H:19]([CH2:21][OH:22])[C@@H:14]([OH:15])[C@H:9]1[OH:10]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C#N)n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC=S
Agent: S
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=S)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 2 h

Procedure:
A mixture of 3-cyano-1-(2,3,5-tri-O-acetyl-β -D-ribofuranosyl)-1,2,4-triazole (8.0 g., 22.7 mmole), triethylamine (14.0 ml.) and ethanol (200 ml.) was stirred at 25° while hydrogen sulfide gas was passed into the solution for 2 hrs. The solvent was removed and the residue was treated with a solution of sodium methoxide (600 mg.) in methanol (150 ml.) for three hours at 25°. After the solution was neutralized with Bio-Rad AG 50W-X2(H), it as filtered, and the solvent was removed. Crystallization of the product from aqueous ethanol provided 4.5 g. (76.0%) of the thiocarboxamide with M.P. 173-175°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C:5](=[O:7])[CH:6]=1>[Pd].CCOC(C)=O>[CH3:1][CH:2]1[CH2:6][C:5](=[O:7])[CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1CC(=O)C=C1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC(=O)CC1C
Temperature: 0 °C
Reaction time: 48 h
Yield: 98.6 %

Procedure:
A round-bottom flask was charged with 10% palladium on carbon (7.6 g, 7.1 mmol). The flask was cooled to about 0° C. and EtOAc (580 mL) was added under a nitrogen atmosphere. The cooling bath was removed and ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate (60.0 g, 357 mmol) was added. Hydrogen gas was bubbled through the mixture for about 5 min and the mixture was then stirred under a hydrogen atmosphere (1 atmosphere) for about 48 h. The hydrogen source was removed and the mixture was bubbled with nitrogen for about 5 min and was filtered through a pad of Celite®. The filter cake was rinsed with EtOAc (500 mL). The filtrate was concentrated under reduced pressure to give ethyl 2-methyl-4-oxocyclopentanecarboxylate (59.9 g, 99%) as a yellow liquid: 1H NMR (CDCl3) δ 4.23-4.14 (m, 2H), 3.18 (ddd, J=5.6, 6.8, 8.1 Hz, 1H), 2.73-2.65 (m, 1H), 2.60 (ddd, J=1.7, 5.5, 18.7 Hz, 1H), 2.42-2.29 (m, 2H), 2.15 (ddd, J=1.7, 7.9, 18.3 Hz, 1H), 1.29 (t, J=7.1 Hz, 3H), 1.07 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[C:4]=1/[CH:22]=[CH:23]/[C:24]([NH:26][CH:27]1[CH2:32][CH2:31][O:30][C:29](C)(C)[CH2:28]1)=[O:25])#[N:2].[C:35](C1C2C(=NC(C)=CC=2)N(C2C3C(=CC=CC=3)CC2)C=1/C=C/C(O)=O)#N.CNC1CCOCC1>>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[C:4]=1/[CH:22]=[CH:23]/[C:24]([N:26]([CH3:35])[CH:27]1[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1)=[O:25])#[N:2]
Reactant: Cc1ccc2c(C#N)c(/C=C/C(=O)NC3CCOC(C)(C)C3)n(C3CCc4ccccc43)c2n1
Reactant: Cc1ccc2c(C#N)c(/C=C/C(=O)O)n(C3CCc4ccccc43)c2n1
Agent: CNC1CCOCC1
Product: Cc1ccc2c(C#N)c(/C=C/C(=O)N(C)C3CCOCC3)n(C3CCc4ccccc43)c2n1

Procedure:
In the same manner described in (4) of Example 2, (E)-3-[3-cyano-1-(2,3-dihydro-iH-inden-1-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl]-N-methyl-N-tetrahydro-2H-pyran-4-yl-2-propenamide was synthesized from (E)-3-[3-cyano-1-(2,3-dihydro-1H-inden-1-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-propenoic acid and N-methyltetrahydro-2H-pyran-4-ylamine.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:3].[Br:12][CH2:13][C:14](Br)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Br:12][CH2:13][C:14]([C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:10]=1)=[O:15]
Reactant: O=C(Br)CBr
Reactant: CS(=O)(=O)Nc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Methanesulfonanilide as prepared in Preparation 1 (172.0 g, 1.0 mole), bromoacetylbromide (363.35 g, 1.8 mole), and 1 liter of carbon disulfide is combined under N2 with vigorous mechanical stirring. Anhydrous aluminum chloride (400.0 g, 3.0 mole) is added in portions to this mixture over 11/2 hour resulting in a deep red color and separation of the reaction mixture into two layers. Following the addition, the reaction is stirred at ambient temperature for 45 minutes and is then heated to reflux. After refluxing for 1 hour the oil bath is removed and the reaction is stirred at room temperature overnight. The two layers are allowed to separate and the upper layer is decanted. The viscous dark brown layer remaining is slowly poured over a mixture of crushed ice and 400 ml of concentrated HCl. This results in decomposition of the dark material with violent fuming, and yellow precipitate formation. The resulting precipitate is filtered then washed with H2O, a small volume of EtOH, and ether. The remaining solid is crystallized from large volumes of CH2Cl2 containing a small amount of MeOH to aid in solubility which yielded 3 crops of the title compound, m.p. 186°-188° C.; [according to the literature, R. H. Uloth, et al., J. Med. Chem. 9, p. 88 (1966), m.p. 190°-191° C. dec⟧
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:7][CH2:6][CH2:5][O:4]1.[Cl:26][CH2:27][CH2:28][CH2:29][S:30](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:32])=[O:31]>>[Cl:26][CH2:27][CH2:28][CH2:29][S:30]([NH:1][CH2:2][C:3]1([CH2:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:7][CH2:6][CH2:5][O:4]1)(=[O:32])=[O:31]
Reactant: CCCCCCCCCCCCCCCCSCC1(CN)CCCO1
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCSCC1(CNS(=O)(=O)CCCCl)CCCO1

Procedure:
2-Aminomethyl-2-hexadecylthiomethyltetrahydrofuran IVb1 is allowed to react and worked by the same procedure as described in (4). m.p. 44.5° to 45.5° C. The summary of the experimental condition and the physical data of the prodcut are listed in the Table 7.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][O:12][C:11](=[O:21])[C:10]=2[CH:22]=1.C(O)(=O)C>O>[C:1]([CH2:13][N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:22][C:10]=1[C:11]([OH:12])=[O:21])#[N:2]
Reactant: COc1ccc2c(c1)C(=O)OCN2c1ccccc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(N(CC#N)c2ccccc2)c(C(=O)O)c1
Temperature: 0 °C
Yield: 96 %

Procedure:
To a solution of 268 g (4.1 mole) of potassium cyanide in 1.6 l of water was added 1021 g (4.0 mole) of 1,2-dihydro-6-methoxy-1-phenyl-4H-3,1-benzoxazine-4-one at a rate such that the reaction mixture temperature was 35°-40° C. The resulting solution was stirred and maintained at 35°-40° C. for two hours, and then added dropwise to a solution of 8.0 l of ice water and 800 ml of acetic acid. The resulting suspended solid was filtered and washed with water to yield 1084 g (96% yield) of the crude nitrile, mp 122°-130° C. This material was used for further synthesis without additional purification.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:20]([CH:23]([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])=[CH:21][OH:22])=[CH:15][CH:14]=1>C(Cl)Cl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)=[C:20]([CH:23]([CH:24]([CH3:25])[CH3:26])[CH:27]([CH3:29])[CH3:28])[CH:21]=[O:22])=[CH:17][CH:18]=1
Reactant: CC(C)C(C(=CO)C(c1ccc(F)cc1)c1ccc(F)cc1)C(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)C(C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1)C(C)C
Reaction time: 48 h
Yield: 95.7 %

Procedure:
Pyridinium chlorochromate (3.5 g) was added to a solution of 3,3-bis(4-fluorophenyl)-2-[2-methyl-1-(1-methylethyl)propyl]propenol (2.1 g, 6.1 mmol) in 75 mL of methylene chloride and the mixture stirred for 48 hours. The methylene chloride was decanted from the gummy precipitate which was washed with fresh solvent. The combined methylene chloride solutions were concentrated in vacuo to give a dark oil. The oil was triturated with 4×50 mL volumes of hexane. The hexane solutions were concentrated in vacuo to give 2.0 g of the title compound as a light yellow oil. M.S.(EI): m/e =342 for M+ of C22H24F2O.
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16](S(N4CCC(O)CC4)(=O)=O)=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][O:33][C:34](=[O:44])[N:35](C1C=CC(N)=CC=1)[CH3:36]>>[CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:35]([CH3:36])[C:34](=[O:44])[O:33][CH3:32])=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)N(C)c1ccc(N)cc1
Reactant: O=S(=O)(c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1)N1CCC(O)CC1
Product: COC(=O)N(C)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1

Procedure:
According to the general procedure for synthesis of 1-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenylsulfonyl)piperidin-4-ol, methyl-4-aminophenyl(methyl)carbamate and 2-Chloro-N-cylclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine gave methyl 4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl(methyl)carbamate (MS calcd for C19H22N6O2 366.2. found [MH] 368.0; UV 209.8, 271.2, 304.5 nm).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10](=[O:13])([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:3]1[C:4]2[C:10](=[O:13])[C:9]3[C:2](=[CH:3][CH:4]=[CH:5][CH:8]=3)[C:6](=[O:7])[C:5]=2[CH:8]=[CH:9][CH:2]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
Subsequently, in 70 ml of DMF, 3.5 g of the compound (F), 2.4 g of p-chlorobenzyl alcohol and 12 g of potassium carbonate were stirred at 120° C. for 5 hours. After filtration, DMF was removed under reduced pressure, and purification was carried out by column chromatography to yield 2.5 g of the target anthraquinone dye No. 8.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:5][N:4]2[C:18]([CH:21]=[O:22])=[CH:19][CH:20]=[C:3]12.[BH4-].[Na+]>C(O)C.O1CCCC1>[OH:22][CH2:21][C:18]1[N:4]2[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][CH:9]=3)[NH:7][C:2](=[O:1])[C:3]2=[CH:20][CH:19]=1
Reactant: O=Cc1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)cn2c(CO)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
A mixture of 1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carbaldehyde (0.02 g, 65.3 μmol) in ethanol (0.25 mL) and tetrahydrofuran (0.25 mL) cooled to 0° C. was treated with sodium borohydride (3 mg, 79.3 μmol). The reaction was stirred at 0° C. for 1 h and then was stored in the refrigerator overnight. At this time, the reaction was concentrated in vacuo. The remaining solid was triturated with water, collected by filtration, washed with water and dried in vacuo to afford 6-hydroxymethyl-3-(4-trifluoromethyl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one (10 mg, 50%) as an off-white solid. 1H NMR (DMSO-d6) δ ppm 7.87-7.96 (m, 3H), 7.79-7.87 (m, 2H), 7.40 (s, 1H), 6.87 (s, 1H), 5.03 (t, J=5.4 Hz, 1H), 4.50 (d, J=5.0 Hz, 2H). LC-MS calcd. for C15H12F3N2O2 [(M+H)+] 309, obsd. 309.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([CH3:25])[CH:19]=[CH:18]2.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([CH3:25])[CH:19]=[CH:18]3)[C:9]1=[O:13]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Cc1ccc2cc(Br)ccc2n1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccc2cc(N3CCN(c4cnccc4C)C3=O)ccc2n1
Yield: 42.6 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 0.150 g, 0.847 mmol) was reacted with 6-bromo-2-methyl-quinoline (0.225 g, 1.016 mmol), 1,4-dioxane (20 mL), copper iodide (0.016 g, 0.084 mmol), trans-1,2-diamino cyclohexane (0.029 g, 0.254 mmol) and potassium phosphate (0.449 g, 2.1 mmol) to afford the crude product. Purification by column chromatography on silica gel (5% MeOH in CHCl3) afforded 115 mg of the product (43% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([O:11][CH2:12][CH3:13])[CH:5]=1.[F:15][C:16]([F:20])([F:19])[CH2:17]I.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH2:17][C:16]([F:20])([F:19])[F:15])[CH:7]=[C:6]([O:11][CH2:12][CH3:13])[CH:5]=1
Reactant: FC(F)(F)CI
Reactant: CCOc1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOc1cc(OCC(F)(F)F)cc(C(=O)OC)c1
Temperature: 130 °C
Yield: 41.8 %

Procedure:
A mixture of 3-ethoxy-5-hydroxy-benzoic acid methyl ester (1.5 g, 7.65 mmol, 1.0 equiv; prepared as described in WO 99/05123 A1, Astra Pharmaceuticals Ltd.), 2,2,2-trifluoroethyl iodide (2.25 mL, 4.82 g, 22.94 mmol, 3.0 equiv) and cesium carbonate (4.98 g, 15.29 mmol, 2.0 equiv) was heated to 130° C. under microwave irradiation for 20 min. The crude reaction mixture was filtered over Hyflo Super Cel and extracted with dichloromethane (3×50 mL). The combined organic phases were dried over MgSO4, the solvent removed by evaporation under reduced pressure and the crude material purified by flash column chromatography on silica eluting with a gradient of heptane/dichloromethane (1:1→0:1) yielding 0.89 g (42%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.35 (t, J=7.0 Hz, 3H), 3.84 (s, 3H), 4.00 (q, J=7.0 Hz, 2H), 4.30 (q, J=8.1 Hz, 2H), 6.62-6.63 (m, 1H), 7.10-7.11 (m, 1H), 7.19-7.21 (m, 1H). MS (ISP): 279.0 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[C:28]=4[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])[CH:19]=3)[C:14](O)=[O:15])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>>[C:44]([CH2:43][CH2:42][C:28]1[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:18]2[CH:17]=[C:13]([C:14]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:15])[CH:12]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[CH:19]=2)=[CH:32][CH:31]=[CH:30][C:29]=1[O:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])([OH:46])=[O:45]
Reactant: C1COCCN1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)OCC
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCOCC3)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)O

Procedure:
The title compound was prepared according to the general procedure described in Example 74 starting from 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid and morpholine.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([N:27]4[N:31]=[C:30]([CH2:32][CH3:33])[CH:29]=[N:28]4)[C@@H:24]([OH:34])[C@H:23]3[OH:35])=[C:15]([NH:36][CH2:37][CH:38]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:14]=2)[CH2:9]1)(C)(C)C.N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4C=C(CC)C=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1>>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([N:27]4[N:31]=[C:30]([CH2:32][CH3:33])[CH:29]=[N:28]4)[C@@H:24]([OH:34])[C@H:23]3[OH:35])=[C:15]([NH:36][CH2:37][CH:38]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:14]=2)[CH2:9]1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)OC(C)(C)C)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)c1
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(4-ethyl-[1,2,3]triazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (step a) using a procedure analogous to that of (1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-pyrazol-1-yl)-cyclopentane-1,2-diol. (Intermediate FB, second step b). MS (ES+) m/e 595.40 (MH+).