Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10].[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CCOC(C)=O>CN(C=O)C>[CH3:12][O:11][C:9](=[O:10])[CH:8]([N:17]1[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]1)[CH3:13]
Reactant: COC(=O)C(C)Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Yield: 95.7 %

Procedure:
2.97 g of potassium carbonate and 1.97 g of methyl 2-bromopropanoate are added to a solution of 2 g of tert-butyl piperazine-1-carboxylate in 36 ml of DMF, and then it is heated at 60° C. for 1 hour. After it returns to RT, 150 ml of EtOAc is added, it is washed with water, with brine, dried over Na2SO4 and then evaporated to dryness. 2.8 g of the expected compound is obtained in the form of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][C@H:30]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][C@H:30]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:29]2)[NH:12][C:11]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[N:10]1
Reactant: CC(C)(O)[C@@H]1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCO[C@H](C(C)(C)O)C2)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Yield: 22.5 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with (S)-2-(morpholin-2-yl)propan-2-ol hydrochloride (0.28 g, 1.53 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.19 g, 22%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:20]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc(C2(Cc3ccccc3)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.16 g, 0.6 mmol) (from Example 6b supra), benzyl bromide (0.12 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 23 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, dichloromethane, then 5% ethyl acetate in dichloromethane as solvent) to give two products. Lower Rf sample was recrystallized from dichloromethane-hexanes to give rac-3-benzyl-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 0.16 g, 73.3%).
Reaction SMILES: CS[C:3]1[S:4][CH2:5][C:6](=[O:8])[N:7]=1.[CH2:9]([NH:12][CH3:13])[CH:10]=[CH2:11]>>[CH2:9]([N:12]([CH3:13])[C:3]1[S:4][CH2:5][C:6](=[O:8])[N:7]=1)[CH:10]=[CH2:11]
Reactant: CSC1=NC(=O)CS1
Reactant: C=CCNC
Product: C=CCN(C)C1=NC(=O)CS1

Procedure:
2-(Allyl-methyl-amino)-thiazol-4-one was prepared from 2-methylsulfanyl-thiazol-4-one and allyl-methyl-amine following General Procedure E.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH3:18])[CH:12]=2)=[C:4]([CH3:20])[CH:3]=1.Cl.[NH2:22][C:23]([NH2:25])=[O:24]>CCO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:25][C:23](=[O:24])[N:22]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH3:18])[CH:12]=3)[CH:9]=2)=[C:4]([CH3:20])[CH:3]=1
Reactant: NC(N)=O
Reactant: Cc1cc(/C=C/C(=O)c2ccc(N)cc2C)ccc1O
Agent: Cl
Solvent: CCO
Product: Cc1cc(-c2cc(-c3ccc(N)cc3C)[nH]c(=O)n2)ccc1O
Temperature: 110 °C
Yield: 63.9 %

Procedure:
To a sealed pressure vessel was added (E)-1-(4-amino-2-methylphenyl)-3-(4-hydroxy-3-methylphenyl)prop-2-en-1-one (2) (1.5 g, 5.6 mmol), EtOH (10 mL), 4N HCl in dioxanes (20 mL, 80 mmol), and urea (1.74 g, 29.1 mmol). The pressure vessel was sealed and heated to 110° C. overnight. Another 1 g of urea was added and heated for another 5 h. The reaction was then cooled to rt, concentrated via rotary evaporation and columned purified on silica gel (10:90 to 20:80 MeOH:EtOAc) to give 6-(4-amino-2-methylphenyl)-4-(4-hydroxy-3-methylphenyl)pyrimidin-2(1H)-one (3) (1.1 g, 64% yield).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[H-].[Na+].[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:9]=[CH:10][C:3]=12
Reactant: Ic1ccnc2[nH]ncc12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
4-iodo-1H-pyrazolo[3,4-b]pyridine (15 g, 61.22 mmol) was dissolved in dimethylformamide (300 mL) and the solution was cooled down in an ice bath to 5° C. Sodium hydride (60%, 2.938 g, 73.46 mmol) was added portionwise and left to stir at this temperature for 2 hours. After this time a solution of trityl chloride (18.77 g, 67.34 mmol) in dimethylformamide (150 mL) was added dropwise over 30 minutes. After an additional 2 hours of stirring, the solvent was removed by evaporation, and the residue was partitioned between ethyl acetate and saturated bicarbonate (2×100 ml). The organic layer was further washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo to give a brown oil. This residue was purified on silica gel by flash column chromatography to afford the title compound as a white solid (less polar fraction: 2-regioisomer, 13.71 g, 46% yield; more polar fraction: 3-regioisomer, pale yellow solid, 8.06 g, 27% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][CH:9]=[O:10])[S:6][CH:7]=1.[SH:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][S:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:4]=1)=[O:10]
Reactant: Sc1ccncc1
Reactant: O=CNc1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=CNc1nc(CSc2ccncc2)cs1
Temperature: 100 °C
Yield: 64.2 %

Procedure:
A mixture of 4-chloromethy-2-formylaminothiazole (1.86 g), 4-mercaptopyridine (1.23 g) and potassium carbonate (1.8 g) in N,N-dimethylformamide (20 ml) was heated at 100° C. for 2 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-formylamino-4-(4-pyridylthiomethyl)thiazole (1.7 g, yield: 68.0%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18](F)[CH:17]=2)=[N:12][N:11]=[N:10]1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:17]=2)=[N:12][N:11]=[N:10]1
Reactant: Fc1cc(CNc2nnnn2-c2cccc(Cl)c2Cl)ccn1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: Clc1cccc(-n2nnnc2NCc2ccnc(N3CCCC3)c2)c1Cl
Temperature: 60 °C
Reaction time: 48 h
Yield: 14.3 %

Procedure:
To an oven-dried N2-purged, 20-mL scintillation vial containing a magnetic stir bar was added the product of Example 143C (34 mg, 0.10 mmol) and anhydrous tetrahydrofuran (1 mL). Neat pyrrolidine (160 mL, 140 mg, 2.0 mmol) was added via syringe, and the vial was sealed. The reaction mixture was heated to 60° C. and the vial was shaken for 48 hours. After cooling to room temperature, the solvent/volatiles were removed by rotary evaporator to give a brown oil. The product was purified by flash chromatography (silica gel: 25% ethyl acetate, 75% hexanes-product Rf˜0.2) to give 5.6 mg (14%) of the title compound as a white powder. MS (ESI+) m/z 390.1 (M+H)+; 1H NMR (DMSO-d6) δ 1.54 (br s, 4H), 3.46 (br s, 4H), 4.61 (d, J=6.1 Hz, 2H), 6.37 (br s, 1H), 6.46-6.48 (m, 1H), 7.39-7.47 (m, 2H), 7.72 (dd, J=7.6, 2.2 Hz, 1H), 8.08 (d, J=5.1 Hz, J=5.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3(O)[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[C:9]2=[S:19])=[C:4]([F:20])[CH:3]=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[S:19])[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=3[C:16]2=[O:17])=[C:4]([F:20])[CH:3]=1
Reactant: O=C1N(c2ccc(Cl)cc2F)C(=S)C2CCCCC12O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=C1C2=C(CCCC2)C(=S)N1c1ccc(Cl)cc1F
Reaction time: 8 h
Yield: 94.8 %

Procedure:
In 75 ml of pyridine was dissolved 28.2 g of 2-(4-chloro-2-fluorophenyl)-3a-hydroxy-1-thioxo-octahydroisoindole-3-one, and 30 ml of acetic acid anhydride was added to the solution, which was allowed to stand at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane, washed with water and dried over anhydrous sodium sulfate. After distilling off the dichloromethane, the resulting crystals were washed with a small amount of cold ethanol and dried, thereby affording 25.2 g (yield of 95%) of the subject compound. Recrystallization from ethanol yielded red-purple crystals, m.p. 101°-102° C.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[CH:18][O:19]C)[CH:15]=3)[N:10]([C:21]([NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)=[O:22])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].Cl.C(=O)([O-])O.[Na+].O>CC(C)=O>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH:18]=[O:19])[CH:15]=3)[N:10]([C:21]([NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)=[O:22])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC=Cc1ccc2c(c1)C1(CCN(C(C)=O)C1)CN2C(=O)Nc1ncc(Cl)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(CC=O)cc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
1′-Acetyl-N-(5-chlorothiazol-2-yl)-5-(2-methoxyvinyl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (83 mg, 0.192 mmol) was dissolved in acetone (3 mL). Thereafter, 6 N hydrochloric acid (1.5 mL) was added to the above obtained solution, and the thus obtained mixture was then stirred at 50° C. for 2 hours. Thereafter, saturated sodium hydrogen carbonate and water were added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo, to obtain 1′-acetyl-N-(5-chlorothiazol-2-yl)-5-(2-oxoethyl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (66.1 mg, 82%) in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])[C:5]2[C:12]([O:34][CH3:35])=[N:13][N:14]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1.C1N=CN([C:41](N2C=NC=C2)=[O:42])C=1>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:41](=[O:42])[NH:11][N:10]=2)[C:5]2[C:12]([O:34][CH3:35])=[N:13][N:14]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:4]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)NN)c12
Solvent: C1COCCO1
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(-c3n[nH]c(=O)o3)c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbohydrazide (122 mg, 0.252 mmol) and CDI (49.1 mg, 0.303 mmol) were taken up in 1,4-dioxane (3.0 ml). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was loaded onto silica gel and purification by MPLC 0-50% EtAOc/hexanes gave 5-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)-1,3,4-oxadiazol-2(3H)-one (53B). MS: [M+H]+ m/z 510.
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:28]2[CH2:27][CH2:26][C@@:24]2([CH3:25])[C@:20]3([OH:38])[CH2:21][CH2:22][C@@H:23]2[C:33]2[CH:37]=[CH:36][O:35][CH:34]=2)[CH2:15]1)[CH:11]=[CH2:12].[OH-:39].[Na+].OO>O1CCCC1.C(O)C>[OH:39][CH2:12][CH2:11][CH2:10][O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:28]2[CH2:27][CH2:26][C@@:24]2([CH3:25])[C@:20]3([OH:38])[CH2:21][CH2:22][C@@H:23]2[C:33]2[CH:37]=[CH:36][O:35][CH:34]=2)[CH2:15]1
Reactant: C=CCO[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@]12CC[C@H](OCCCO)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Reaction time: 6 h

Procedure:
To a solution of 0.17 g of 9-borabicyclo[3.3.1]nonane in 35 ml of dry tetrahydrofuran, 0.50 g of 3β-(prop-2-enoxy)-17β-(3-furyl)-5β-androstan-14β-ol in 10 ml of tetrahydrofuran were added under nitrogen atmosphere, at room temperature. The solution was stirred for 6 hrs then 0.75 ml of ethanol, 0.25 ml of sodium hydroxide 6N and 0.50 ml of hydrogen peroxide 30% were added. The mixture was stirred at 50° C. for an hr, quenched with a solution of 0.76 g of potassium carbonate in 20 ml of water and the organic solvent distilled under reduced pressure. The residue was extracted with methylene chloride, the organic solution was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 70/30 as eluant to give 0.40 g of 3β-(3-hydroxypropoxy)-17β-(3-furyl)-5β-androstan-14β-ol as a white amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.Br[CH:26]([CH2:30]Br)[C:27]([NH2:29])=[O:28]>>[Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:11][CH2:12][N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH:26]([C:27]([NH2:29])=[O:28])[CH2:30]2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: NC(=O)C(Br)CBr
Reactant: COc1cc(Br)cc(NCCNCc2ccc(OC)c(OC)c2)c1
Product: COc1cc(Br)cc(N2CCN(Cc3ccc(OC)c(OC)c3)C(C(N)=O)C2)c1

Procedure:
In a manner similar to Preparation 1, react N-(3-bromo-5-methoxyphenyl)-N'-[(3,4-dimethoxyphenyl)methyl]-1,2-ethanediamine with 2,3-dibromopropanamide to obtain the title compound.
Reaction SMILES: [O:1]([CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH:18]2[O:20][CH2:19]2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:34][CH2:35][C:36](=[O:39])[NH:37][N:38]=2)=[CH:29][C:28]=1[CH3:40]>>[O:1]([CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH:18]([OH:20])[CH2:19][NH:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH2:34][CH2:35][C:36](=[O:39])[NH:37][N:38]=3)=[CH:29][C:28]=2[CH3:40])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C2=NNC(=O)CC2)ccc1OCCN
Reactant: c1ccc(OCCOCc2ccc(OCC3CO3)cc2)cc1
Product: Cc1cc(C2=NNC(=O)CC2)ccc1OCCNCC(O)COc1ccc(COCCOc2ccccc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-phenoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-4,5-dihydro-3-(2H)-pyridazinone.
Reaction SMILES: C1(S(C2(SC)[CH2:15][C@@H:14]3[C@@:12]([C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:18][CH:17]=4)([CH2:13]3)[CH2:11]2)(=O)=O)C=CC=CC=1.[CH3:28][OH:29].Cl>C(OCC)(=O)C.CCCCCC>[C:16]1([C@@:12]23[CH2:13][C@@H:14]2[CH2:15][C:28](=[O:29])[CH2:11]3)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CSC1(S(=O)(=O)c2ccccc2)C[C@H]2C[C@@]2(c2cccc3ccccc23)C1
Reactant: CO
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1C[C@H]2C[C@@]2(c2cccc3ccccc23)C1
Yield: 99 %

Procedure:
(1R,5R)-3-Benzenesulfonyl-1-(1-naphthyl)-3-methylsulfanyl-bicyclo[3.1.0]hexane (620 mg, 1.6 mmol), methanol (4 mL) and concentrated hydrochloric acid (0.7 mL) were heated to reflux for 7 hours. The reaction was monitored by TLC (ethyl acetate/hexane (20:80)) The reaction mixture was concentrated under reduced pressure to remove methanol. The pH of the reaction mass was adjusted to 8-9 with saturated sodium bicarbonate solution. The aqueous layer was extracted with diethyl ether (50 mL). The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 458 mg of crude oil, which was purified by preparative HPLC to yield 135 mg (39%) of 99% pure product. 1H NMR δ(300 MHz,CDCl3) 0.76-0.79 (1H,t, J=4 Hz), 1.38 (1H,m), 2.01 (1H,m), 2.49-2.56 (1H,d, J=10Hz), 2.75 (2H,d,J=6 Hz), 3.05-3.15 (2H,dd,J=10 Hz), 7.40-7.45 (1H,m), 7.50-7.56 (3H,m), 7.76-7.79 (1H,d,J=9 Hz), 7.88-7.90 (1H,m), 8.13-8.15 (2H,d ,J=6 Hz). 13CNMR(CDCl3)δ: 218.25, 139.12, 134.01, 128.96, 127.80, 126.77, 126.17, 125.78, 125.33, 124.0, 48.18, 42.46, 27.80, 20.62, 20.05.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.CC([N:21]([C@@H:25]([C:28](NC1C=NC(OC2C=CC(C#N)=C(C(C)C)C=2)=CC=1)=[O:29])[CH2:26][CH3:27])[C:22](=O)[O-:23])(C)C.Cl>ClCCl.CN(C1C=CN=CC=1)C.CCOCC>[CH2:26]([C@H:25]1[NH:21][C:22](=[O:23])[N:14]([C:13]2[CH:15]=[CH:16][C:10]([O:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:11][CH:12]=2)[C:28]1=[O:29])[CH3:27]
Reactant: COc1cccc(Oc2ccc(N)cc2)c1
Reactant: CC[C@H](C(=O)Nc1ccc(Oc2ccc(C#N)c(C(C)C)c2)nc1)N(C(=O)[O-])C(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3cccc(OC)c3)cc2)C1=O
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To Boc-anhydride (138 mg, 0.631 mmol) in dichloromethane (1 mL) was added DMAP (55.1 mg, 0.451 mmol) followed by a solution of 4-{[3-(methyloxy)phenyl]oxy}aniline (97 mg, 0.451 mmol) in dichloromethane (1 mL). The mixture was stirred for 10 min. The brown solution thus obtained was added to Solution 1 via syringe with shaking at 35° C. and shaking was continued at this temperature for 2 hours. The solution was then kept at room temperature for ca. 64 hours. Conc. aq. HCl (ca. 0.8 mL) was added and the heterogenous mixture was heated at 100° C. for 2 hours with shaking, allowing the DCM to distill off through a glass capillary. After cooling to room temperature, the residue was diluted with water (ca. 3 mL) and extracted with dichloromethane (2 times ca. 2 mL). The dichloromethane extracts were concentrated under vacuum. The residue was purified by silica gel chromatography (Biotage system, 10 g column) eluting with a gradient cHex/EtOAc from 95/5 to 0/100 to give a brown viscous oil that was dissolved in Et2O (ca. 0.7 mL) and cHex (ca. 0.1 mL) and kept over night. The overstanding faint brown solution was decanted from a small quantity of a brown oil that had separated out. As the solvent was allowed to evaporate from this solution crystallisation initiated. The material thus obtained was allowed to dry and then triturated with Et2O (2 times ca. 0.5 mL) to afford, after drying, the title compound as a solid (28 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Br:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[C:23]([NH2:37])=[CH:24][C:25]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][CH3:35])[CH2:28][CH2:27][C:26]=2[CH:36]=1.Cl>C(O)CCC.O1CCOCC1>[Br:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:37][C:23]2[C:22]([O:21][CH3:20])=[CH:36][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:34][CH3:35])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CCOC)CC3)ncc1Br
Yield: 25 %

Procedure:
2-(2-chloro-5-bromo-pyrimidin-4-ylamino)-N-methyl-benzamide (52 mg, 0.15 mmol) and 8-methoxy-3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (48 mg, 0.19 mmol) were combined in 5 mL n-butanol. Two drops of a solution of 4N hydrochloric acid in dioxane was added and the mixture was refluxed for eight hours. The mixture was concentrated and the organics were partitioned between dichloromethane and saturated sodium bicarbonate solution (100 mL each). The organic layer was separated, was dried (sodium sulfate), and was concentrated to afford an oil which was purified on silica (methanol:dichloromethane gradient elution) to afford 2-{5-bromo-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide as a tan foam (25%). Mp: 171-5° C.; MS: 556.78 (M+H); 1H NMR (chloroform-d): δ 10.81 (s, 1H), δ 8.60 (d, J=8 Hz, 1H), δ 8.21 (s, 1H), δ 8.08 (s, 1H), δ 7.53-7.41 (m, 3H), δ 6.92 (t, J=8 Hz, 1H), δ 6.66 (s, 1H), δ 6.24 (br s, 1H), δ 3.78 (s, 3H), δ 3.57 (t, J=5 Hz, 35), δ 3.39 (s, 3H), δ 3.06 (dd, J=2.4 Hz, 2H), δ 2.91 (m, 2H), δ 2.82-2.67 (m, 8H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][CH:18]([CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[CH2:17][CH2:16]3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:30].C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][CH:18]([C:21]([OH:30])([OH:26])[C:22]([F:24])([F:25])[F:23])[CH2:17][CH2:16]3)[C:12]2=[O:27])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC(C)(C)c1ccc(N2CCC3(CCC(C(O)C(F)(F)F)CC3)C2=O)cc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(N2CCC3(CCC(C(O)(O)C(F)(F)F)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of 2-(4-tert-butyl-phenyl)-8-(2,2,2-trifluoro-1-hydroxy-ethyl)-2-aza-spiro[4.5]decan-1-one (100 mg, 319 μmol, described in example 360 and 361) in DCM (1 mL) was added to a stirred suspension of Dess-Martin periodinane (501 mg, 1.18 mmol) in DCM (2.5 mL) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and poured into a 1:7 mixture of aqueous sat. NaHCO3 and Na2S2O3 and the mixture was stirred for 10 min. The organic phase was separated and washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue which was purified by reverse phase prep HPLC to give the title compound as a white solid (94%). MS (m/e): 400.3 (MH+).