Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.Cl[CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[CH3:11][CH:12]1[C:18]2[S:19][CH:20]=[CH:21][C:17]=2[C:16](=[O:22])[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[CH2:13]1.[Cl-].[NH4+]>C(Br)CBr.O1CCCC1>[CH3:11][CH:12]1[C:18]2[S:19][CH:20]=[CH:21][C:17]=2[C:16]([CH:4]2[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]2)([OH:22])[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[CH2:13]1
Reactant: CC1Cc2ccccc2C(=O)c2ccsc21
Reactant: CN1CCC(Cl)CC1
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC1Cc2ccccc2C(O)(C2CCN(C)CC2)c2ccsc21
Reaction time: 2 h

Procedure:
4.8 g of iodine-activated magnesium are covered with a layer of 60 cc of anhydrous tetrahydrofuran and cauterized with a few drops of ethylene bromide. A solution of 25.0 g of 4-chloro-1-methylpiperidine in 160 cc of anhydrous tetrahydrofuran is then added dropwise at such a rate that the solvent boils continually, and stirring is subsequently effected at the boil for 2 hours. The reaction mixture is cooled to 10°, and a solution of 20.0 g of 9,10-dihydro-10-methyl-4H-benzo[4,5]cyclohepta-[1,2-b]thiophen-4-one in 100 cc of anhydrous tetrahydrofuran is added dropwise at this temperature. After stirring at room temperature for 11/2 hours and at the boil for 30 minutes, the reaction mixture is cooled, poured on 300 cc of a 20% ammonium chloride solution, and the organic phase is separated. The aqueous solution is extracted with methylene chloride, the combined organic solutions are washed with water, dried over sodium sulphate and concentrated by evaporation. The 9,10-dihydro-10-methyl-4-(1-methyl-4-piperidyl)-4H-benzo[4,5]cyclohepta-[1,2-b]thiophen-4-ol, obtained as residue, is recrystallized twice from isopropanol. M.P. 177°-178°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[H-].[Na+].CS([C:15]1[N:20]=[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([Cl:31])[CH:24]=2)[C:18]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:17][N:16]=1)(=O)=O>O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:1][C:15]1[N:20]=[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([Cl:31])[CH:24]=2)[C:18]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:17][N:16]=1
Reactant: OCc1ccccn1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1NCc1ccc(OC)c(Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(OCc2ccccn2)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-hydroxymethylpyridine 32 mg and sodium hydride (suspension in 60% oil) 11.8 mg in tetrahydrofuran 2.5 ml is stirred at room temperature for 5 minutes. To the mixture is added at room temperature a solution of 2-methylsulfonyl-5-ethoxycarbonyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine (prepared in the above (2)) 118 mg in tetrahydrofuran 2.5 ml, and the mixture is stirred for 30 minutes at room temperature. The reaction mixture is diluted with an aqueous 10% citric acid solution and extracted twice with ethyl acetate. The combined organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (solvent; chloroform:ethyl acetate=4:1→1:2) and concentrated in vacuo to give 2-(2-pyridylmethoxy)-5-ethoxycarbonyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine as a colorless caramel, 106 mg.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:15][CH3:16])[C:6]([C:17]([OH:19])=[O:18])=[C:5]([C:20]([F:23])([F:22])[F:21])[N:4]=1.S(Cl)(Cl)=O.[CH2:30](O)[CH3:31]>>[F:25][C:2]([F:24])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:15][CH3:16])[C:6]([C:17]([O:19][CH2:30][CH3:31])=[O:18])=[C:5]([C:20]([F:22])([F:21])[F:23])[N:4]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)O)c1OCC
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1OCC

Procedure:
This material was obtained from product of Example 14 and ethanol according to the following general procedure: 5.0 g portion of the acid product of Example 14 was refluxed with excess thionyl chloride until te reaction was completed. Excess thionyl chloride was removed in vacuo. The residual acid chloride was refluxed with an excess of appropriate alcohol (ethanol in this Example) for 2-4 hours and concentrated to give the desired product. The crude product was purified by a wash with 20% K2CO3 and isolated as a solid (20.3% yield), mp 28°-30° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([O:11][CH2:12][O:13][CH3:14])=[CH:4][C:3]=1[O:15][CH2:16][O:17][CH3:18].O1CCCC1.[Li+].CCC[CH2-].[C:29](=[O:31])=[O:30]>O.CCCCCC>[CH:8]([C:6]1[C:5]([O:11][CH2:12][O:13][CH3:14])=[CH:4][C:3]([O:15][CH2:16][O:17][CH3:18])=[C:2]([CH:7]=1)[C:29]([OH:31])=[O:30])([CH3:10])[CH3:9]
Reactant: O=C=O
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1Br
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)O
Temperature: -60 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
1-bromo-5-isopropyl-2,4-bis-methoxymethoxy-benzene (IM2-a: 12.0 g, 37.8 mmol) and tetrahydrofuran (150 mL) were placed in a 300 mL three-neck flask and cooled to −60° C. To this mixture a hexane solution of N-butyllithium (24 mL, 1.59 M) was added slowly, and after adjusting the temperature of the solution to −40° C. the mixture was stirred for 1 hour. Dry ice powder was added to the reaction mixture and the reaction mixture was allowed to come to room temperature. After completing the reaction, the reaction mixture was mixed with distilled water and extracted with ethyl acetate. The extracted organic layer was dried over anhydrous sodium sulfate. After filtration and evaporation, the solid material obtained was purified by suspending in hexane to obtain the title compound (IM3-a: 6.6 g, 62%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:22]=[C:23](CC(O)=O)[CH:24]=[CH:25][CH:26]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[OH:34]N1C2N=CC=CC=2N=N1.C([N:46]([CH:49](C)C)CC)C.[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=4)[C:49]([NH2:46])=[O:34])[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCN(CC)C(C)C
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(CC(=O)O)c1
Reactant: On1nnc2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(N)=O)c1
Temperature: 25 °C

Procedure:
A solution of 3-[5-[1-(4-cyanophenyl)1H-pyrazol-5-yl]-3,6-dimethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)yl]phenylacetic acid (prepared in Example 103), benzotriazol-1-yl-oxytripyrrolidine phosphonium hexafluorophosphate (30.8 mg), 1-hydroxy-7-azabenzotriazole (8.6 mg) and N,N-diethylisopropylamine (76 μl) in N,N-dimethy formamide (0.7 ml) was stirred at room temperature for thirty minutes. Thereto was added ammonium chloride (15.7 mg) and the resulting mixture was stirred at room temperature for twenty-two hours, and to the reaction mixture was added ethyl acetate (30 ml) and the resulting mixture was washed with 1M hydrochloric acid (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 3-(5-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3,6-dimethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)benzamide (18.0 mg).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C@H:3]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10]/[N:11]=[CH:12]/[C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([F:23])[CH:19]=3)[N:14]=2)=[CH:8][CH:9]=1.C(O)(=O)C.I(C1C=CC=CC=1)=O>C(Cl)Cl>[F:40][C:2]([F:1])([F:39])[C@H:3]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36])[CH2:27]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:12]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: COc1cc2nc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)ccc2cc1F
Agent: O=Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-((E)-2-((6-fluoro-7-methoxyquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (150 mg, 0.267 mmol) in DCM (5 mL) was added iodosobenzene acetate (112 mg, 0.347 mmol), and the reaction was stirred at ambient temperature for 2 hours. After concentration, the residue was purified by reverse phase chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-methoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (109 mg, 72.9% yield) as beige solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][S:23]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([CH:36]([OH:38])[CH3:37])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:18][CH2:17]1)=[O:15])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][S:23]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([C:36](=[O:38])[CH3:37])=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH2:18][CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(C)O)c3ccccc23)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(C)=O)c3ccccc23)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 25.1 %

Procedure:
To a −78° C. solution of oxalyl dichloride (85 mg, 0.665 mmol) in CH2Cl2 (10 mL) was added DMSO (104 mg, 1.33 mmol). After stirred at −78° C. for 10 min, a solution of 4-[4-(1-hydroxy-ethyl)-naphthalene-1-sulfonylamino]-piperidine-1-carboxylic acid ethyl ester 38 (180 mg, 0.443 mmol) in CH2Cl2 was added into the mixture by dropwise. The resultant mixture was stirred at −78° C. for another 30 min, then was added triethyl amine (224 mg, 2.22 mmol). The reaction mixture was warmed up to room temperature and stirred for 2 h. The resultant mixture was quenched with saturated ammonium chloride solution and the aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product. The crude material was purified by Flash column chromatography (CH2Cl2:MeOH) to provide 45 mg of 4-(4-acetyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester 39 in 25% yield. LCMS showed m/z: 409 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[NH:16][C:15](=[O:17])[C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:19]([CH3:29])[C:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[O:21].CC1C(=O)NC(C2C=CC=CC=2)=NC=1C.BrCC(N(CCC)CCC)=O>>[C:1]1([C:7]2[N:16]=[C:15]([O:17][CH:19]([CH3:29])[C:20]([N:22]([CH2:23][CH2:24][CH3:25])[CH2:26][CH2:27][CH3:28])=[O:21])[C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCN(CCC)C(=O)C(C)Br
Reactant: O=c1[nH]c(-c2ccccc2)nc2c1CCCC2
Agent: CCCN(CCC)C(=O)CBr
Agent: Cc1nc(-c2ccccc2)[nH]c(=O)c1C
Product: CCCN(CCC)C(=O)C(C)Oc1nc(-c2ccccc2)nc2c1CCCC2

Procedure:
The same procedures as Example 136 are repeated except that 5,6,7,8-tetrahydro-2-phenyl-4-(3H)-quinazolinone and 2-bromo-N,N-dipropylpropanamide are used instead of 5,6-dimethyl-2-phenyl-4-(3H)-pyrimidinone and 2-bromo-N,N-dipropylacetamide, respectively. The product thus obtained is recrystallized from n-hexane to give the desired compound, m.p. 73-74° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH3:45])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH3:45])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(-c2ccccc2C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2ccccc2C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.30 g), sodium hydrogen carbonate (0.45 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-1-(2-methylphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.24 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (4 mL), N,N′-carbonyldiimidazole (0.086 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.079 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.11 g, 42%).
Reaction SMILES: [OH2:1].C[C:3]1[C:20]2[C@:15]([CH3:22])([CH2:16][CH2:17][C:18](=[O:21])[CH:19]=2)[C@@H:14]2[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:23])[C:8](=[CH2:24])[CH2:7]3)[CH:4]=1.[CH2:25]1COC[CH2:26]1>S(=O)(=O)(O)O.CO>[C:25]([C@:9]1([OH:23])[C:8](=[CH2:24])[CH2:7][C@H:6]2[C@H:5]3[C:14](=[CH:13][CH2:12][C@:10]12[CH3:11])[C@:15]1([CH3:22])[C:20](=[CH:19][C:18](=[O:21])[CH2:17][CH2:16]1)[CH2:3][CH2:4]3)(=[O:1])[CH3:26]
Reactant: O
Reactant: C1CCOC1
Reactant: C=C1C[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)C1=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]2(C)[C@]1(O)C(C)=O
Reaction time: 8 h

Procedure:
The mercuric oxide (red, 1.2 g), which had been dissolved in concentrated sulfuric acid (1.6 ml) and water (25 ml) was added to a solution of 17α-ethinyl-17β-hydroxy-16-methyleneandrosta-4,9(11)-dien-3-one (IVA, Example 11, 10 g) in methanol (600 ml) and THF (125 ml). The reaction mixture was stirred overnight at 20°-25° at which time the reaction was complete as measured by TLC. The solids were removed by filtration through a Celite pad. The filtrate was concentrated under reduced pressure to a solid which was triturated with methanol (25 ml). The mixture was filtered and the solids dried to give the title compound, m.p. 147°-162°; NMR (CDCl3) 0.88, 1.35, 2.35, 5.02, 5.50 and 5.75 δ.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35](=[O:36])[NH:1][C@H:2]1[CH2:3][CH2:4][C@@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)[CH3:39]
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c13)OCO2
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCCOC)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from cis-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A186) and ethyl chloroformate the title compound was obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH2:14][CH2:15][CH2:16][C:17](OCC)=[O:18])[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[N:3]=1
Reactant: CCOC(=O)CCCc1nc(Cl)cc(N2CCOCC2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCCc1nc(Cl)cc(N2CCOCC2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
To a solution of 4-chloro-2-(4-ethoxy-4-oxo-butyl)-6-morpholinopyrimidine (1.108 g, 3.54 mmol) in 50 mL THF at −78° C., a diisobutylaluminum hydride (DIBAL) solution (4.72 mL1.5 M in Toluene, 7.08 mmol) was slowly added. After addition, the obtained reaction mixture was warmed up slowly to 0° C. and kept at 0° C. for 10 min. After routine workup, flash chromatography was performed to obtain 4-chloro-2-(4-hydroxybutyl)-6-morpholinopyrimidine (0.76 g, 2.80 mmol, 79%) as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][CH2:23][CH2:24][CH2:25][NH2:26]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][CH2:25][CH2:24][CH2:23][O:22][CH3:21])=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: COCCCN
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: COCCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (150 mg, 0.41 mmol) and 3-methoxypropylamine (44 mg, 0.49 mmol). The title compound was obtained as a solid (80 mg, 46% yield). 1H NMR (400MHz, d6-DMSO) δ: 8.99 (2H, s), 8.84 (1H, m), 8.42 (1H, s), 3.34 (1H, m), 3.33 (1H, m), 3.23 (5H, m), 1.69 (2H, m). MS m/z: 422.03, 424.03 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cu][C:11]#[N:12].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:8][C:4]1[C:3]([CH3:9])=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:11]#[N:12]
Reactant: N#C[Cu]
Reactant: Cc1c(O)cccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(O)cccc1C#N
Temperature: 120 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
To a solution of 3-bromo-2-methylphenol (20.0 g) in DMF (250 mL) were added copper(I) cyanide (19.0 g) and tetrakis(triphenylphosphine)palladium(0) (3.70 g), and the mixture was heated with stirring at 120° C. for 16 hr under nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with tert-butyl methyl ether to give the title compound (7.00 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH2:20][OH:21].C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CCO.ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC[C@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@@H]2CO)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
A solution of 5.98 g (30.0 mmol) of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 3.55 ml=3.64 g (36.0 mmol) of (R)-(−)-pyrrolidin-2-yl-methanol in 60.0 ml of EtOH was treated with 60.0 ml of 1,2-dichloroethane, followed by 4.50 ml (36 mmol) of borane-pyridine complex (8 molar). Then, 4.46 ml=4.68 g (78.0 mmol) of acetic acid was added to this solution. After stirring at RT for 16 hours, the reaction mixture was poured into crashed ice; then, the pH was adjusted to 9-10 with sodium carbonate solution and the mixture was extracted twice with EtOAc; the combined organic phases were washed with water, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 8:2) to give 7.69 g (90%) of the title compound as light yellow oil. MS: 285.1 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.CO[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Br)[CH:16]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]2[C@:33]3([C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[NH:35][C:34]3=[O:42])[CH2:32]2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C@@H:31]2[C@:33]3([C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]([CH2:21][C:17]4[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([N:8]5[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:11])[CH3:1])[CH2:6][CH2:7]5)=[O:23])[CH:16]=4)[C:34]3=[O:42])[CH2:32]2)=[CH:29][CH:30]=1
Reactant: CN(C)CCN1CCNCC1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Product: CN(C)CCN1CCN(C(=O)c2cccc(CN3C(=O)[C@]4(C[C@@H]4c4ccc(Cl)cc4)c4ccccc43)c2)CC1

Procedure:
The title compound was prepared in analogy to Example 60 starting from N,N-dimethyl-2-(piperazin-1-yl)ethanamine, 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C32H35ClN4O2: 542, observed (M+H)+: 543.1 1H NMR (400 MHz, CDCl3) δppm 2.04 (dd, J=7.96, 4.67 Hz, 1 H) 2.28 (dd, J=8.97, 4.67 Hz, 1H) 2.93 (s, 6 H) 3.18 (br. s., 4 H) 3.34 (t, J=8.59 Hz, 1 H) 3.62 (br. s., 4 H) 3.87 (br. s., 4 H) 4.95 (d, J=15.92 Hz, 1 H) 5.16 (d, J=15.92 Hz, 1 H) 6.02 (d, J=7.58 Hz, 2 H) 6.70-6.84 (m, 2 H) 7.06-7.19 (m, 3 H) 7.31 (s, 1H) 7.35 (d, J=5.31 Hz, 1 H) 7.43 (d, J=6.06 Hz, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][N:44]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:41]([CH3:42])=[CH:40][C:39]([C:43]6[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][N:44]=6)=[CH:38][C:37]=5[CH3:50])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1ccc(-c2cc(C)c(Cl)c(C)c2)nc1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccc(C)cn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-chloro-3,5-dimethyl-phenyl)-5-methyl-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.08 min; Mass spectrum (ESI+): m/z=538 [M+H]+.