Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[CH:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])[CH3:4].C(Cl)Cl.C(N)CN.O>C(O)(C(F)(F)F)=O>[OH:1][CH:2]([CH:36]1[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1)[CH:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])[CH3:4]
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(O)C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: O
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(O)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
2-(6-Fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [2-hydroxy-1-methyl-2-(tetrahydro-pyran-4-yl)-ethyl]-amide, diastereomer B (70 mg, 0.120 mmol) was dissolved in a 4:6 solution of TFA:DCM (5.7 mL). After stirring at room temperature overnight, the volatiles were removed under reduced pressure. The crude material was then dissolved in dichloromethane and treated with ethylenediamine (722 mg, 12 mmol). After stirring at room temperature overnight, water was added and the resulting precipitate was collected by filtration to provide 30 mg (55%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [2-hydroxy-1-methyl-2-(tetrahydro-pyran-4-yl)-ethyl]-amide (diastereomer B) as an off-white solid. MS: (M+H)+=453. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.73 (br. s., 1H) 8.99-9.30 (m, 1H) 8.70 (dd, J=9.06, 5.29 Hz, 1H) 8.22-8.48 (m, 1H) 7.65 (dd, J=9.82, 1.89 Hz, 2H) 6.94-7.22 (m, 1H) 4.97 (d, J=6.80 Hz, 1H) 4.35 (m, 1H) 4.2 (s, 1H), 3.71 (m, 2H) 1.87 (d, J=13.60 Hz, 1H) 1.43-1.77 (m, 2H) 0.97-1.43 (m, 5H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH2:20])[N:19]=[C:15]4[CH:14]=[CH:13][CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH:20][C:28](=[O:31])[CH:29]=[CH2:30])[N:19]=[C:15]4[CH:14]=[CH:13][CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Nc1nc2cccc(-c3ccc4c(c3)OCCO4)n2n1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Nc1nc2cccc(-c3ccc4c(c3)OCCO4)n2n1
Reaction time: 8 h

Procedure:
To a solution of 5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.3 g, 1.12 mmol) in dichloromethane (10 mL), triethylamine (0.19 mL, 1.34 mmol) and acryloyl chloride (0.11 mL, 1.23 mmol) were added successively and the mixture was stirred overnight. The reaction was hydrolysed, and the organic phase washed with water, dried over magnesium sulfate and concentrated under reduced pressure. A minimum amount of dichloromethane was added to the crude, diethylether was added and the resulting solid collected by filtration. LCMS Method: 2: RT: 4.23 min, 323 [M+1].
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.[CH2:20]([O:22][C:23](=[O:27])[CH2:24][CH2:25]Br)[CH3:21]>C1COCC1>[CH2:20]([O:22][C:23](=[O:27])[CH2:24][CH2:25][CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)[CH3:21]
Reactant: CCOC(=O)CCBr
Reactant: Cc1cnccn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CCCc1cnccn1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
Butyllithium (1.6 M in hexane solution, 10 ml, 16 mmol) was added dropwise to a solution of diisopropylamine (2.25 ml, 16 mmol) in anhydrous THF (50 ml) at −20° C. under a nitrogen atmosphere. The mixture was stirred at −20° C. for 30 minutes and after cooling at −70° C. a solution of 2-methyl-pyrazine (1.47 ml, 16 mmol) in THF (10 ml) was added dropwise. After 15 minutes, a solution of 3-bromo-propionic acid ethyl ester (2.54 ml, 19.2 mmol) in THF (10 ml) was added and the mixture maintained at −70° C. for 2 hours and then stirred at room temperature overnight. The reaction was then quenched with a saturated solution of NH4Cl and extracted with ethyl acetate, the organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (hexane/ethyl acetate from 9/1 to 1/1 respectively) to give the title compound (1 g, 33% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1.Cl>CO.O1CCOCC1>[Cl:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH2:30])[CH2:25]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(Cl)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(Cl)c(N3CCC[C@H](N)C3)n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To a solution of tert-butyl N-[(3S)-1-[3-chloro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (0.140 mmol; 72.7 mg) in Methanol (5 mL) was added hydrochloric acid, 4.0 M in 1,4-Dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 176 as an off-white solid (23.3 mg, 40%). 1H NMR (400 MHz, DMSO) δ 9.67-9.61 (s, 1H), 9.47-9.42 (s, 1H), 9.34-9.28 (s, 1H), 8.71-8.67 (s, 1H), 8.64-8.61 (s, 1H), 8.01-7.94 (d, J=8.4 Hz, 1H), 7.57-7.51 (d, J=8.4 Hz, 1H), 3.91-3.83 (d, J=8.8 Hz, 1H), 3.81-3.72 (d, J=12.3 Hz, 1H), 3.25-3.19 (m, 1H), 2.97-2.89 (m, 1H), 2.77-2.71 (dd, J=11.9, 9.1 Hz, 1H), 2.67-2.62 (d, J=8.6 Hz, 3H), 1.98-1.87 (dd, J=16.2, 6.5 Hz, 2H), 1.84-1.40 (dd, J=32.9, 22.1 Hz, 3H), 1.36-1.23 (td, J=13.5, 4.6 Hz, 1H); MS (ESI) m/z: 421.1 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.C([O-])(O)=O.[Na+]>C(O)C.O>[NH2:9][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)ccc1O
Temperature: 70 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A mixture of compound 4-bromo-2-nitrophenol (1 g, 4.59 mmol) and 5 nCl2 (5.2 g, 22.9 mmol) in ethanol (10 mL) was stirred at 70° C. for 2 h. After cooled down, the mixture was diluted with water (100 mL), adjusted to pH 7 with saturated aqueous NaHCO3 and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, concentrated to give 2-amino-4-bromophenol (770 mg, 89%) as a grey solid. LCMS: 188 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 4.79 (s, 2H), 6.48 (dd, J1=2.4 Hz, J2=8.4 Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 9.26 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[C:29]([F:53])=[CH:30][C:31]([Cl:52])=[C:32]([CH:51]=1)[O:33][C:34]1[CH:48]=[CH:47][C:37]2[N:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH2:45]3)=[O:43])[S:40][C:36]=2[C:35]=1[C:49]#[N:50]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:28]1[CH:51]=[C:32]([O:33][C:34]2[CH:48]=[CH:47][C:37]3[N:38]=[C:39]([NH:41][C:42]([CH:44]4[CH2:46][CH2:45]4)=[O:43])[S:40][C:36]=3[C:35]=2[C:49]#[N:50])[C:31]([Cl:52])=[CH:30][C:29]=1[F:53])=[O:6]
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Reactant: N#Cc1c(Oc2cc(N)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1c(Oc2cc(NC(=O)c3cccc(C4(C#N)CC4)c3Cl)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (75 mg, 0.339 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (36 μL, 0.427 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(5-Amino-2-chloro-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (100 mg, 0.248 mmol) was added to the solution, and the mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (25 mL) and saturated brine (25 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from diethyl ether to give the title compound (85 mg, 57%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.O=[C:25]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:26][CH2:27][C:28]([NH2:30])=[O:29].C(O)(=O)C.C([O-])(=O)C.[Na+]>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:25](\[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)/[CH2:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:22][CH:23]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Reactant: NC(=O)CCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/CCC(N)=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 7.9 %

Procedure:
After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (1.00 g), 4-oxo-4-phenylbutanamide (571 mg), acetic acid (0.553 ml), sodium acetate (528 mg) and ethanol (20 ml) was heated to reflux for 10 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography and concentrated a portion from an ethyl acetate-hexane (3:1, v/v)-eluted fraction which eluted following the E- compound, to obtain crystals. The crystals were recrystallized from ethanol to obtain Z-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutanamide (120 mg, yield 8%) as colorless crystals. m.p. 110-112° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=2[O:37][CH3:38])=[CH:22][CH:21]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:38][O:37][C:29]1[CH:30]=[C:31]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=4)=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:32]=[CH:33][C:28]=1[O:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1
Reactant: Oc1ccc(-c2c[nH]c3ncc(Br)cc23)cn1
Reactant: COc1ccc(COc2ccc(B(O)O)cc2OC)cc1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(COc2ccc(-c3cnc4[nH]cc(-c5ccc(O)nc5)c4c3)cc2OC)cc1
Reaction time: 0.33 h
Yield: 46 %

Procedure:
To the 5-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-2-ol, 4-(4-methoxyphenylmethoxy)-3-methoxyphenylboronic acid (1.3 equiv.), and 6 mol % of dichlorobis(triphenylphosphino)palladium (II) in a Smith process vial was added a 3:2:1 mixture of acetonitrile, water and a 2 M aqueous solution of sodium carbonate (0.10 M). The reaction was run in a Personal Chemistry® microwave reactor at 165° C. for 1200 s. Water was added and the mixture was extracted three times with ethyl acetate Purification on silica gel with a gradient or methanol/dichloromethane by flash chromatography afforded 5-{5-[3-methoxy-4-(4-methoxy-benzyloxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-pyridin-2-ol as a tan solid (46% yield). 1H NMR (DMSO-d6): δ 11.86 (broad s, 1H), 11.67 (broad s, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.22 (s, 1H), 7.89 (dd, J=2.5, 9.5 Hz, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.72 (s, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.30 (d, J=2.0 Hz, 1H), 7.20 (dd, J=2.0, 8.5 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.94 (d, J=8.5 Hz, 2H), 6.44 (d, J=9.5 Hz, 1H), 5.03 (s, 2H), 3.85 (s, 3H), 3.75 (s, 3H); HPLC/MS m/z: 454.1 [MH]+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]([OH:44])[CH3:43])[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:51][CH2:50][C:16]([CH3:52])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:49])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:48])=[C:28]([F:47])[C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]([OH:44])[CH3:43])[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:52])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:49])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:48])=[C:28]([F:47])[C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:50][CH2:51]1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C(C)O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1C(C)O)-c1cccc(c1)-c1c(ccc(F)c1F)O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 25.9 %

Procedure:
Prepared in 25.9% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-16,17-difluoro-5-(1-hydroxyethyl)-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.08 (d, J=7.7 Hz, 1H), 7.98 (s, 1H), 7.90 (s, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.39 (q, J=9.4 Hz, 1H), 7.34 (d, J=7.0 Hz, 1H), 7.00 (d, J=7.7 Hz, 1H), 5.97 (br. s., 1H), 5.50 (br. s., 1H), 4.62 (br. s., 1H), 3.89-3.83 (m, 1H), 3.60 (t, J=11.0 Hz, 1H), 3.42-3.34 (m, 2H), 3.15 (d, J=8.4 Hz, 1H), 2.64 (br. s., 1H), 2.41 (s, 3H), 1.92-1.82 (m, 2H), 1.77-1.58 (m, 8H), 1.51 (d, J=6.6 Hz, 3H), 1.19 (s, 3H), 1.17 (s, 9H), 1.07 (d, J=5.9 Hz, 3H); LCMS (ESI, M+1): 706.10.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].Cl[CH:17]1[O:21][CH:20]([CH2:22][O:23][C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[CH:19]([O:33][C:34](=[O:42])[C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[CH2:18]1>C(#N)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([CH:17]2[O:21][CH:20]([CH2:22][O:23][C:24](=[O:32])[C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[CH:19]([O:33][C:34](=[O:42])[C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=3)[CH2:18]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(I)c2c1
Reactant: Cc1ccc(C(=O)OCC2OC(Cl)CC2OC(=O)c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(C(=O)OCC2OC(n3cc(I)c4cc([N+](=O)[O-])ccc43)CC2OC(=O)c2ccc(C)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a suspension of 1.0 g (3.5 mmol) 3-iodo-5-nitroindole in 15 ml acetonitrile were added 0.16 g (6.7 mmol) sodium hydride (Aldrich 223441-50G). The stirring was continued and the suspension turned red. After 15 min. 2.02 g (5.2 mmol) 5-chloro-2-(4-methyl-benzoyloxymethyl)-3-(4-methyl-benzoyloxy)-tetrahydro-furan were added in small portions and the stirring was continued for another 60 minutes at room temperature. The precipitate was removed by filtration and washed once with acetonitrile. The combined yellow filtrates were concentrated until a product precipitated. For complete precipitation of the product 50 ml ethanol were added. The yellow precipitate was removed by filtration und washed with ethanol. The residuum was dried over phosphorus pentoxide and potassium hydroxide in a vacuum (yield: 1.9 g).
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Na+:6].[Na+].[Cl-:8].[NH4+:9].[Cl-].[Na+]>O>[ClH:8].[NH4+:9].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Na+:6].[Na+:6]
Reactant: [Cl-]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: Cl

Procedure:
The remaining solution after the second filtration operation which contains unreacted sodium sulfate, ammonium chloride, sodium chloride and water may be reused in order to obtain hydrochloric acid and neutralized ammonium and sodium sulfate by the following sequence:
Reaction SMILES: C1(C)CCC(C(C)C)[CH:3]([C:10]2([CH:51]3C(C(C)C)CCC(C)C3)[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:20]4C(C(C)C)CCC(C)C4)[CH:18]=3)[C:13]([CH:40]3C(C(C)C)CCC(C)C3)([CH:30]3C(C(C)C)CCC(C)C3)[CH2:12][C:11]2=[O:50])C1.[BH4-].[Na+]>C(O)C>[CH3:20][C:17]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:40])([CH3:30])[CH2:12][CH:11]([OH:50])[C:10]([CH3:3])([CH3:51])[C:19]=2[CH:18]=1
Reactant: CC1CCC(C(C)C)C(c2ccc3c(c2)C(C2CC(C)CCC2C(C)C)(C2CC(C)CCC2C(C)C)C(=O)CC3(C2CC(C)CCC2C(C)C)C2CC(C)CCC2C(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2c(c1)C(C)(C)C(O)CC2(C)C
Temperature: 25 °C
Yield: 39.7 %

Procedure:
To a solution of 10 g (46.2 mmol) of 1,1,4,4,7-pentamenthyl-2-tetralone in 100 mL of ethyl alcohol was added 7 g (185 mmol) of sodium borohydride portionwise over 15 minutes. After the addition was complete the reaction was stirred at room temperature. After 16 hours the reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with 5-10% ethyl acetate/hexane), followed by crystallization from hexane to afford 4 g (40%) of 3-methyl-6-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene.(M+=218).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[O:3]1.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[S:27](Cl)(=[O:29])=[O:28]>>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[S:27]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)[CH:10]=1)(=[O:28])=[O:29]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Product: COc1ccc(S(=O)(=O)Nc2cccc(B3OC(C)(C)C(C)(C)O3)c2)c(OC)c1
Yield: 66.1 %

Procedure:
3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (450 mg, 2.05 mmol, prepared as described at Wing Kin Chow et al. Chemistry—A European Journal, 2011, 17(25), 6913-6917) was treated with 2,4-dimethoxybenzene-1-sulfonyl chloride (850 mg, 3.5 mmol) according to the method described in Preparation 15b to give 568 mg (77% yield) of the title compound as an oil. Purity 99%.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[CH3:9][NH:10][NH2:11]>C(O)(=O)C>[CH3:9][N:10]1[C:5]([NH2:6])=[CH:4][C:3]([CH:2]([CH3:8])[CH3:1])=[N:11]1
Reactant: CNN
Reactant: CC(C)C(=O)CC#N
Solvent: CC(=O)O
Product: CC(C)c1cc(N)n(C)n1

Procedure:
4-Methyl-3-oxo-pentanenitrile (39.58 g; 0,356 mol) dissolved in glacial acetic acid (400 ml) and methylhydrazine (18.05 g; 0.382 mol) is added thereto, at 15°-20° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH2:12])[C:3]=1[NH2:13].C(O[C:17]([S-])=[S:18])C.[K+]>O>[CH3:1][C:2]1[C:3]2[N:13]=[C:17]([SH:18])[NH:12][C:4]=2[CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Cc1c(N)c(N)cc2ccccc12
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: O
Product: Cc1c2ccccc2cc2[nH]c(S)nc12
Reaction time: 1 h
Yield: 48.5 %

Procedure:
16.9 g of 1-methyl-2,3-diamino-naphthalene (crude base) were suspended in 250 ml of alcohol in a 500 ml sulfonation flask equipped with stirrer, thermometer and reflux condenser and, after adding 25 ml of water as well as 18.8 g of potassium ethylxanthate, recrystallized from isopropanol, boiled at reflux overnight. The insoluble particles were removed by filtration, the solution was diluted with 200 ml of water and made neutral with 10-15 ml of glacial acetic acid. After stirring at 60°-70° C. for 1 hour, the mixture was cooled and suction filtered. There were obtained 10.2 g (48.5% of theory) of 4-methyl-1H-naphth(2,3-d)imidazole-2-thiol with a melting point above 300° C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[C:19]1([CH:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15](=[O:17])[N:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:33][CH:25]3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: c1ccc(C2Cc3ccccc3N2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1c2ccccc2CC1c1ccccc1
Yield: 53.9 %

Procedure:
(±)-6-(Morpholin-4-yl)-2-{2-oxo-2-[2-phenyl-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one is prepared by following the procedure described in example 1d, step 3d, using 0.50 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 0.42 g of 2-phenylindoline (which can be prepared according to Santangelo, E. M. et al. Eur. J. Org. Chem. 2008, 5915), and 0.48 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.31 ml of pyridine and 10 ml of N,N-dimethylformamide. After purification by chromatography on a 50 g column of 20-45 μm silica, elution being carried out with a 90/10 v/v dichloromethane/methanol mixture, 0.43 g of (±)-6-(morpholin-4-yl)-2-{2-oxo-2-[2-phenyl-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one is obtained in the form of a cream-colored solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([CH2:10][CH2:11][C:12](O)=[O:13])=O)=[CH:6][CH:5]=1>CCO>[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]2[CH:10]=[CH:11][C:12](=[O:13])[NH:1][N:2]=2)=[CH:6][CH:5]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: NN
Solvent: CCO
Product: O=c1ccc(-c2ccc(Cl)cc2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrazine (8.9 mL, 0.28 mol) was added to a suspension of 3-(4-chlorobenzoyl)propionic acid (30.0 g, 0.14 mol) in EtOH. The resulting mixture was heated to reflux for 1 hour, stirred at room temperature overnight and chilled with an ice bath. The title compound precipitated out of this mixture (23.85 g, 81%) as a yellow solid: mp 175°-176° C.