Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:6]=2[C:7]=1[CH3:8].[N+](=[CH2:18])=[N-].C(O)(=O)C>CO>[CH3:18][O:14][C:13]([C:10]1[CH:11]=[CH:12][C:5]2[O:4][C:3]([CH2:2][OH:1])=[C:7]([CH3:8])[C:6]=2[CH:9]=1)=[O:15]
Reactant: Cc1c(CO)oc2ccc(C(=O)O)cc12
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc2oc(CO)c(C)c2c1

Procedure:
A solution of 2-hydroxymethyl-3-methylbenzofuran-5-carboxylic acid (0.69 g) in methanol (250 ml) was treated with an excess of an ethereal solution of diazomethane. The solution was allowed to stand for 11/2 hours at 0° and then the excess of diazomethane was decomposed by dropwise addition of acetic acid until no further effervescence was apparent. The solution was evaporated and the residue was dissolved in ether. The solution was washed with sodium bicarbonate, dried (Na2SO4) and evaporated to give a quantitative yield of 2-hydroxymethyl-3-methylbenzofuran-5-carboxylic acid methyl ester, m.p. 96°-98° (from ethyl acetate/petrol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]=1[O:13][CH3:14].C([Li])CCC.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>O1CCCC1.CCCCCC>[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:8]1[CH:7]=[CH:6][C:5]([C:9]([CH3:11])([CH3:10])[CH3:12])=[C:4]([O:13][CH3:14])[C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(C(C)(C)C)c1OC
Reactant: BrCCCCCCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(CCCCCCBr)ccc(C(C)(C)C)c1OC
Reaction time: 3 h
Yield: 15 %

Procedure:
To 27.0 g (0.139 mole) of 1,2-dimethoxy-3(1,1-dimethylethyl)benzene in 350 mL of anhydrous tetrahydrofuran cooled in an ice-brine bath at -5° was added. 87 mL (0.139 mole) of 1.6M butyl lithium in hexane over 30 minutes. The reaction mixture was stirred at -5° for 3 hours and then at reflux for 1 hour. After cooling in an ice bath, 21.5 mL (0.139 mole) of 1,6-dibromohexane in 75 mL of tetrahydrofuran was added dropwise. The reaction mixture was then stirred at reflux for 17 hours. The solvent was removed under reduced pressure, 50 mL of 3N hydrochloric acid was added and the product was extracted with ether. The extract was washed with sodium bicarbonate solution, dried and concentrated at reduced pressure to an oil. Purification by HPLC using 20% toluene-hexane gave 7.6 g ((15% yield) of 1-(6-bromohexyl)-2,3-dimethoxy-4-(1,1-dimethylethyl)benzene.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:23]([O:27][C:28]([N:30]1[CH2:37][C@H:36]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH2:35][C@H:31]1[C:32]([OH:34])=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].[N:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[C:47]([NH:55][C:56](=[O:75])[C@@H:57]2[CH2:61][C@@H:60]([NH:62][C:63](=[O:74])[C@H:64]([OH:73])[CH2:65][CH2:66][C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[CH2:59][NH:58]2)[CH:46]=1>ClCCl.C(N(CC)CC)C>[N:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[C:47]([NH:55][C:56](=[O:75])[C@@H:57]2[CH2:61][C@@H:60]([NH:62][C:63](=[O:74])[C@H:64]([OH:73])[CH2:65][CH2:66][C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[CH2:59][N:58]2[C:32](=[O:34])[C@@H:31]2[CH2:35][C@@H:36]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH2:37][N:30]2[C:28]([O:27][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:29])[CH:46]=1
Reactant: CN(C)CC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(N[C@H]1CN[C@H](C(=O)Nc2cnc3ccccc3c2)C1)[C@H](O)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)N[C@@H]1C[C@@H](C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Triethylamine (33 μL), 1-hydroxybenzotriazole (30 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (46 mg) were added to a suspension of the crude N-tert-butoxycarbonyl-trans-4-(N,N-dimethylglycylamino)-L-proline (B) and trans-4-((R)-2-hydroxy-4-phenylbutyrylamino)-L-proline 3-quinolylamide (Compound D101 (H), 84 mg) in dichloromethane (5 mL) at 0° C. After stirring at 0° C. for 30 min and at room temperature for 14 hr, the solvent was removed in vacuo. The residue was diluted with saturated sodium hydrogen carbonate and extracted with chloroform-methanol (10:1,v/v). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (Whatman, PLK5F Silica Gel 150, chloroform:methanol=10:1, v/v) to afford the title compound (76 mg) as a colorless glassy solid: mass spectrum (EI+) m/e 715 (M+); (FAB+) m/e 716 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][O:25][CH2:26][C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([C:27](=[O:28])[CH2:26][O:25][CH3:24])[CH2:14][CH2:13]3)[CH2:11]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(C(c2ccccc2)N2CC(N3CCNCC3)C2)cc1
Reactant: COCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
To a solution of 1-[1-(diphenylmethyl)azetidin-3-yl]piperazine (see Method 7a; 615 mg, 2.0 mmol) in DMF (8 mL) were added methoxy acetic acid (272 mg, 3.0 mmol), DIPEA (310 mg, 2.4 mmol) and TBTU (770 mg, 2.4 mmol). The reaction mixture was stirred at RT for 12 h and then partitioned between methylene chloride and aqueous NaHCO3. The aqueous phase was extracted twice with methylene chloride and then the combined organic solutions were washed with brine and dried over MgSO4. The solvent was removed by evaporation and the product was purified by means of reversed phase chromatography is using a mixture of acetonitrile and aqueous 0.1 M ammonium acetate as eluent. There was obtained 610 mg (80%) of 1-[1-(diphenylmethyl)azetidin-3-yl]-4-(methoxyacetyl)-piperazine. 1H NMR (500 MHz, CD3OD): 2.3-2.4 (m, 4H), 3.0 (m, 3H), 3.4 (s, 3H), 3.4 m, 2H), 3.5 (m, 2H), 3.6 (m, 2H), 4.1 (s, 2H), 4.5 (s, 1H), 7.2 (t, 2H), 7.3 (t, 4H), 7.4 (d, 41-1); LCMS: m/z 380 (M+1)+.
Reaction SMILES: [CH2:1]([C:6]1[N:7]([CH2:34][CH2:35][CH3:36])[N:8]=[C:9]2[C:18]=1[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:11]=[C:10]2[N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:2][CH2:3][C:4]#[CH:5].Cl[C:38](=[N:45][OH:46])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C>ClCCl>[C:39]1([C:38]2[CH:5]=[C:4]([CH2:3][CH2:2][CH2:1][C:6]3[N:7]([CH2:34][CH2:35][CH3:36])[N:8]=[C:9]4[C:18]=3[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:11]=[C:10]4[N:19]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[O:46][N:45]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: ON=C(Cl)c1ccccc1
Reactant: C#CCCCc1c2c3c(nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2nn1CCC)CCCC3
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2c1CCCc1cc(-c2ccccc2)no1)CCCC3
Temperature: 40 °C
Yield: 59.9 %

Procedure:
Under a nitrogen atmosphere, a mixture of di(tert-butyl) 1-pent-4-ynyl-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (4.00 g, 8.05 mmol), prepared as described in Example 615, α-chlorobenzaldoxime (2.51 g, 16.1 mmol), prepared as described in Example 596, anhydrous triethylamine (1.7 mL, 12.1 mmol), and anhydrous dichloromethane (25 mL) was heated at 40° C. for 18 hours. The reaction mixture was diluted with dichloromethane, washed sequentially with potassium carbonate, water, and brine, dried over sodium sulfate, and filtered. The filtrate was loaded onto a silica gel column (250 g) and eluted with a gradient of 30-40% ethyl acetate in hexanes. The fractions containing product were combined and concentrated under reduced pressure to provide 2.97 g of di(tert-butyl) 1-[3-(3-phenylisoxazol-5-yl)propyl]-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].IC.[C:13](=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:13])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(F)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc(F)cc1C=O

Procedure:
20.0 g (0.143 mol) of 5-fluoro-2-hydroxybenzaldehyde are dissolved in 250 ml of acetonitrile. 81.04 g (0.57 mol) of iodomethane and 39.5 g (285 mol) of potassium carbonate are added, and the suspension is heated at reflux for 3 hours. The suspension is filtered and the mother liquor is diluted with ethyl acetate, washed twice with water, dried over magnesium sulphate and filtered, and the solvents are evaporated under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.C([Li])CCC.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>O1CCCC1.[Cl-].[Na+].O>[C:11]([O:10][C:9]([NH:8][C:4]1[CH:3]=[C:2]([CH2:1][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:7]=[CH:6][N:5]=1)=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: Cc1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: COC(=O)CBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCc1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: -78 °C
Yield: 59 %

Procedure:
tert-Butyl N-(4-methyl-2-pyridyl)carbamate (5 g, 24.0 mmol) was dissolved in tetrahydrofuran (120 ml), cooled to −78° C., and then added dropwise with n-butyl lithium (40 ml, 60 mmol). Then, the reaction solution was warmed and stirred at room temperature. The reaction mixture was stirred for 1 hour, then again cooled to −78° C., and added dropwise with methyl bromoacetate (3.4 ml) dissolved in tetrahydrofuran (10 ml). After the reaction mixture was stirred for 30 minutes, the reaction was stopped with saturated brine and the reaction mixture was extracted with ethyl acetate. The resulting organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:ethyl acetate=3:1→5:1) to obtain 3.95 g (59%) of the title compound as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[N:11]=[N:12][NH:13][N:14]=1.[C:15]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1
Reactant: Fc1cc(Cl)cc(Br)c1-c1nn[nH]n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nnnc1-c1c(F)cc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
A mixture of 5-(2-bromo-4-chloro-6-fluoro-phenyl)-2H-tetrazole (4.15 g, 14.95 mmol), K2CO3 (3.1 g, 22.43 mmol) and iodomethane (1.3 ml, 20.94 mmol) in DMF (30 ml) was stirred at 25° C. for 3 h. The mixture was partitioned between EtOAc (80 ml) and water (60 ml), the organic layer was separated, washed with water and brine, dried with Na2SO4 and concentrated. The remaining residue was purified by chromatography (silica gel; hexane/EtOAc 100:0-90:10) to obtain 5-(2-bromo-4-chloro-6-fluoro-phenyl)-1-methyl-1H-tetrazole as pale yellow solid (1.5 g, 35%) and the title compound as reddish liquid (1.7 g, 39%). MS: 291.0 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][N:29]=1.O>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([Cl:27])=[N:29][CH:30]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CBr)cn1
Temperature: 25 °C

Procedure:
N-bromosuccinimide (6.1 g, 3.44 mmol) and benzoyl peroxide (218 mg, 0.09 mmol) were added successively to a solution of 2-chloro-5-methyl-pyridine (4.0 g, 3.13 mmol) in carbon tetrachloride (20 mL) and refluxed for 90 min. The reaction mixture was cooled to room temperature, water added and the organic layer separated. The organic layer was washed successively with water, brine, dried over anhydrous sodium sulfate and filtered. The resultant solution of 5-bromomethyl-2-chloro-pyridine was used as such for the next step.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[CH2:11][CH2:10][NH:9][CH2:8][C:6]=2[N:7]=1.[C:18]([O:23][C@@H:24]([C:26]1[N:31]=[C:30](Cl)[CH:29]=[CH:28][N:27]=1)[CH3:25])(=[O:22])[CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>C(O)(C)C>[C:18]([O:23][C@@H:24]([C:26]1[N:27]=[C:28]([N:9]2[CH2:10][CH2:11][C:5]3[C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:3][C:2]([CH3:1])=[N:7][C:6]=3[CH2:8]2)[CH:29]=[CH:30][N:31]=1)[CH3:25])(=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: Cc1nc2c(c(-c3ccccc3)n1)CCNC2
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCc3c(nc(C)nc3-c3ccccc3)C2)n1
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of 2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine (prepared according to the method of Example 86, Step D, 6.8 g, 30.0 mmol) in isopropanol (125 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 6.8 g, 30 mmol) followed by triethylamine (12.5 mL, 89.9 mmol). This mixture was stirred at reflux for 8 h, cooled to room temperature overnight, and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2% methanol/ethyl acetate) to give 11.0 g (88%) of the title compound of Example 86, Step E, as a yellow oil. 1H NMR (CDCl3, 250 MHz) δ 8.28 (d, 1H), 7.62-7.40 (c, 5H), 6.45 (d, 1H), 5.69 (q, 1H), 4.78 (s, 2H), 3.93 (app s, 2H), 2.95 (t, 2H), 2.77 (s, 3H), 2.40 (t, 2H), 1.77-1.63 (c, 2H), 1.60 (d, 3H), 0.98 (t, 3H); MS (APCI) 418 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([N:9]1[CH2:8][C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[S:12][CH2:11][CH2:10]1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc2c1CNCCS2
Agent: Cl
Product: CC(=O)N1CCSc2cccc(C)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.91 g, prepared in a similar manner to its hydrochloride, Example 4 above) in acetic anhydride (10 ml) was stirred at room temperature for one hour. The reaction mixture was poured into ice and extracted with dichloromethane. The organic layer was dried and the solvent removed by evaporation to give 4-acetyl-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from hexane. Yield 0.93 g (m.p. 71°-73° C.).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([Sn](C)(C)C)[CH:15]=[C:14]([NH2:23])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:26]=[C:27]2[CH:33]=[N:32][N:31]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:28]2=[N:29][CH:30]=1>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.CN(C=O)C>[CH3:43][C:40]1[CH:41]=[CH:42][C:37]([S:34]([N:31]2[C:28]3=[N:29][CH:30]=[C:25]([C:16]4[CH:15]=[C:14]([NH2:23])[C:13]5[CH:12]=[N:11][N:10]([S:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)(=[O:9])=[O:8])[C:18]=5[CH:17]=4)[CH:26]=[C:27]3[CH:33]=[N:32]2)(=[O:36])=[O:35])=[CH:38][CH:39]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3cc(Br)cnc32)cc1
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ncc3cc(-c4cc(N)c5cnn(S(=O)(=O)c6ccccc6)c5c4)cnc32)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
1-(Phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (775 mg), Pd(PPh3)4 (212 mg) and 5-bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrazolo[3,4-b]pyridine (775 mg) were introduced into a microwave vial and DMF (10 ml) was added. The mixture was heated in the microwave at 120° C. for 4 h. The solvent was removed in vacuo and the crude residue was placed on a high vacuum line overnight. The resulting brown oil was purified by FlashMaster II. The crude material was dissolved in chloroform and added to the top of 2×100 g silica SPE cartridges that were subsequently eluted with 0-100% ethyl acetate:cyclohexane over 60 min. The product-containing fractions were combined and the solvent was removed in vacuo. The residue was dried on a high vacuum line to give the title product, 371 mg as a cream solid.
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+].[CH3:19][CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:19][CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH2:21]1
Reactant: CC1CNc2ccccc21
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1CN(C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c2ccccc21
Yield: 81.1 %

Procedure:
The product is prepared according to the procedure described in example 5, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 170 mg of 3-methylindoline and 487 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 310 μl of pyridine and 6.0 ml of N,N-dimethylformamide. 367 mg of 2-[2-(3-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white crystalline powder, the characteristics of which are the following:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1F>>[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:25])=[O:26])[CH:20]=[CH:21][C:22]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Reactant: O=S(=O)(Cc1ccccn1)c1ccc(F)c(Cl)c1
Product: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)Cc3ccccn3)cc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from step (ii).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([CH2:12][C:13](=O)[CH3:14])(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[CH3:14][C:13]1[NH:3][N:2]=[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:12]=1
Reactant: NN
Reactant: CC(=O)CC(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2ccccc2)n[nH]1
Reaction time: 14 h
Yield: 155.2 %

Procedure:
Hydrazine hydrate (9.0 mL, 99 mmol, 35 wt. % in H2O; 0.64 equiv) was added to a solution of benzoylacetone (25.00 g, 154.1 mmol, 1 equiv) in ethanol (250 mL). After stirring 14 h, more hydrazine hydrate (8.0 mL, 88 mmol, 0.57 equiv) was added. After 2 h, the reaction solution was concentrated (95° C.) to give the title compound as a white solid (24.31 g, 99.7%). HRMS Calculated for C10H11N2: m/z 159.0922. Found: 159.0917.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.C(Cl)(=O)C([Cl:13])=O>C(Cl)Cl>[CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([Cl:13])=[O:9])[N:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nc(C(=O)O)co1
Solvent: ClCCl
Product: Cc1nc(C(=O)Cl)co1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 2-methyl-oxazole-4-carboxylic acid (30 mg) in DCM (2.0 mL), oxalyl chloride (3.0 eq) was added at room temperature. The reaction mixture was stirred for 30 minutes. Solvents were evaporated and dried under vacuo to afford 2-methyl-oxazole-4-carbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])/[C:13]([NH:28][C:25]2[CH:26]=[CH:27][N:23]([CH3:22])[N:24]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CC(C)CO/N=C(/C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: Cn1ccc(N)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CO/N=C(/C(=O)Nc1ccn(C)n1)c1ccc(S(C)(=O)=O)c(Cl)c1
Reaction time: 2 h
Yield: 95.3 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-isobutoxyimino-acetic acid (104 mg, 0.31 mmol), 1-methyl-1H-pyrazol-3-ylamine (30 mg, 0.31 mmol) and N,N-diisopropylethylamine (163 μL, 0.94 mmol) were combined in methylene chloride (1.5 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (119 mg, 0.31 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-isobutoxyimino-N-(1-methyl-1H-pyrazol-3-yl)-acetamide (122 mg, 95%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C17H21ClN4O4S [M+] 412.10, found 413 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 0.94 (d, J=6.7 Hz, 6 H, 2×CH3), 2.05 (m, 1 H, CH), 3.29 (s, 3 H, SO2CH3), 3.84 (s, 3 H, NCH3), 4.06 (d, J=6.8 Hz, 2 H, OCH2), 6.68 (d, J=2.3 Hz, 1 H, Ar), 7.28 (d, J=2.3 Hz, 1 H, Ar), 7.58 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.69 (d, Jm=1.5 Hz, 1 H, Ar), 8.19 (d, Jo=8.2 Hz, 1 H, Ar), 9.13 (brs, 1 H, NH).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1
Reactant: O=c1ccoc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C1CCOc2ccccc21
Reaction time: 48 h
Yield: 65.3 %

Procedure:
According to the general procedure, a solution of chromone (45 mg, 0.31 mmol), Hünig's base (540 μL) and rac-32 (9.8 mg, 0.0062 mmol, 2.0 mol %) in PhMe (3 mL) was pressurized with H2 to 100 bar and stirred for 48 h. Filtration of the reaction mixture and evaporation of the solvent gave the crude product, which was purified by column chromatography (30% EtOAc in hexane, silica gel) to give 48 (30 mg, 66%) as a colorless oil. 1H NMR35 (300 MHz, CDCl3): δ 7.90 (dd, 1H J=7.8, 1.5 Hz), 7.50-7.45 (m, 1H), 7.05-6.96 (m, 2H), 4.54 (t, 2H, J=6.6 Hz), 2.82 (t, 2H, J=6.3 Hz); 13C NMR (75.5 MHz, CDCl3): δ 192.0, 162.0, 136.1, 127.3, 121.5, 118.0, 67.1, 37.9.