Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=O)[N:10]([CH3:18])[N:9]=2)=[C:4]2[NH:19][CH:20]=[C:21]([C:22](=[O:42])[C:23](=[O:41])[N:24]3[CH2:29][CH2:28][N:27]([C:30]4[N:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:33]=[N:32][N:31]=4)[CH2:26][CH2:25]3)[C:3]=12.[CH3:43][N:44]([CH3:49])[CH2:45][CH2:46][CH2:47][NH2:48]>CN(C=O)C>[CH3:43][N:44]([CH3:49])[CH2:45][CH2:46][CH2:47][NH:48][C:13]([C:11]1[N:10]([CH3:18])[N:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([F:1])=[C:3]3[C:21]([C:22](=[O:42])[C:23](=[O:41])[N:24]4[CH2:29][CH2:28][N:27]([C:30]5[N:34]([C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)[N:33]=[N:32][N:31]=5)[CH2:26][CH2:25]4)=[CH:20][NH:19][C:4]=23)[CH:12]=1)=[O:15]
Reactant: CCOC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)nn1C
Reactant: CN(C)CCCN
Solvent: CN(C)C=O
Product: CN(C)CCCNC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)nn1C
Temperature: 50 °C

Procedure:
To a sealable flask containing ethyl 3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxylate (0.058 g, 0.10 mmol) was added N1,N1-dimethylpropane-1,3-diamine (0.7 mL). The mixture was sealed and heated to 50° C. for 20.5 h. The mixture was cooled to rt, and was diluted with DMF and was passed through a plug of celite to remove any solids. The DMF solution was purified by prep HPLC to give N-(3-(dimethylamino)propyl)-3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide.TFA. (0.020 g) as an off-white solid. LCMS: m/e 629.5 (M+H)+, ret time 1.93 min (method 2). 1H NMR (500 MHz, MeOD) δ ppm 8.75 (s, 1 H) 8.61 (s, 1 H) 7.97-8.11 (m, 5 H) 7.79 (s, 1 H) 4.69 (s, 3 H) 4.21-4.25 (m, 2 H) 4.01-4.04 (m, 2 H) 3.91 (t, J=6.26 Hz, 2 H) 3.76-3.82 (m, J=3.66 Hz, 2 H) 3.65-3.75 (m, 10 H) 2.45-2.52 (m, 2 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)=[O:7].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[OH:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29].Cl>CN(C)C=O>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][O:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])=[CH:9][CH:10]=1)#[N:13]
Reactant: N#Cc1ccc(C(=O)CCCCCl)cc1
Reactant: N#Cc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)CCCCOc2cccc(C#N)c2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
53 mg (0.24 mmol) of 4-(5-chloro-1-oxopentyl)benzonitrile was dissolved in 2 ml of dimethylformamide. 33 mg (0.24 mmol) of potassium carbonate, 40 mg of potassium iodide and 29 mg (0.24 mmol) of 3-hydroxybenzonitrile were added to the solution, and they were stirred at 70° C. overnight. 1 N Hydrochloric acid was added to the reaction mixture. After the extraction with ethyl acetate, the extract was washed with 1 N aqueous sodium hydroxide solution and saturated aqueous common salt solution, and then dried over powdery magnesium sulfate. The solvent was evaporated, and the residue was purified by the silica gel chromatography to obtain the title compound.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C([O-])(=O)C.[Na+].[CH3:10][N:11]1[C:15](=[O:16])[CH:14]=[C:13](Br)[C:12]1=[O:18]>CO>[CH3:10][N:11]1[C:15](=[O:16])[CH:14]=[C:13]([NH:4][CH2:1][CH2:2][CH3:3])[C:12]1=[O:18]
Reactant: CCCN
Reactant: CN1C(=O)C=C(Br)C1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCCNC1=CC(=O)N(C)C1=O
Reaction time: 0.17 h
Yield: 31 %

Procedure:
To propylamine (52 μL, 0.78 mmol) and sodium acetate (64 mg, 0.78 mmol) in methanol (30 mL) was added N-methylmonobromomaleimide (150 mg, 0.78 mmol) dropwise in methanol (30 mL). After 10 minutes, solvent was removed in vacuo and purification by flash chromatography (10% ethyl acetate in petroleum ether) afforded the desired compound as a bright yellow waxy solid (41 mg, 0.24 mmol) in 31% yield. δH (500 MHz, CDCl3) 5.43 (s, 1H, NH), 4.80 (s, 1H, H-2), 3.16-3.13 (m, 2H, H2-9), 2.98 (s, 3H, H3-6), 1.71-1.64 (m, 2H, H2-8), 0.99 (t, J=7.5, H3-7); δC (125 MHz, CDCl3) 172.71 (C═O), 167.66 (C═O), 149.51 (C3), 83.84 (C2), 46.01 (C9), 23.44 (C6), 21.87 (C8), 11.38 (C7); IR (film, cm−1) 3317 (m), 2944 (w), 1698 (s), 1651 (s); MS (EI) m/z (relative intensity): 168 (M+, 70), 139 (100), 111 (40); Exact Mass Calcd for [C8H12N2O2]+ requires m/z 168.0893 Found 168.0887 (EI); UV (Acetonitrile) ε210=15900, ε240=2800, ε283=500 and ε368=500 cm−1M−1 d3.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[N+:24]([O-:26])=[O:25].C(N(CC)CC)C>O1CCCC1>[C:4]([O:3][C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:19]1[CH:20]=[CH:15][C:16]([N+:24]([O-:26])=[O:25])=[CH:17][C:18]=1[N+:21]([O-:23])=[O:22])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 149.1 %

Procedure:
To a stirred solution of N-Boc-1,4-butanediamine (0.400 g; 2.12 mmol) and 1-fluoro-2,4-dinitrobenzene (280 μL; 2.23 mmol) in anhydrous tetrahydrofuran (THF) (10 mL) was added triethylamine (886 μL; 6.36 mmol). The reaction solution was stirred at ambient temperature for 17 hours and was then concentrated. The residue was dissolved in ethyl acetate and washed with water, saturated NaHCO3 and saturated NaCl. The organic solution was dried over MgSO4 and concentrated to give a yellow oil (1.12 g). Purification using a Thomson Instruments Single StEP™ silica gel column (25 g) and eluting with 20% ethylacetate/80% hexanes followed by 50% ethyl acetate/50% hexanes produced the product as a yellow oil (0.751 g, 100%). 1H NMR (d6-DMSO) 1.36 (9H, s), 1.44 (2H, m) 1.58 (2H, m), 2.93 (2H, m), 3.46 (2H, m), 6.82 (1H, t, J=5.6 Hz), 7.23 (1H, d, J=9.5 Hz), 8.27 (1H, dd, J=2.7 Hz, J=9.6 Hz), 8.85 (2H, m).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(O)C>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:22]1[N:13]=[C:12]([C:11]2[C:3]([CH3:2])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[S:14][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Cc1nn2ccccc2c1C(N)=S
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1Cl
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1ccccc1Cl
Yield: 91.8 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (300 mg, 1.3 mmol) produced in Example 11(v), ethyl 2-chloro-3-(2-chlorophenyl)-3-oxopropanoate (1.0 g, 3.9 mmol) produced above and 2-propanol (20 mL) as starting materials and in the same manner as in Example 11-B(vi), the title compound (475 mg, 91%) was obtained as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:13]2=[O:30])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[C:31]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]3([C:11]4[C:2](=[CH:3][C:4]5[O:8][N:7]=[C:6]([CH3:9])[C:5]=5[CH:10]=4)[O:1][CH2:31]3)[C:13]2=[O:30])=[CH:27][CH:26]=1
Reactant: COc1ccc(CN2C(=O)C(c3cc4c(C)noc4cc3O)c3ccccc32)cc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: COc1ccc(CN2C(=O)C3(COc4cc5onc(C)c5cc43)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(6-hydroxy-3-methyl-1,2-benzisoxazol-5-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(4-methoxybenzyl)-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 138-139° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.46 (d, J=9.0 Hz, 2H), 7.35 (d, J=9.0 Hz, 2H), 7.21-7.18 (m, 1H), 7.11-7.09 (m, 1H), 6.96 (d, J=9.0 Hz, 1H), 6.94-6.88 (m, 2H), 6.79 (d, J=9.0 Hz, 1H), 5.16-4.79 (m, 4H), 3.78 (s, 3H), 2.45 (s, 3H); MS (ES+) m/z 412.9 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=3)[C:9](=[O:25])[C:8]=2[C:7]([O:26][CH2:27][CH3:28])=[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=12)[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(O)C>O>[CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=3)[C:9](=[O:25])[C:8]=2[C:7]([O:26][CH2:27][CH3:28])=[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=12)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOc1c2c(c(OCC)c3ccccc13)C(=O)N(c1ccc(CC(=O)O)cc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
Ethyl [4-(4,9diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate (5.86 g, 13.5 mmol) and potassium carbonate (12 g) were added td a mixture of ethanol (146 ml) and water (70 ml) and heated to reflux for 2 h. The solution was cooled to room temperature and the solvent evaporated under vacuum to leave an off-white solid. The solid was slurried in water and the water was evaporated under vacuum. The residue was stirred in hydrochloric acid (2N) for 2 h, filtered and washed with water. Drying of the solid at 40° C. in a vacuum oven gave the title compound as a white solid (4.5 g, 82%)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=2)[CH:6]=[CH:7][CH:8]=1.[OH:18][C:19]1[C:24]([CH2:25][CH2:26][CH3:27])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:29](=[O:31])[CH3:30]>>[C:29]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([S:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=3)[CH:6]=[CH:7][CH:8]=2)=[C:24]([CH2:25][CH2:26][CH3:27])[C:19]=1[OH:18])(=[O:31])[CH3:30]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: N#Cc1ccc(Sc2cccc(CO)c2)cn1
Product: CCCc1c(OCc2cccc(Sc3ccc(C#N)nc3)c2)ccc(C(C)=O)c1O
Yield: 42.5 %

Procedure:
Using the method of Preparation 166 using 5-(3-(hydroxymethyl)phenylthio) picolinonitrile (1.70 g, 7.02 mmol) and 1-(2,4-dihydroxy-3-propylphenyl)ethanone (1.36 g, 7.02 mmol) affords the title compound (1.25 g, 43%). MS (APCI-neg) m/z (rel intensity): 417 (M−H, 100%).
Reaction SMILES: [CH2:1]([OH:6])[C:2]#[C:3][CH2:4][CH3:5].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[OH-].[K+]>C1COCC1.[Cl-].[Na+].O>[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13]([O:6][CH2:1][C:2]#[C:3][CH2:4][CH3:5])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC#CCO
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC#CCOS(=O)(=O)c1ccc(C)cc1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 76.4 %

Procedure:
A solution of 2-pentyn-1-ol (8.40 g, 100 mmol) in THF (60 mL) was treated with p-toluenesulfonyl chloride (23.9 g, 125 mmol) at -10° C., followed by pulverized KOH (11.3 g, 200 mmol) without allowing the temperature to exceed -5° C. After 1.5 hours of stirring at -10° C., 50 mL of saturated brine was added and the product extracted into CH2Cl2. The product, 2-pentyn-1-yl p-toluenesulphonate (2), was isolated by flash chromatography (18.17 g 76.4% yield). 1H NMR (200 MHz) δ: 7.81 (d, J=8.4 Hz, 2H, arom. CH), 7.33 (d, J=7.9 Hz, 2H, arom. CH), 4.68 (t, J=2.2, 2.2 Hz, 2H, CH2O-1), 2.44 (s, 3H, arom. CH3), 2.13 (tq, J=2.2, 2.2, 2.2, 7.5, 7.5 Hz, 2H, CH2 -4), 1.00 (t, J=7.5, 7.5 Hz, 3H, CH3 -5).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:22]([CH3:24])[CH3:23])[C:7]([N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][C:11]2([CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:10]1)=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:50][CH2:51][C:52]([C:54]1[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][CH:55]=1)=[O:53].CCN(C(C)C)C(C)C>[Cl-].[Na+].O.CN(C=O)C>[Br:60][C:57]1[CH:56]=[CH:55][C:54]([C:52](=[O:53])[CH2:51][NH:50][C:14]([CH:13]2[CH2:12][C:11]3([CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:10][N:9]2[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:22]([CH3:24])[CH3:23])=[O:16])=[CH:59][CH:58]=1
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCOCC2)CC1C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CC2(CCOCC2)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
In a 50 mL flask, 2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-8-oxa-2-azaspiro[4.5]decane-3-carboxylic acid (200 mg, 584 μmol) was combined with DMF (5.00 ml) to give a colorless solution. HATU (222 mg, 584 μmol) was added and stirred at room temperature for 10 min followed by addition of 2-amino-1-(4-bromophenyl)ethanone HCl (146 mg, 584 μmol). DIPEA (264 mg, 357 μl, 2.04 mmol) was then added dropwise and the suspension became a yellow solution once the DIPEA was added. It was stirred at room temperature for 1 hr and poured into brine solution (80 ml) and extracted with EtOAc (2×60 ml). The organic layer was washed with brine and H2O, dried with MgSO4, filtered and concentrated in vacuo to give a yellow solid. It was purified on a silica gel column (CH2Cl2, 2%, 4%, 6% MeOH/CH2Cl2) to afford methyl (2S)-1-(3-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-8-oxa-2-azaspiro[4.5]decan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate as a solid (200 mg, 63.6%). ESI-LRMS m/e calcd for C24H32BrN3O6 [M+] 538. found 539 [M+H+].
Reaction SMILES: O.O.[C:3]1([CH3:13])[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.N1C=CC=C[CH:15]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.S(OC)(OC)(=O)=O>C(Cl)Cl.C1CCCCC1>[C:3]1([CH3:13])[CH:4]=[CH:5][C:6]([S:9]([O:12][CH3:15])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccncc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: COS(=O)(=O)OC
Product: COS(=O)(=O)c1ccc(C)cc1

Procedure:
To a suspension of p-toluenesulfonic acid dihydrate (10 g, 0.05 mol) in methylene chloride (50 mL), pyridine (5.1 g, 0.06 mol) was added dropwise, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure to obtain a crude product containing pyridinium p-toluenesulfonate salt. To a suspension of this crude product (5 g, 0.020 mol) in cyclohexane (50 mL), dimethyl sulfate (5.0 g, 0.040 mol) was added, and the mixture was reacted at 80° C. for 2 hours. The reaction liquid was condensed under the reduced pressure to obtain the desired product of methyl p-toluenesulfonate. Quantitative analysis by 1H-NMR showed a conversion rate of 90%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:29])[C:5]2[C:10]([C:11]#[C:12][C@@:13]([CH3:17])([OH:16])[CH2:14][OH:15])=[CH:9][N:8]([CH2:18][C:19]3[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[CH:21][N:20]=3)[C:6]=2[N:7]=1.[CH3:30][O:31][C@@:32]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:36]([F:39])([F:38])[F:37])[C:33](Cl)=[O:34].CCN(CC)CC.CCOC(C)=O.C(Cl)Cl>C1COCC1>[F:37][C:36]([F:38])([F:39])[C@@:32]([O:31][CH3:30])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:33]([O:15][CH2:14][C@@:13]([OH:16])([CH3:17])[C:12]#[C:11][C:10]1[C:5]2[C:4]([Cl:29])=[N:3][C:2]([NH2:1])=[N:7][C:6]=2[N:8]([CH2:18][C:19]2[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[CH:21][N:20]=2)[CH:9]=1)=[O:34]
Reactant: COc1c(C)cnc(Cn2cc(C#C[C@@](C)(O)CO)c3c(Cl)nc(N)nc32)c1C
Reactant: CO[C@@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1c(C)cnc(Cn2cc(C#C[C@@](C)(O)COC(=O)[C@](OC)(c3ccccc3)C(F)(F)F)c3c(Cl)nc(N)nc32)c1C
Temperature: 40 °C

Procedure:
A mixture of (R)-4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbut-3-yne-1,2-diol (see example 53) (22 mg), (S)-(+)-α-methoxy-alpha-(trifluoromethyl)phenylacetyl chloride (45 μL), and Et3N (50 μL) in THF (3.0 mL) was heated to 40° C. overnight. Preparative TLC (EtOAc/DCM 25:65) gave the title compound, as a solid. HPLC Rt=6.44 min.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](CO)=[CH:3][N:2]=1.N1C2C(=CC=CC=2)C(CO)C=N1.CN1C2N=C(Cl)N(CC=C(C)C)C=2C(=O)NC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=[N:2]1
Reactant: OCc1cnnc2ccccc12
Agent: CC(C)=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: OCC1C=NNc2ccccc21
Solvent: C1CCOC1
Product: C1=NNc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
510 mg of a mixture of (cinnolin-4-yl)-methanol and (1,4-dihydro-cinnolin-4-yl)-methanol (see Ex. XXVII) are added to 830 mg of 3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine and 1.25 g of triphenylphosphine in 25 ml of tetrahydrofuran. The reaction mixture is combined with 0.92 ml diethyl azodicarboxylate and stirred overnight at ambient temperature. Then it is evaporated down and chromatographed through a silica gel column with ethyl acetate/petroleum ether (7:3 to 0:1) as eluant. A mixture of cinnoline and 1,4-dihydro-cinnoline compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:11]([C:18]1[S:22][C:21]([CH2:23][NH2:24])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:24][CH2:23][C:21]1[S:22][C:18]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:19][CH:20]=1)=[O:6]
Reactant: Nc1ncccc1C(=O)O
Reactant: NCc1ccc(Oc2ccccc2)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.4 %

Procedure:
To a solution of 2-aminonicotinic acid (3245 mg, 23.49 mmol) in N,N-dimethylformamide (200 mL) were added C-(5-phenoxy-thiophen-2-yl)methylamine (5305 mg, 25.84 mmol) described in Preparation Example 24, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (12.49 g, 28.19 mmol) and triethylamine (7.86 mL, 56.38 mmol), and the solution was stirred for 2 days at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate, the organic layer was sequentially washed with an aqueous solution of saturated sodium bicarbonate, water, then brine, the solvent was evaporated in vacuo, and 2-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (4999 mg, 15.36 mmol, 65%) was obtained as crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][NH:32]C(=O)OC(C)(C)C)[CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>CS(C)=O.C(N(CC)CC)C>[NH2:32][CH2:31][CH:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][CH2:8][C:9]3[NH:13][C:12]4[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=4[N:10]=3)=[O:6])=[CH:3][C:2]=2[Cl:1])=[O:23])[CH2:26]1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: NCC1CCCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)C1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, tert-butyl piperidin-3-ylmethylcarbamate, TBTU, and triethylamine in DMSO at ambient temperature followed by Boc cleaving with trifluoroacetic acid analogously to Example 17. HPLC-MS results: retention time: 2.96 minutes; C22H23Cl2N5O2 (460.36); mass spectrum: (M+H)+=460.2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[N:17]=[C:16]([NH:18][C@@H:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:20][OH:21])[C:15]([F:26])=[CH:14][N:13]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[Cl:11][C:12]1[N:17]=[C:16]([NH:18][C@@H:19]([C:22]([CH3:24])([CH3:23])[CH3:25])[CH:20]=[O:21])[C:15]([F:26])=[CH:14][N:13]=1
Reactant: CC(C)(C)[C@@H](CO)Nc1nc(Cl)ncc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[C@@H](C=O)Nc1nc(Cl)ncc1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a cold (−78° C.) solution of oxalyl chloride (1.06 mL, 12.11 mmol) in dichloromethane (10 mL) was added dimethyl sulfoxide (1.43 mL, 20.18 mmol) dropwise. After stirring the mixture for 10 minutes at −78° C., a suspension of (2S)-2-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-3,3-dimethyl-butan-1-ol, 14a, (1.0 g, 4.04 mmol) in dichloromethane (10 mL) was added. The reaction mixture was stirred for 30 minutes at −78° C. and triethylamine (3.38 mL, 24.22 mmol) was added. The mixture was slowly warmed to 0° C. over 2 hours. The mixture was diluted into aqueous saturated NaHCO3 solution and extracted twice with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-15% EtOAc/CH2Cl2 gradient) to afford 680 mg of the desired product as a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Br.ClCCl.[OH-].[Na+].[CH2:11]([OH:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:11]([O:21][CH2:1][CH:3]1[O:5][CH2:4]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCO
Reactant: BrCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCOCC1CO1

Procedure:
4.23 ml. (0.05 mole) epibromohydrin in a two-phase mixture of 150 ml. dichloromethane, 150 ml. 50% aqueous sodium hydroxide solution and 3.4 g. tetrabutylammonium hydrogen sulphate are mixed at ambient temperature with 9.52 ml. (0.05 mole) decan-1-ol and stirred overnight. The reaction mixture is then diluted with water and the organic phase is separated off, washed with water and evaporated. The oily residue is purified by column chromatography on silica gel with diethyl ether/isohexane (1:15 v/v). Yield 5.0 g. (47% of theory).