Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].C[O-].[Na+].[Cl:10][C:11]1[CH:28]=[CH:27][C:14]([C:15]([C:17]2[CH:26]=[CH:25][C:20]([CH2:21][N:22]=[N+:23]=[N-:24])=[CH:19][CH:18]=2)=[O:16])=[CH:13][CH:12]=1>C(O)C>[NH2:2][C:1]1[N:22]([CH2:21][C:20]2[CH:19]=[CH:18][C:17]([C:15](=[O:16])[C:14]3[CH:27]=[CH:28][C:11]([Cl:10])=[CH:12][CH:13]=3)=[CH:26][CH:25]=2)[N:23]=[N:24][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N#CCC(N)=O
Reactant: [N-]=[N+]=NCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1nnn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1N
Temperature: 25 °C
Yield: 11.2 %

Procedure:
To a suspension of 2-cyanoacetamide (527 mg, 6.27 mmol) in ethanol (20 ml) was added sodium methoxide (330 mg, 6.11 mmol). The mixture was refluxed 15 minutes, cooled slightly, and 4-(4-chlorobenzoyl)benzyl azide (1.24 g, 4.56 mmol) was added. The mixture was refluxed 2 hours, cooled to ambient temperature, and filtered. The filtrate was evaporated under vacuum and the residue was triturated with hot 19:1 (v/v) dichloromethane-methanol (50 ml) and filtered. The remaining solid was triturated with hot methanol (3 ml), filtered, and dried at 60° C. under vacuum to provide 182 mg (11%) of 5-amino-1-(4-[4-chlorobenzoyl]benzyl)-1,2,3-triazole-4-carboxamide, m.p. 229°-231° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][CH:21]1[CH2:27][CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:49][C:50]1[C:58](O)=[CH:57][CH:56]=[C:55]2[C:51]=1[CH:52]=[N:53][NH:54]2.Cl.O1CCOCC1>O1CCCC1.CO>[NH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:21]([O:20][C:58]2[C:50]([CH3:49])=[C:51]3[C:55](=[CH:56][CH:57]=2)[NH:54][N:53]=[CH:52]3)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCCC(O)C1
Reactant: Cc1c(O)ccc2[nH]ncc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(OC2CCCCNC2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
Under a nitrogen atmosphere, triphenylphosphine (146 mg, 0.559 mmol), tert-butyl 3-hydroxyazepane-1-carboxylate (100 mg, 0.466 mmol) and diisopropyl azodicarboxylate (101 μl, 0.512 mmol) were added at 0° C. to a solution of the 4-methyl-1H-indazol-5-ol (69 mg, 0.466 mmol) obtained in Example 402 in tetrahydrofuran (4 ml). After 30 minutes, the mixture thus obtained was warmed up to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was diluted with chloroform and washed with a 1M-aqueous sodium hydroxide solution. After the aqueous layer was re-extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). The oil thus obtained was dissolved in methanol (2 ml) at room temperature, and 4N-hydrochloric acid-dioxane (2 ml) was added thereto. After 1 hour, the mixture thus obtained was concentrated under reduced pressure and the resulting residue was dissolved in methanol (5 ml). The resulting solution was adjusted to pH 10 by dropwise addition of a 2M-aqueous sodium hydroxide solution. The solution adjusted was concentrated under reduced pressure and the resulting residue was re-dissolved in methanol (5 ml). Silica gel (1 g) was added thereto and the resulting mixture was concentrated under reduced pressure and then dried. The resulting solid was purified by a silica gel column chromatography (eluent: chloroform/methanol→chloroform/methanol (1%-aqueous ammonia)) to obtain 5-(azepan-3-yloxy)-4-methyl-1H-indazole (45.1 mg, 39%).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:32]=[CH:31][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH:59]2[CH2:61][O:60]2)=[CH:53][CH:52]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH3:30][O:29][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][NH:20][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:61][C@H:59]([OH:60])[CH2:58][O:57][C:54]4[CH:55]=[CH:56][C:51]([OH:50])=[CH:52][CH:53]=4)=[CH:32][CH:31]=3)[CH2:17][CH2:16]2)=[O:19])[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(CCNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)c1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: O=CO
Solvent: ClC(Cl)Cl
Product: COc1cccc(CCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)c1
Yield: 19.7 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(3-methoxyphenethyl)-1-piperidine-carboxamide formate (0.398 g, 0.899 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.290 g, 0.71 mmol) according to Procedure G to yield (eluant: 20:1 chloroform-methanol) the title compound (0.110 g, 0.14 mmol)
Reaction SMILES: [Li+].[OH-].[C:3]([C@@H:7]1[NH:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]2[CH:32]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:19]2=[CH:33][C:15](=[CH:16][CH:17]=[CH:18]2)[CH2:14][O:13][C@H:12]2[CH2:34][N:9]([C@H:10]([C:35]([O:37]C)=[O:36])[CH2:11]2)[C:8]1=[O:39])([CH3:6])([CH3:5])[CH3:4]>C1COCC1.CCO.O>[C:3]([C@@H:7]1[NH:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]2[CH:32]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:19]2=[CH:33][C:15](=[CH:16][CH:17]=[CH:18]2)[CH2:14][O:13][C@H:12]2[CH2:34][N:9]([C@H:10]([C:35]([OH:37])=[O:36])[CH2:11]2)[C:8]1=[O:39])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NCCCCCCc1cccc(c1)-c1cccc(c1)CO2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)[C@@H]1NCCCCCCc2cccc(c2)-c2cccc(c2)CO[C@@H]2C[C@@H](C(=O)O)N(C2)C1=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
LiOH (3.0 eq.) was added to a 0.05 M solution of methyl (9R,11S,14S)-14-tert-butyl-13-oxo-8-oxa-12,15-diazatetracyclo[20.3.1.12,6.1 9,12]octacosa-1(26),2(28),3,5,22,24-hexaene-11-carboxylate 104 in a mixture of THF:EtOH:H2O (2:1:1). The reaction mixture was stirred at 40° C. for 2 h then the solvent was evaporated under reduced pressure. Aqueous HCl (1N) was added to reach pH=6 and the mixture was evaporated to dryness to yield a dark solid which was used without further purification. MS (ES+) m/z 493 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][CH2:7][N:8]([C:11]([CH:13]3[CH2:18][O:17][CH2:16][CH2:15][O:14]3)=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.O1CCOCC1C=O.Cl[C:30]1[N:35]=[C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[S:43]([N:46]([CH3:48])[CH3:47])(=[O:45])=[O:44])[C:33]([Cl:49])=[CH:32][N:31]=1>>[Cl:49][C:33]1[C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[S:43]([N:46]([CH3:48])[CH3:47])(=[O:45])=[O:44])=[N:35][C:30]([NH:1][C:2]2[CH:20]=[CH:19][C:5]3[CH2:6][CH2:7][N:8]([C:11]([CH:13]4[CH2:18][O:17][CH2:16][CH2:15][O:14]4)=[O:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:31][CH:32]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCN(C(=O)C1COCCO1)CC2
Agent: O=CC1COCCO1
Product: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(C(=O)C2COCCO2)CC3)ncc1Cl

Procedure:
(7-Amino-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1,4-dioxinan-2-yl-methanone, prepared in a similar manner as 7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1,4-dioxinan-2-yl-methanone of Example 633b, was reacted with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide, in a similar manner as Example 601b, to yield desired product 2-{5-Chloro-2-[3-([1,4]dioxane-2-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide as a lyophylate (25%); 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.33 (s, 1H), 8.49 (bs, 1H), 8.29 (s, 1H), 7.84 (d, J=7.97 Hz, 1H), 7.71 (m, 1H), 7.41-7.32 (m, 3H), 7.07-7.01 (m, 1H), 4.39 (m, 1H), 3.78-3.49 (m, 10H), 2.87-2.77 (m, 2H), 2.65 (s, 6H); MS (m/e) 587.15 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:13]([O:14][CH2:15][O:16][CH3:17])[C@H:12]([O:18][CH2:19][O:20][CH3:21])[C@H:11]([O:22][CH2:23][O:24][CH3:25])[CH:10]([CH2:26][O:27][CH2:28][O:29][CH3:30])[O:9]2)=[CH:4][C:3]=1[CH2:31]O.C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:45].[Li+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:45][CH2:31][C:3]1[CH:4]=[C:5]([C@H:8]2[C@@H:13]([O:14][CH2:15][O:16][CH3:17])[C@H:12]([O:18][CH2:19][O:20][CH3:21])[C@H:11]([O:22][CH2:23][O:24][CH3:25])[CH:10]([CH2:26][O:27][CH2:28][O:29][CH3:30])[O:9]2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COCOCC1O[C@@H](c2ccc(Cl)c(CO)c2)[C@@H](OCOC)[C@H](OCOC)[C@@H]1OCOC
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COCOCC1O[C@@H](c2ccc(Cl)c(CBr)c2)[C@@H](OCOC)[C@H](OCOC)[C@@H]1OCOC
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a stirred solution of the product from step B (470 mg, 0.98 mmol) and triethylamine (0.54 mL, 3.90 mmol) in toluene/ethyl acetate (1:1, 12 mL) at 0° C. was added dropwise methanesulfonyl chloride (0.15 mL, 1.95 mmol). The reaction mixture was stirred at 0° C. for 2 h. The white precipitate formed during the reaction was filtered off and washed with ethyl acetate. The combined filtrate and washing were concentrated. The residual oil was dissolved in acetone (6 mL) and treated with lithium bromide (850 mg, 10.0 mmol) at 0° C. After stirring at room temperature for 1 h, the reaction was quenched with water (25 mL) and extracted with ethyl acetate (4×). The combined extracts were dried over sodium sulfate, filtered, and concentrated to give compound (2S,3R,4S,5R)-2-(3-(bromomethyl)-4-chlorophenyl)-3,4,5-tris(methoxymethoxy)-6-((methoxymethoxy)methyl)tetrahydro-2H-pyran (517 mg, 97%) as a white solid: 1H NMR (CDCl3, 500 MHz) δ 7.46 (d, J=2.0 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.30 (dd, J=8.3, 2.0 Hz, 1H), 4.91 (d, J=6.4 Hz, 1H), 4.89-4.86 (m, 2H), 4.77 (d, J=6.4 Hz, 1H), 4.66 (s, 2H), 4.60-4.55 (m, 2H), 4.54 (d, J=6.4 Hz, 1H), 4.17 (d, J=9.4 Hz, 1H), 4.13 (d, J=6.5 Hz, 1H), 3.92 (dd, J=11.2, 1.6 Hz, 1H), 3.75 (t, J=8.8 Hz, 1H), 3.71 (dd, J=11.2, 5.2 Hz, 1H), 3.63-3.58 (m, 2H), 3.52 (t, J=9.3 Hz, 1H), 3.450 (s, 3H), 3.446 (s, 3H), 3.34 (s, 3H), 2.79 (s, 3H); ESI MS m/z 543 [M+H]+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].CN(C)C=O.[CH3:12][C:13]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[N:26][O:27][CH3:28])[C:24]#[N:25]>C(OCC)(=O)C>[CH3:28][O:27][N:26]=[C:23]([C:24]1[NH:25][N:3]=[N:2][N:1]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:14]1[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:13]=1[CH3:12]
Reactant: [N-]=[N+]=[N-]
Reactant: CON=C(C#N)c1ccccc1COc1cc(C)ccc1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON=C(c1nnn[nH]1)c1ccccc1COc1cc(C)ccc1C
Temperature: 115 °C
Reaction time: 9 h
Yield: 87.4 %

Procedure:
Sodium azide (1.30 g, 20 mmol), ammonium chloride (1.07 g, 20 mmol) and dimethylformamide (10 ml) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetonitrile (0.59 g, 2 mmol), and the mixture was stirred at 115° C. for 9 hours. After completion of the reaction, ethyl acetate (150 ml) was added, and the mixture was washed with saturated brine (100 ml) twice. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl 1H-tetrazol-5-yl ketone O-methyloxime (0.59 g, 87.4%) as colorless crystals.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5](=O)[C:6]([F:9])([F:8])[F:7].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCCl.C1(C)C(C)=CC=CC=1>[F:9][C:6]([F:7])([F:8])[C:5]1[CH:4]=[CH:3][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1
Reactant: CN(C)/C=C/C(=O)C(F)(F)F
Reactant: Nc1ccccc1
Solvent: ClCCCl
Solvent: Cc1ccccc1C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: FC(F)(F)c1ccc2ccccc2n1

Procedure:
According to instructions in the literature (Baraznenok, I. L., Nenajdenko, V. G., Balenkova, E. S. Eur. J. Org. Chem. 1999, 937-941), 1.2 g (7.18 mmol) of (E)-4-(dimethylamino)-1,1,1-trifluoro-3-buten-2-one is reacted with 2.03 g (7.18 mmol) of trifluoroacetic acid anhydride and 1.30 ml (14.36 mmol) of aniline in 72 ml of 1,2-dichloroethane, then in 36 ml of xylene. After working-up and purification on silica gel with hexane-ethyl acetate (0-100%), 1.01 g (71% of theory) of the product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH:15]=[CH:14][NH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.C([C:18]([O-:20])=[O:19])C.C(O)(=O)C.[Cl:25][S:26](O)(=[O:28])=[O:27]>>[Cl:25][S:26]([C:3]1[C:2]([F:1])=[CH:11][C:10]2[NH:9][C:8](=[O:12])[C:7]3[NH:13][CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:6]=3[C:5]=2[CH:4]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(O)Cl
Reactant: CCC(=O)[O-]
Reactant: O=c1[nH]c2cc(F)ccc2c2cc[nH]c12
Solvent: CC(=O)O
Product: O=C(O)c1c[nH]c2c(=O)[nH]c3cc(F)c(S(=O)(=O)Cl)cc3c12
Temperature: 85 °C
Yield: 93.5 %

Procedure:
In a sealed tube, 601 mg (1.8 mmol) of 7-fluoro-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate cocrystallized with one equivalent of acetic acid is dissolved in 2.4 mL (36 mmol) of chlorosulfonic acid. The reaction mixture is placed on an oil bath heated beforehand to 85° C. for 2 hours, cooled on an ice bath then poured slowly onto crushed ice. The solid is filtered, rinsed with water, diisopropyl ether and pentane then dried under vacuum to give 580 mg (93%) of 8-chlorosulfonyl-7-fluoro-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:13][CH3:14])[CH:3]=1.[I:15]Cl.CC(O)=O>C(O)(=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:12]([I:15])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:13][CH3:14])[CH:3]=1
Reactant: CCOC(=O)c1ccc(N)cc1SC
Reactant: ClI
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(I)c(N)cc1SC
Temperature: 60 °C
Yield: 62.4 %

Procedure:
To a pre-heated 60° C. solution of ethyl 4-amino-2-(methylthio)benzoate (65 mmol) in acetic acid (150 mL) was added ICl/AcOH solution (1M, 72 mL, 72 mmol) dropwise during 40 min and the temperature was maintained at 60° C. for 3 h. After cooling to rt the reaction was diluted with EtOAc (500 mL) and washed with 5% sodium thiosulfate solution (3×100 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-20% EtOAc/Hexanes) to afford ethyl 4-amino-5-iodo-2-(methylthio)benzoate (13.67 g, 53% yield). For ethyl 4-amino-2-(methylthio)benzoate: LC-MS m/z 212 [M+H]+. For ethyl 4-amino-5-iodo-2-(methylthio)benzoate: LC-MS m/z 338 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H), 6.47 (s, 1H), 4.49 (br s, 2H), 4.31 (q, J=7.2 Hz, 2H), 2.38 (s, 3H), 1.37 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([O:16]C)=[N:10][C:11]([O:14]C)=[N:12][CH:13]=2)=[CH:4][CH:3]=1>CO>[ClH:1].[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9](=[O:16])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COc1ncc(-c2ccc(Cl)nc2)c(OC)n1
Solvent: CO
Product: Cl
Product: O=c1[nH]cc(-c2ccc(Cl)nc2)c(=O)[nH]1
Yield: 193.6 %

Procedure:
5-(6-Chloro-pyridin-3-yl)-2,4-dimethoxy-pyrimidine (Prep90, 4.17 mmol) was dissolved in MeOH (30 ml) and then 2N HClaq (10 ml) was added. After refluxing the reaction mixture for 4 hours, the solvent was removed under vacuum to give 1.05 g of the title compound (quantitative yield).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[C:15]([N:17]3[CH2:22][C@H:21]([CH3:23])[NH:20][C@H:19]([CH3:24])[CH2:18]3)[CH:14]=[CH:13][C:12]=2[O:25][CH3:26])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.CC(C)([O-])C.[K+]>COCCOC.O.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>[CH3:24][C@H:19]1[NH:20][C@@H:21]([CH3:23])[CH2:22][N:17]([C:15]2[CH:14]=[CH:13][C:12]([O:25][CH3:26])=[C:11]([NH:10][S:7]([C:5]3[S:6][C:2]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[F:27])=[CH:3][CH:4]=3)(=[O:9])=[O:8])[CH:16]=2)[CH2:18]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)s1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccccc2F)s1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 5-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-2-thiophenesulfonamide (E122) (150 mg, 0.33 mmol) and (2-fluorophenyl)boronic acid (91 mg, 0.65 mmol) in DME (3 ml) was added potassium tert-butoxide (329 mg, 2.94 mmol) and tetrakis(triphenylphosphine)palladium(0) (37 mg, 0.033 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then reduced in vacuo, azeotroped with toluene (×3) and purified using SCX then mass directed autoprep HPLC to afford the title product (E124). MS (ES+) m/e 476 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:16]=[C:4]2[N:3]=1.O.[NH2:25][NH2:26]>O1CCOCC1>[CH3:23][C:20]1[N:19]=[CH:18][C:17]([C:15]2[CH:16]=[C:4]3[N:3]=[C:2]([NH:25][NH2:26])[CH:7]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:5]3[N:14]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)cn1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cc3nc(NN)cc(N4CCOCC4)n3n2)cn1
Reaction time: 15 h
Yield: 27 %

Procedure:
There was suspended, in 1,4-dioxane (24 mL), 5-chloro-2-(6-methyl-pyridin-3-yl)-7-morpholin-4-yl-pyrazolo[1,5-a]-pyrimidine (0.79 g, 2.4 mM) prepared in the preceding step 1, then hydrazine monohydrate (1.2 mL, 24 mM) was added to the suspension and the mixture was stirred for 15 hours, while refluxing the same with heating. After the stirring operation, the reaction liquid was concentrated, the concentrate was diluted with water and then extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate and then the solvent was distilled off to thus give a crude product of the title compound (210 mg, yield: 27%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[CH2:3][OH:4].[N:14]#[C:15]Br>>[C:8]1([CH:6]([CH3:7])[CH2:5][C@H:2]2[CH2:3][O:4][C:15]([NH2:14])=[N:1]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#CBr
Reactant: CC(C[C@H](N)CO)c1ccccc1
Product: CC(C[C@H]1COC(N)=N1)c1ccccc1

Procedure:
In analogy to example 1b (S)-2-amino-4-phenyl-pentan-1-ol was reacted with cyanogen bromide to give (S)-4-(2-phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine. Off-white waxy solid.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC.[N:37]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.O>CN(C=O)C>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:43]([N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:44])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N1CCCCC1)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of the compound (100 mg) obtained in Example 1 and Et3N (70 mg). in DMF (5.0 ml), piperidine-1-carbonyl chloride (44 mg) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 3% potassium hydrogensulfate solution and saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate) to obtain the title compound as pale yellow oil (0.11 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O)(=O)=[O:16]>>[CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][OH:16])=[O:10])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CS(=O)(=O)O
Product: CS(=O)(=O)c1ccc(C(=O)OO)cc1

Procedure:
A stirred mixture of 5 g of 4-(methylsulfonyl)-benzoic acid and 50 mL of methanesulfonic acid froze when it was cooled in an ice bath. The ice bath was removed and when the mixture was partially melted, stirring was resumed and the addition of 2.83 g of 90% hydrogen peroxide was started. The 90% hydrogen peroxide was added gradually over ten minutes. When the addition of the hydrogen peroxide was completed, the reaction mixture was still partially frozen. A water bath of cold tap water was used to warm the reaction mixture. The temperature of the reaction mixture rose briefly to 28° C. One hour after the addition of the hydrogen peroxide was started, the reaction mixture was heated for 70 minutes within a temperature range of 40° C.-45° C. The stirred reaction mixture was then cooled in an ice bath. A solid precipitated from solution. When the temperature of the reaction mixture was between 10° C.-15° C., the solid product was filtered from solution. A second fraction of solid product was collected when the filtrate was poured onto ice prepared from deionized water and the solid which formed was filtered away from solution. Fraction one was washed four times with 60 mL each time of cold deionized water. Fraction two was washed four times with 150 mL each time of cold deionized water. Both fractions of the solid product were very easy to wash and to isolate by filtration. The two fractions were each transferred to a watchglass and dried overnight. The dried solids were fine, dry powders.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:18]=1[CH2:19][N:20]1[CH:24]=[CH:23][C:22]([NH2:25])=[N:21]1>>[Cl:16][C:17]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:18]=1[CH2:19][N:20]1[CH:24]=[CH:23][C:22]([NH:25][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:21]1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1ccn(Cc2ccc(Cl)cc2Cl)n1
Product: Cc1cn(-c2ccc(Nc3ccn(Cc4ccc(Cl)cc4Cl)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(2,4-dichloro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a light yellow solid (Yield=72%). MS ISP (m/e): 423.1 (100) [(M+H)+].