Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[S:19][CH:20]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.C1COCC1.[OH-].[Na+]>O>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[S:19][CH:20]=3)=[CH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cc(-c2cn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(-c2cn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Temperature: 90 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a solution of methyl 4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)thiophene-2-carboxylate (27.0 mg) obtained in Example 3 in a mixed solvent of methanol (2 mL)/THF (2 mL)/water (2 mL) was added 8N aqueous sodium hydroxide solution (0.025 mL) at 0° C. The reaction mixture was stirred at 90° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.1N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (26.0 mg).
Reaction SMILES: [C:1]([C:4]1[NH:8][C:7]2[C:9]([Cl:13])=[C:10]([Cl:12])[S:11][C:6]=2[CH:5]=1)([OH:3])=O.[C:14]([O:18][C:19](=[O:32])[NH:20][CH2:21][C@H:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][C@H:23]1[NH2:31])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:14]([O:18][C:19](=[O:32])[NH:20][CH2:21][C@H:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][C@H:23]1[NH:31][C:1]([C:4]1[NH:8][C:7]2[C:9]([Cl:13])=[C:10]([Cl:12])[S:11][C:6]=2[CH:5]=1)=[O:3])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1c2ccccc2C[C@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.7 %

Procedure:
5-Carboxy-2,3-dichloro-4H-thieno[3,2-b]pyrrole (Method 4, 472 mg, 2.0 mmol), tert-butyl[(1R,2R)-2-amino-2,3-dihydro-1H-inden-1-yl]methylcarbamate (Method 13; 524 mg, 2.0 mmol), DIPEA (348 μL, 2.0 mmol), HOBT (270 mg, 2.0 mmol) and EDCI (480 mg, 2.5 mmol) were dissolved in DCM (10 mL) and stirred at ambient temperature for 20 hours. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (50 mL), washed with water (3×25 mL), brine (25 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (900 mg, 93%) as a pale brown foam.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([C:13]3[N:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=4)[C:23]#[N:24])[O:15][N:14]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[S:30](N)([NH2:33])(=[O:32])=[O:31].CCN(C(C)C)C(C)C>O1CCOCC1>[C:23]([C:22]1[CH:25]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH2:10][CH2:11][CH2:12][C@H:3]4[NH:2][S:30]([NH2:33])(=[O:32])=[O:31])[N:17]=2)[CH:19]=[CH:20][C:21]=1[O:26][CH:27]([CH3:29])[CH3:28])#[N:24]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4N)no2)cc1C#N
Reactant: NS(N)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4NS(N)(=O)=O)no2)cc1C#N
Temperature: 110 °C
Yield: 41.9 %

Procedure:
Prepared using General Procedure 5: To a stirring solution of (R)-5-(3-(5-amino-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile HCl 3 (50 mg, 0.12 mmol) in dioxane (3 mL) were added sulfamide (58 mg, 0.61 mmol) and DIEA (47.2 μL, 0.37 mmol) and the mixture was heated to 110° C. for 14 h. The solvent was evaporated and the residue was purified by preparative HPLC to provide 22.8 mg (42%) of (R)-N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)sulfamide 26. LCMS-ESI (m/z) calculated for C22H23N5O4S: 453.5; found 454.1 [M+H]+, tR=3.47 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.2 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 7.97 (dd, J=7.7, 1.2 Hz, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 4.78 (ddd, J=13.4, 11.7, 5.7 Hz, 2H), 4.59 (d, J=19.8 Hz, 2H), 4.55 (d, J=8.2 Hz, 1H), 3.19 (dt, J=18.0, 5.6 Hz, 1H), 3.02 (dt, J=18.2, 7.2 Hz, 1H), 2.23-2.03 (m, 2H), 1.92 (dt, J=12.4, 6.3 Hz, 2H), 1.48 (d, J=6.1 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[C@@H:3]([C:15]([OH:17])=O)[N:4]2[CH2:9][C@@H:7]([CH:8]=1)[N:6]([O:10][CH2:11][CH:12]=[CH2:13])[C:5]2=[O:14].[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C)C=O>[CH3:1][C:2]1[C@@H:3]([C:15]([NH:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]2)=[O:17])[N:4]2[CH2:9][C@@H:7]([CH:8]=1)[N:6]([O:10][CH2:11][CH:12]=[CH2:13])[C:5]2=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: C=CCON1C(=O)N2C[C@H]1C=C(C)[C@H]2C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCON1C(=O)N2C[C@H]1C=C(C)[C@H]2C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.4 %

Procedure:
Into a 100-mL round-bottom flask, was placed N,N-dimethylformamide (20 mL), crude of (2S,5R)-3-methyl-7-oxo-6-(prop-2-en-1-yloxy)-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxylic acid (Intermediate 150, 700 mg, 2.94 mmol, 1.00 equiv), tert-butyl 4-aminopiperidine-1-carboxylate (1.17 g, 5.84 mmol, 1.99 equiv), HATU (1.67 g, 4.39 mmol, 1.49 equiv), DIEA (1.51 g, 11.68 mmol, 3.98 equiv) at 0° C. The resulting solution was stirred for 12 h at 25° C. The resulting solution was diluted with 150 mL of ethyl acetate and it was washed with 3×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5-1:2). This resulted in 0.500 g (40%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:40][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 14.5 g 4-{(S)-4-tert-butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 110 ml DMF were added 4.5 ml benzyl bromoacetate and 17.8 g cesium carbonate. After stirring at RT for 12 h the solution was reduced to a volume of 50 ml, diluted with 400 ml ethyl acetate and extracted with aqueous LiCl (4% w/w). The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica eluting with a gradient of n-heptane/ethyl acetate.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:19]=O)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([S:8][CH:9]([CH2:19][N:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC(C=O)SCc1ccccc1
Reactant: C1CSCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(CN1CCSCC1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of tert-butyl [2-(benzylthio)-3-oxopropyl]carbamate (820 mg) in tetrahydrofuran (30 mL) was added thiomorpholine (0.42 mL), and the mixture was stirred at room temperature for 1 hr. Sodium triacetoxyborohydride (1.76 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give the title compound (936 mg, yield 91%) as a colorless oil from a fraction eluted with ethyl acetate-hexane (3:7).
Reaction SMILES: C1(S([N:10]2[CH2:17][CH:16]3[N:18]([CH3:19])[CH:12]([CH2:13][O:14][CH2:15]3)[CH2:11]2)(=O)=O)C=CC=CC=1.C1(C)C=CC=CC=1.[ClH:27]>C1(C)C(C)=CC=CC=1>[ClH:27].[CH3:19][N:18]1[CH:12]2[CH2:11][NH:10][CH2:17][CH:16]1[CH2:15][O:14][CH2:13]2
Reactant: CN1C2COCC1CN(S(=O)(=O)c1ccccc1)C2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: CN1C2CNCC1COC2
Temperature: 140 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
To a mixture of the above described 7-benzenesulfonyl-9-methyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (880 mg, 3.177 mmol) in xylene (20 ml) was added sodium dihydro-bis(2-methoxyethoxy)aluminate in toluene (2.423 ml, 7.947 mmol) and the mixture was stirred at 140° C. for 18 h. Cooled to 23° C., poured into 2 M HCl, extracted twice with tert-butyl methyl ether, the aqueous layer was made alkaline with 10 M NaOH-sol., extracted twice with tert-butyl methyl ether, the combined organic layer was dried over sodium sulfate, filtered, to the filtrate was added ethanol (5 ml) and chlorotrimethylsilane (ca. 0.5 ml) and all volatiles were removed in vacuum to give the title compound as a colorless oil (190 mg, 43%), MS (ISP) m/e=143.2 [(M+H)+].
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([C:19]([CH2:23][CH2:24][CH3:25])=[CH:20][CH2:21][CH3:22])=[CH:13][N:12]=1)[CH3:2]>CO.[Pd]>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([CH:19]([CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH3:25])=[CH:13][N:12]=1)[CH3:10]
Reactant: CCC=C(CCC)c1cnc(-c2c(CC)cccc2CC)cc1OC
Agent: [Pd]
Solvent: CO
Product: CCCC(CCC)c1cnc(-c2c(CC)cccc2CC)cc1OC

Procedure:
A mixture of 2-(2,6-diethyl-phenyl)-4-methoxy-5 (1-propyl-but-1-enyl)-pyridine (20 mg) and 10% Pd/C (20 mg) in MeOH (1 mL) is hydrogenated at 50 psi overnight. The mixture is filtered through celite and washed with MeOH. The filtrate is concentrated to give 2-(2,6-diethyl-phenyl)-4-methoxy-5-(1-propyl-butyl)-pyridine. 1H NMR (CDCl3) 8.29 (s, 1H), 7.26 (d, 1H), 7.13 (d, 2H), 6.71 (s, 1H), 3.81 (s, 3H), 3.00 (m, 1H), 2.37 (m, 4H), 1.65 (m, 4H), 1.23 (m, 4H), 1.07 (t, 6H), 0.86 (t, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:28]>>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[NH:28])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N
Reactant: Fc1ccc(NC(=S)Nc2ncccc2OCc2c(F)cccc2Cl)cc1
Product: N=C(Nc1ccc(F)cc1)Nc1ncccc1OCc1c(F)cccc1Cl

Procedure:
A mixture of yellow men:uric oxide (0.65g, 0.003 mol), N-[3-(2-chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-4-fluorophenylthiourea (1 .0g, 0.0025 mol) and methanolic ammonia solution (30 ml) was stirred for 3 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by recrystallisation from ethanol gave the desired product. Yield 0.38 g, (40%), m.p. 152°-154 ° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:49][N:50]([CH3:54])[C:51](Cl)=[O:52]>CN(C=O)C>[CH3:49][N:50]([CH3:54])[C:51]([N:22]1[CH2:21][CH2:20][CH:19]([N:14]2[CH2:13][C:12]3[C:16](=[CH:17][C:9]([NH:8][C:5]4[N:4]=[C:3]([NH:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[C:2]([Cl:1])=[CH:7][N:6]=4)=[C:10]([O:25][CH:26]([CH3:28])[CH3:27])[CH:11]=3)[C:15]2=[O:18])[CH2:24][CH2:23]1)=[O:52]
Reactant: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCNCC1)C2
Reactant: CN(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCN(C(=O)N(C)C)CC1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-one (Example 1, 20 mg, 0.033 mmol) and triethylamine (23 uL, 0.165 mmol) in DMF (1.5 mL) is added dimethylcarbamyl chloride (11 mg, 0.1 mmol). The mixture is stirred at room temperature for 1 hour. The reaction is filtered and the filtrate is purified by mass-trigger preparative RP LC-MS to afford the title compound 4-(6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid dimethylamide (155) as a white solid: 1H NMR (400 MHz, MeOD-d4) δ 8.29 (s, 1H), 8.26 (br, 1H), 7.96 (dd, 1H), 7.93 (s, 1H), 7.72(dd, 1H), 7.48 (dd, 1H), 7.35 (s, 1H), 4.50 (s, 2H), 4.35-4.29 (m, 1H), 3.83 (d, 2H), 3.38-3.30 (m, 2H), 3.02-2.95 (m, 3H), 2.88 (s, 6H), 1.88-1.84 (m, 3H), 1.36 (d, 6H), 1.25 (d, 6H); ESMS m/z 670.2 (M+H+).
Reaction SMILES: [CH3:1][Si:2]1([CH3:8])[CH2:7][CH2:6][CH2:5][CH2:4][O:3]1.[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].[C:14]1([CH:21]=[CH:20][C:18]([OH:19])=CC=1)O.S(=O)(=O)(O)O>C1CCCCC1>[C:9]([O:13][CH2:4][CH2:5][CH2:6][CH2:7][Si:2]([CH3:8])([CH3:1])[O:3][Si:2]([CH3:7])([CH3:1])[CH2:14][CH2:21][CH2:20][CH2:18][O:19][C:4](=[O:3])[CH:5]=[CH2:6])(=[O:12])[CH:10]=[CH2:11]
Reactant: C[Si]1(C)CCCCO1
Reactant: C=CC(=O)O
Reactant: Oc1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: C1CCCCC1
Product: C=CC(=O)OCCCC[Si](C)(C)O[Si](C)(C)CCCCOC(=O)C=C
Temperature: 100 °C
Reaction time: 6 h

Procedure:
523.8 g. 1,1-dimethyl-1-sila-2-oxacyclohexane (4.0 moles), 304.7 g. acrylic acid (4.2 moles), 1.0 g. hydroquinone, 13.5 ml concentrated sulfuric acid, and 1200 ml cyclohexane are measured into a 3 liter reactor. The mixture is stirred during heating. The mixture is heated with steam (100° C.) and kept under dry air. Water formed during the reaction is removed continuously as the cyclohexane and water azeotrope. After 6 hrs. of heating, 31.9 ml water is collected and heating is stopped. The solution is then column filtered over 1 kg. activated alumina and filtered again over 740 g. grade 12 silica gel. The cyclohexane is removed from the product by rotary evaporation at reduced pressure. 1,3-bis (4-acryloxy butyl) tetramethyl disiloxane is obtained. The product is 98.3% pure by gas chromatography. The identity of the product is confirmed by infrared spectrum and elemental analysis. The analysis results are 55.96% C, 9.26% H, and 13.85% Si.
Reaction SMILES: [CH2:1]([C:4]1([S:7]([O-:10])(=O)=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[K+].S(Cl)([Cl:14])=O>CN(C=O)C>[CH2:1]([C:4]1([S:7]([Cl:14])(=[O:10])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(S(=O)(=O)[O-])CC1
Reactant: O=S(Cl)Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCC1(S(=O)(=O)Cl)CC1

Procedure:
A solution of potassium 1-allylcyclopropane-1-sulfonate (3.44 g, 17.2 mmol), thionyl chloride (10 ml) and DMF (5 drops) was refluxed at 60° C. for 16 h. The volatiles evaporated under reduced pressure and the residue extracted with CH2Cl2 (50 ml). The extract was washed with water, dried (MgSO4) and evaporated to obtain the crude product as yellow gummy oil which was washed with hexane and used in the next reaction without further purification (2.7 g, 15 mmol, 87%).
Reaction SMILES: O[CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9].C(N(CC)CC)C.CS([Cl:38])(=O)=O.O>O1CCCC1>[Cl:38][CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9]
Reactant: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1CO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1CCl
Temperature: 25 °C
Reaction time: 10 h
Yield: 85 %

Procedure:
To a solution of 2-(hydroxymethyl)-N-methyl-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-3-sulfonamide (405 mg) and triethylamine (167 μL) in tetrahydrofuran (5 mL) was added methanesulfonyl chloride (93 μL). The reaction mixture was stirred at room temperature for 10 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was crystallized from diethyl ether-hexane to give the title compound (360 mg, yield 85%) as colorless crystals. melting point 190° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23].C(Cl)(=O)C1C=CC=CC=1>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([C:18]([F:17])([F:28])[F:29])[CH:20]=2)[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Solvent: O=C(Cl)c1ccccc1
Product: NC(=O)c1c(NC(=O)c2cccc(C(F)(F)F)c2)ncn1Cc1ccccc1
Yield: 92 %

Procedure:
out under the same conditions as in Example 1, using 2.16 g (9.99 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide which was prepared in the same manner as in Reference Example 2 and 3-trifluoromethylbenzoyl chloride, instead of benzoyl chloride, to obtain 3.56 g 1-benzyl-4-(3-trifluoromethylbenzoylamino)-5-imidazolecarboxamide (yield 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[C:24]([NH:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:22]=2)[CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)cn2)c1

Procedure:
N-tert-Butyl-3-{1-[6-(4-fluoro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(4-fluoro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.79) (0.25 g, 0.57 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.175 g, 0.68 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.52 g) which was subsequently deprotected.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]([CH2:32]C(Cl)=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:36]([NH2:40])([CH3:39])([CH3:38])[CH3:37]>>[CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15](=[O:17])[CH2:32][O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:12]([C:22]([NH:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:24])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: O=C(Cl)COc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)C[C@H]1C(=O)O
Product: CC(C)(C)NC(=O)[C@@H]1CC(=NOCc2ccccc2)CN1C(=O)COc1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, phenoxyacetyl chloride, and tert-butylamine the title compound was obtained in 100% purity by LC/MS. MS(ESI+): m/z=424.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[O:5][C:4](=[O:13])[C:3]=1[C:14](=[O:17])[CH2:15][CH3:16].[Na].C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH:11]=[O:12])[O:5][C:4](=[O:13])[C:3]=1[C:14](=[O:17])[CH2:15][CH3:16]
Reactant: CCC(=O)c1c(O)cc(CCCCO)oc1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)c1c(O)cc(CCCC=O)oc1=O
Temperature: 28 °C
Reaction time: 3 h

Procedure:
To 4-hydroxy-6-(4-hydroxybutyl)-3-propionyl-2H-pyran-2-one (XV; 1.47 g; 6.12 mmol) in 60 ml CH2Cl2 and 2.19 ml pyridine, was added sodium periodinate (6.13 g; 15.3 mmol; Aldrich). The reaction was stirred at 28° C. for 3 h, neutralized with saturated NaHCO3, extracted with 3×150 ml CH2Cl2, dried with brine and Na2SO4, and evaporated. The product was purified via silica flash chromatography (20% EtOAc in hexanes).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH3:23])[N:15]=[C:14]([NH:24][CH3:25])[N:13]=2)[CH:9]=[C:8](F)[C:5]=1[C:6]#[N:7])[CH3:2].CCO.CCN(C(C)C)C(C)C.[NH2:39][NH2:40]>O>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH3:23])[N:15]=[C:14]([NH:24][CH3:25])[N:13]=2)[CH:9]=[C:8]2[C:5]=1[C:6]([NH2:7])=[N:39][NH:40]2)[CH3:2]
Reactant: NN
Reactant: CCOc1cc(-c2cc(N3CCC[C@H]3C)nc(NC)n2)cc(F)c1C#N
Solvent: O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(-c2cc(N3CCC[C@H]3C)nc(NC)n2)cc2[nH]nc(N)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
In a sealable tube, 2-(ethyloxy)-6-fluoro-4-{2-(methylamino)-6-[(2R)-2-methyl-1-pyrrolidinyl]-4-pyrimidinyl}benzonitrile (87 mg, 0.245 mmol), EtOH (5 mL), Hunig's base (0.046 mL, 1.469 mmol), and hydrazine anhydrous (0.043 mL, 0.245 mmol) were added, and the yellow suspension mixture was heated at 100° C. overnight in an oil bath. After overnight, there was a yellow solution as well as a little amount of white colored solid formed. LCMS showed no more starting material. The reaction was cooled to room temperature. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was purified by flash column chromatography. The fractions containing product were combined, and the solvent was removed under reduced pressure to afford the title compound (48 mg) as a white solid. LC-MS (ES) m/z=368 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.21 (d, J=6.1 Hz, 3H), 1.44 (t, J=7.0 Hz, 3H), 1.66 (m, 1H), 2.02 (m, 3H), 2.82 (d, J=4.8 Hz, 3H), 3.56 (m, 1H), 4.12-4.24 (q, J=7.1 Hz, 2H), 4.99 (s, 2H), 6.19 (s, 1H), 6.32-6.51 (m, 1H), 6.87-6.98 (m, H), 7.41-7.56 (m, 1H), 11.50 (s, 1H).