Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](Cl)=[O:11])=[CH:6][CH:5]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[N:28][C:29]=3[NH2:31])[N:24]([C@H:32]3[CH2:37][CH2:36][C@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:23]=2)=[CH:18][C:17]=1[O:45][CH3:46]>ClCCl.N1C=CC=CC=1>[NH2:31][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:24]([C@H:32]3[CH2:37][CH2:36][C@H:35]([N:38]4[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]4)[CH2:34][CH2:33]3)[N:23]=[C:22]([C:19]3[CH:20]=[CH:21][C:16]([NH:15][C:10](=[O:11])[C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=4)=[C:17]([O:45][CH3:46])[CH:18]=3)[C:30]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(Trifluoromethoxy)-1-benzenecarbonyl chloride (283 mg, 1.256 mmol) in dichloromethane (1 mL) was added to a solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.145 mmol) in pyridine (8 mL) at 0° C. After 30 minutes, the ice bath was removed the reaction mixture was stirred at room temperature for 1.5 hour. Solvent was evaporated and the residue was purified by flash column chromatography using dichloromethane/methanol (80:20) as mobile phase to give trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide (526 mg, 74%). 1H NMR (CDCl3) δ 1.57 (m, 2H), 1.74 (m, 2H), 2.10-2.27 (m, 6H), 2.30 (s, 3H), 2.51 (m, 4H), 2.66 (m, 3H), 4.03 (s, 3H), 4.77 (m, 3H), 5.56 (bs, 2H), 7.26-7.37 (m, 4H), 7.99 (m, 2H), 8.38 (s, 1H), 8.59 (s, 1H), 8.67 (d, J=8.21 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14](I)[CH:13]=3)[C:6]=2[N:5]=[CH:4]1)[CH3:2].CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)O1>>[CH2:1]([N:3]1[C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:28]4[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=4)[CH:13]=3)[C:6]=2[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc2c(-c3ccc(F)c(I)c3)cnnc21
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Product: CCn1cnc2c(-c3ccc(F)c(-c4ccc(S(N)(=O)=O)cc4)c3)cnnc21
Yield: 57 %

Procedure:
Prepared according to the method described above for Example 1 using 7-ethyl-4-(4-fluoro-3-iodophenyl)-7H-imidazo[4,5-c]pyridazine (Preparation 10) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (Preparation 80) to afford the title compound in 57% yield, 24.8 mg.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:5]2[CH:12]=[C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[S:14][C:4]=2[C:3]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)=[O:29].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:22]1([C:3]2[C:4]3[S:14][C:13]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])=[CH:12][C:5]=3[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]=2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:28]=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: O=Cc1ccccc1B(O)O
Reactant: COC(=O)Cn1c(Br)c(C2CCCCC2)c2sc(C(=O)OC(C)(C)C)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)Cn1c(-c2ccccc2C=O)c(C2CCCCC2)c2sc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Yield: 68 %

Procedure:
tert-Butyl 5-bromo-6-cyclohexyl-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1 eq., from Step 3) and 2-formyl-phenylboronic acid (1.5 eq.) were dissolved in dioxane (0.1 M) and treated with 2 M Na2CO3 solution (2 eq.). The solution was degassed by bubbling argon through it and Pd(PPh3)2Cl2 (0.1 eq.) was added. The reaction mixture was heated to reflux for 20 min then allowed to cool down to RT, diluted with EtOAc and washed with 1 N hydrochloric acid and with brine. The organic layer was dried over sodium sulfate, evaporated in vacuo and the residue purified by chromatography (PE:EtOAc, 9:1) to afford the pure title compound (68%) as a solid. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 9.70 (s, 1H), 7.96 (dd, J 7.7, 1.3, 1H), 7.91 (s, 1H), 7.84 (dt, J 7.6, 1.5, 1H), 7.80 (t, J 7.7, 1H), 7.47 (d, J 7.6, 1H), 4.93 (d, J 18.2, 1H), 4.76 (d, J 18.2, 1H), 3.48 (s, 3H), 2.15-2.08 (m, 1H), 1.73-1.02 (m, 10H), 1.52 (s, 9H). MS (ES+) m/z: 482 [M+H]+.
Reaction SMILES: [C:1](=[O:12])([S:9][CH2:10][CH3:11])[O:2][O:3][CH:4](Cl)[CH2:5][CH2:6][CH3:7].[CH:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[C:1](=[O:12])([S:9][CH2:10][CH3:11])[O:2][O:3][CH:4]([O:20][C:18]([CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19])[CH2:5][CH2:6][CH3:7]
Reactant: O=C(O)C1CCCC1
Reactant: CCCC(Cl)OOC(=O)SCC
Product: CCCC(OOC(=O)SCC)OC(=O)C1CCCC1
Temperature: 75 °C
Reaction time: 120 h
Yield: 82.5 %

Procedure:
A mixture of (66) (1.33 g, 6.76 mmol) and cyclopentancarboxylic acid (1.30 g, 10.1 mmol) was stirred at 75° C. for five days. The reaction was then cooled to room temperature and partitioned between water and ether. The ether layer was washed with brine, dried over anhydrous Na2SO4. Filtration then removal of the solvent by rotary evaporation gave the title thiocarbonate (67) (1.62 g, 86%). 1H NMR (CDCl3, 400 MHz): δ 0.95 (t, 3H), 1.20–1.85 (m, 15H), 2.68 (m, 1H), 2.82 (m, 2H). 6.84 (t, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18](O)=O)=[N:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[OH:35][N:36]=[C:37]([NH2:49])[C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][C:39]=1[C:45]([F:48])([F:47])[F:46]>CN(C)C=O>[C:1]1([C:7]2[C:8]([C:18]3[O:35][N:36]=[C:37]([C:38]4[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][C:39]=4[C:45]([F:47])([F:46])[F:48])[N:49]=3)=[N:9][O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(N)=NO)c(C(F)(F)F)c1
Reactant: O=C(O)c1noc(-c2ccccc2)c1-c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc(-c2noc(-c3noc(-c4ccccc4)c3-c3ccccc3)n2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
A 2 dram reaction vial containing a stir bar was charged with 4,5-diphenylisoxazole-3-carboxylic acid (17-B, 48.6 mg, 0.183 mmol), EDC (43.9 mg, 0.229 mmol), HOBT (35.1 mg, 0.229 mmol), and dimethylformamide (1 mL). The vial was flushed with dry nitrogen, sealed, and the reaction was stirred at room temperature for 30 minutes. N′-Hydroxy-4-methyl-2-(trifluoromethyl)benzimidamide (40.0 mg, 0.183 mmol) was introduced. The vial was flushed with dry nitrogen, sealed, stirred at room temperature for 30 minutes, and then placed on a reactor block set to 60° C. overnight. Water was added dropwise (−0.5 mL) until the solution remained cloudy, and then the reaction was cooled to room temperature. Additional water (5 mL) was added after cooling, and the reaction was placed in a sonicator bath for 60 min. A gummy solid formed on the side of the flask and stir bar. The aqueous solution was decanted and the residue washed with water and then partially dried under a stream of air. The gummy solid was dissolved in methanol (1-2 mL), transferred, and evaporated to dryness to give a pale yellow solid The pale yellow solid was purified by flash chromatography (12 g Isco silica gel). Elution with dichloromethane afforded the major product. The product containing fractions were evaporated to afford 5-(4,5-diphenylisoxazol-3-yl)-3-(4-methyl-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (24 mg) MS M+1=448.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])[C:3]=1[CH2:22][OH:23].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:31]([O:23][CH2:22][C:3]1[C:4]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: O=C1c2cc3c(n2CCN1c1nccc(Cl)c1CO)CCCC3
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1c(Cl)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a mixture of 113g (900 mg, 2.7 mol) and triethylamine (900 mg, 9.0 mol) in dichloromethane (5 mL) was added dropwise acetyl chloride (600 mg, 6.0 mol) while stirring at room temperature and stirred for another 1 h. The reaction mixture was concentrated and purified by silica-gel column chromatography eluting with dichloromethane to afford 113h as white solid (950 mg, 94%). MS: [M+H]+ 374.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24]>CCCCCC>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH2:25])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: Nc1ccccc1NS(=O)(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
The title compound was prepared according to General Method C using 4-phenoxyphenylsulfonyl chloride (969 mg, 3.6 mmol) and o-phenylenediamine (300 mg, 2.77 mmol). The reaction mixture was partitioned between water (200 ml) and toluene:methylene chloride (1:3). The organic phase collected and the methylene chloride evaporated leaving the toluene. Hexane added and the product precipatated from solution. (317 mg, 34%) EI-MS m/z 341 (M+H)+
Reaction SMILES: [ClH:1].C([N:9]1[CH2:15][CH2:14][C:13](=[O:16])[NH:12][CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C.CO.[C].[Pd]>[ClH:1].[NH:9]1[CH2:15][CH2:14][C:13](=[O:16])[NH:12][CH2:11][CH2:10]1
Reactant: O=C1CCN(Cc2ccccc2)CCN1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: O=C1CCNCCN1
Yield: 96 %

Procedure:
1M HCl in ethanol (7.2 mL) and 10% palladium-carbon (0.34 g) were added to 1-benzylhexahydro-1H-1,4-diazepin-5-one (1.490 g) in methanol (10 mL) at room temperature, and the resultant mixture was stirred in a hydrogen atmosphere for 4 hours. After the reaction atmosphere was purged with nitrogen, insoluble matter was removed by filtration. The solvent of the filtrate was evaporated under reduced pressure, and diethyl ether was added to the residue, and then the precipitated solid was recovered by filtration, to thereby give the title compound (1.045 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:12][C:13]([F:26])([F:25])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22]>CN(C1C=CN=CC=1)C>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][C:13]([F:12])([F:25])[F:26])(=[O:23])=[O:22])[CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1ccccc1OC(F)(F)F
Yield: 59 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.69 mmol), 2-trifluoromethoxybenzenesulfonyl chloride (200 mg, 0.69 mmol) and DMAP (cat.) gave the title compound (150 mg, 60%) after column purification with DCM elution.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:12]=[N:13][CH:14]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]cn2)cc1
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cncc1-c1ccc([N+](=O)[O-])cc1
Yield: 62.6 %

Procedure:
Reaction of 4-(4-nitrophenyl)-1H-imidazole (160 mg, 0.85 mmol), NaH (60%, 33 mg, 0.82 mmol), and SEMCl (158 uL, 0.89 mmol) followed by column chromatography on silica gel (hexane/EtOAC 3:2) gave the title compound (170 mg, 65%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.94 (t, 2H, J=7.5 Hz), 3.55 (t, 2H, J=7.5 Hz), 5.33 (s, 2H), 7.50 (s, 1H), 7.69 (s, 1H), 7.94 (d, 2H, J=6.0 Hz), 8.26 (d, 2H, J=6.0 Hz).
Reaction SMILES: [Br:1][CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[CH3:8][N:9]([CH3:20])[N:10](C1C=CC=CC=1)[C:11](=O)[O-:12]>N1C=CC=CC=1>[Br:1][CH:2]1[CH2:6][CH2:5][N:4]([C:11](=[O:12])[NH:10][N:9]([CH3:20])[CH3:8])[C:3]1=[O:7]
Reactant: O=C1NCCC1Br
Reactant: CN(C)N(C(=O)[O-])c1ccccc1
Solvent: c1ccncc1
Product: CN(C)NC(=O)N1CCC(Br)C1=O
Yield: 63.7 %

Procedure:
Substantially in the same manner as in Example 39 (1), 8.2 g (50 mmol) of 3-bromopyrrolidin-2-one and 9.91 g (55 mmol) of N-dimethylaminophenylcarbamate in 100 ml of pyridine were treated to give 7.96 g of the objective compound as white crystal in 63.6% yield.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:16])[CH:12]=2)[CH:7]=1)=[O:5].CC(C[AlH]CC(C)C)C.Cl>C1COCC1>[Br:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([CH:4]=[O:5])[CH:15]=[CH:14]2
Reactant: CON(C)C(=O)c1ccc2cc(Br)ccc2c1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ccc2cc(Br)ccc2c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-bromo-naphthalene-2-carboxylic acid methoxy-methyl-amide (Step c, 6.3 g, 21.4 mmol) in THF (200 mL) at −78° C., DIBAL (1M in THF, 25.7 mL, 25.7 mmol) was added. The mixture was stirred at −78° C. for 10 min, warmed to RT and stirred for 2 h. The reaction was poured into 1N HCl and extracted with EtOAc 3×. The combined organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography with (5-20% EtOAc/hexane) to give the titled compound as a white solid. MS (ESI, pos. ion) m/z: 236.0 (M+1).
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8](=[O:36])[N:9]=[C:10]([S:34][CH3:35])[C:11]([C:25]1[CH:30]=[C:29]([OH:31])[CH:28]=[C:27]([C:32]#[CH:33])[CH:26]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][CH2:45][O:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][O:48]1>O>[CH3:6][O:7][C:8](=[O:36])[N:9]=[C:10]([S:34][CH3:35])[C:11]([C:25]1[CH:30]=[C:29]([O:31][CH2:44][CH2:45][O:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[CH:28]=[C:27]([C:32]#[CH:33])[CH:26]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: BrCCOC1CCCCO1
Reactant: C#Cc1cc(O)cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1cc(OCCOC2CCCCO2)cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 6 ml of a DMF solution containing 512 mg of {2-(3-ethynyl-5-hydroxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (45b)), 1.3 g of potassium carbonate and 0.64 ml of 2-(2-bromoethoxy)tetrahydropyran were added. The resulting mixture was stirred at room temperature overnight, and then water was added thereto and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give [2-{3-ethynyl-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (491 mg, isomer mixture) as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl>CC(C)=O>[O:22]1[CH2:21][CH:20]1[CH2:18][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: ClCC1CO1
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1OCC1CO1
Yield: 12 %

Procedure:
A mixture of 15.2 g (0.10 mole) of methyl 2-hydroxybenzoate, 27.6 g (0.20 mole) of K2CO3 and 31 mL (0.40 mole) of epichlorohydrin in 250 mL of acetone was heated to reflux for 24 hours. The reaction medium was then filtered and evaporated under reduced pressure. The resulting oil was dissolved in 100 mL toluene and washed consecutively with 100 mL water, 2×100 mL 1.0N NaOH, and 2×100 mL water. The organic phase was then dried over MgSO4 and evaporated under reduced pressure to provide the crude product as an oil. Purification was effected by vacuum distillation to provide an oil in 12% yield: boiling point 148° C. (75 u). The NMR and IR spectra and elemental analysis were consistent with the assigned structure.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:10][S:11](O)(=[O:13])=[O:12].S(Cl)(Cl)=O>>[N+:1]([C:4]1[CH:9]=[C:8]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccccc1
Solvent: O=S(Cl)Cl
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 107.2 %

Procedure:
123.1 g (1.0 mol) of nitrobenzene was added dropwise at 112° C. to 521.0 g (4.4 mol) of chlorosulfonic acid over the course of 4 hours. The mixture was then stirred at this temperature for 4 hours. After it had been cooled to 70° C., 110.0 g (0.92 mol) of thionyl chloride were added dropwise over the course of 2 hours. The reaction mixture was then stirred at this temperature until evolution of gas had ended. It was then cooled and discharged at 5° C. into ice-water. The precipitated 3-nitrobenzenesulfonyl chloride was then filtered off with suction and washed with water and with sodium hydrogen carbonate. 237.5 g of moist 3-nitrobenzenesulfonyl chloride having a purity of 89.9% were obtained in this manner. The dry content was 213.5 g, which corresponds to a yield of 96.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:34]1C=C(S(Cl)(=O)=O)C=C[CH:39]=1>>[CH2:34]([O:29][C:28](=[O:30])[C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)(=[O:10])=[O:9])[C:16]=3[CH:17]=2)=[O:22])=[CH:32][CH:31]=1)[CH3:39]
Reactant: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCO3)cc1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCO3)cc1

Procedure:
4-{[4-(3-Chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=471.1 (M−H), was prepared as described for example 14, steps 1 to 8. Step 7 was performed using 3-chloro-benzenesulfonyl chloride and yielded 4-{[4-(3-chlorobenzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH2:7][CH2:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:12]=3)[C:5]2=[CH:4][N:3]=1>[OH-].[Na+].[Pd]>[CH3:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:5]2=[CH:4][N:3]=1
Reactant: Cc1ncc2n1CCC=C2c1ccc(NS(C)(=O)=O)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: Cc1ncc2n1CCCC2c1ccc(NS(C)(=O)=O)cc1

Procedure:
Dissolve 5 g (16.5 mmol) of the product from Example VI in 100 ml of 1N sodium hydroxide and hydrogenate over 2 g of 10% palladium on carbon at 50 psi for 16 hr. Remove the catalyst and neutralize the filtrate with ammonium chloride. Extract with 2×100 ml of methylene chloride. Dry the combined extracts over sodium sulfate and remove the solvent in vacuo. Crystallize the residue from ethyl acetate to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([S:16](Cl)(=[O:18])=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24].O>C(Cl)Cl>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH:24][S:16]([CH:13]1[CH2:14][CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)(=[O:18])=[O:17]
Reactant: CN(C)CCN
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)C1
Solvent: O
Solvent: ClCCl
Product: CN(C)CCNS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
A solution of 3-chlorosulfonyl-pyrrolidine-1-carboxylic acid benzyl ester (110 mg, 0.362 mmol) in CH2Cl2 (1.5 mL) was added to a solution of N,N-dimethylethylenediamine (0.20 mL, 1.83 mmol) in CH2Cl2 (1 mL) at 0° C. The mixture was stirred at 0° C. for 10 min, and then warmed to room temperature and stirred for 1 hr. Water was added and the phases were separated. The aqueous phase was extracted with CH2Cl2 (2 x), the combined organic extracts were dried (Na2SO4), and the solvent was removed under vacuum to give benzyl 3-({[2-(dimethylamino)ethyl]amino}sulfonyl)-1-pyrrolidinecarboxylate (102 mg, 88%), which was used in the next step without further purification: 1H NMR (CDCl3) δ 7.36-7.29 (m, 5H), 5.14 (d, J=1.8 Hz, 2H), 3.80-3.72 (m, 4H), 3.50 (m, 1H), 3.16 (br s, 2H), 2.42 (t, J=5.7 Hz, 2H), 2.31 (m, 2H), 2.21 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N+:12]=[N-:13].[CH2:14]([OH:17])[C:15]#[CH:16]>CCOCC.C(O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:11])[N:12]3[N:13]=[C:15]([CH2:14][OH:17])[CH:16]=[C:5]3[C:4]=2[CH:3]=1
Reactant: [N-]=[N+]=C1C(=O)Nc2ccc(F)cc21
Reactant: C#CCO
Solvent: CCOCC
Solvent: CCO
Product: O=c1[nH]c2ccc(F)cc2c2cc(CO)nn12
Reaction time: 0.25 h

Procedure:
2.0 g (0.0113 mole) of 5- fluoro-3-diazooxindole (part B9 and 13.1 g (0.226 mole of 20 equivalents) of 97% propargyl alcohol are refluxed under argon for 4 hours. The reaction mixture is cooled, diluted with ether (200 ml) and stirred for 15 minutes. The beige-colored precipitates are filtered off and dried in vacuo overnight. Yield: 2.3 g, mp 295°-297°, 87.5% crude yield. The crude produce is taken up in absolute ethanol (500 ml), treated with activated carbon, filtered through a Celite pad, the pad is washed with 50 ml of hot ethanol. The clear filtrate is concentrated down to a volume of 100 ml and cooled. The white precipitates are filtered off and dried in vacuo at 60° to yield the product (title compound) 1.16 g, mp 303°-304°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=O)[CH:10]([CH3:12])[CH3:11].Cl.[NH2:15][OH:16]>N1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[N:15][OH:16])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)C(=O)c1c(O)cccc1O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(=NO)c1c(O)cccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
1-(2,6-dihydroxyphenyl)-2-methyl-1-propanone (Intermediate 37, 416 mg) was dissolved in pyridine (2.0 ml) and hydroxylamine hydrochloride (209 mg, 3.0 mmol) was added. The reaction mixture was then stirred at room temperature overnight. After night, additional hydroxylamine hydrochloride (64 mg, 0.92 mmol) was added and the mixture was heated at 100° C. for 3 hours. After removal of the volatiles, the crude was treated with water and extracted with ethyl acetate. The gathered organic layers were dried over sodium sulphate, filtered and evaporated to afford the title compound (370 mg).