Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.C([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)#N>ClCCl>[CH3:27][O:26][C:24]([C:23]1[CH:28]=[CH:29][C:20]([C:12]2[N:11]3[C:7](=[N:8][C:9]4[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=43)[S:6][N:5]=2)=[CH:21][CH:22]=1)=[O:25]
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Reactant: COC(=O)c1ccc(C#N)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nsc3nc4ccccc4n23)cc1
Yield: 43.1 %

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (0.3 g, 1.2 mmole) and methyl 4-cyanobenzoate (0.41 g, 2.5 mmole) in 7 mL of dichloromethane was heated to reflux for 20 h. The precipitate was filtered and washed with dichloromethane to give 0.16 g (48%) of 3-[4-(methoxycarbonyl)phenyl]-1,2,4-thiadiazolo [4,5-a]benzimidazole as a white solid: mp 204-206° C.; 1H NMR (CDCl3) δ 8.33 (d, 2H), 7.98 (d, 2H), 7.83 (d, 1H), 7.49 (m, 2H), 7.20 (t, 1H), 4.02 (s, 3H) ppm; 13C NMR (CDCl3) δ165.96, 165.30, 151.08, 149.10, 133.16, 132.55, 130.24(2C), 128.69(3C), 125.34, 121.58, 119.96, 112.01, 52.56 ppm; IR (KBr) ν 1729, 1508, 1448, 1275, 733 cm-1 ; HRMS calcd for C16H11N3O2S, 309.0572 found 309.05719.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:33][NH:34][C:35]([C:37]1[CH:42]=[C:41](Cl)[CH:40]=[CH:39][N:38]=1)=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:33][NH:34][C:35]([C:37]1[CH:42]=[C:41]([O:22][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=2)[CH:21]=[N:20]3)[CH:40]=[CH:39][N:38]=1)=[O:36]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: CC(C)(C)c1cccc(Nc2cnc3cc(O)ccc3n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3nc(Nc4cccc(C(C)(C)C)c4)cnc3c2)ccn1

Procedure:
The mixture containing 2-(3-tert-butyl-phenylamino)-quinoxalin-6-ol (1 eq), potassiumbis(trimethylsilyl)amide (4eq), was stirred in dimethylformamide for 30 min. at room temperature. To this mixture was added 4-chloro-pyridine-2-carboxylic acid methylamide (1 eq) and potassium carbonate (1.2 eq) and microwaved for 6 mins. at 170° C. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered and concentrated. Purification on Prep LC yielded the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@@H:12]3[CH2:15][C@H:14]([C:16]([NH2:18])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:19]1([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][C:29](B4OC(C)(C)C(C)(C)C4)=[CH:30][CH:31]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>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.O>[NH2:1][C:2]1[C:3]2[C:10]([C:29]3[CH:28]=[C:27]4[C:32]([CH:33]=[CH:34][C:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:26]4)=[CH:31][CH:30]=3)=[CH:9][N:8]([C@@H:12]3[CH2:15][C@H:14]([C:16]([NH2:18])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@@H](C(N)=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@@H](C(N)=O)C1
Temperature: 80 °C

Procedure:
A mixture of cis-3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylic acid amide (131 mg, 0.367 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (146 mg, 0.441 mmol), Na2CO3 (97.2 mg, 0.917 mmol), Pd(PPh3)4 (25.5 mg, 0.0221 mmol), DMF (5 mL), and water (1 mL) was purged with nitrogen for 30 min and heated to 80° C. for 18 h. To the cooled reaction solution was added water (15 mL), the mixture was extracted with EtOAc (3×20 mL), the combined organic layers were washed with water (2×15 mL) and brine, dried over MgSO4, filtered, and concentrated. The residue was triturated with MeOH to give the title compound as yellow solid. 1H NMR (CDCl3, 400 MHz): δ=2.60-2.70 (m, 4H), 2.84-2.90 (m, 1H), 5.14-5.23 (quintet, 1H, J=8.7 Hz), 6.31 (brs, 2H), 6.92 (s, 1H), 7.40 (s, 1H), 7.50-7.62 (m, 3H), 7.78-7.82 (m, 2H), 8.08-8.10 (d, 1H, J=8.4 Hz), 8.15-8.23 (m, 3H), 8.30-8.37 (m, 2H), 8.49-8.51 (d, 1H, J=8.4 Hz). MS (ES+): 435.0 [MH+]. HPLC: tR=2.4 min (polar—5 min).
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:35]([N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[CH:34][C:19]4[NH:20][C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:32])[F:31])=[N:22][C:18]=4[CH:17]=3)=[O:15])[CH:11]=2)[CH:6]=[N:5]1.[C:42]([OH:46])(=[O:45])[CH:43]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:35]([N:36]4[CH2:37][CH2:38][N:39]([CH2:43][C:42]([OH:46])=[O:45])[CH2:40][CH2:41]4)=[CH:34][C:19]4[NH:20][C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:31])([F:32])[F:33])=[N:22][C:18]=4[CH:17]=3)=[O:15])[CH:11]=2)[CH:6]=[N:5]1
Reactant: O=C(Nc1ccc2cn[nH]c2c1)c1cc2nc(Nc3ccccc3C(F)(F)F)[nH]c2cc1N1CCNCC1
Reactant: O=CC(=O)O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)CN1CCN(c2cc3[nH]c(Nc4ccccc4C(F)(F)F)nc3cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide trihydrochloride (0.25 mmol; see Example 88) in methanol (1 mL) was added glyoxylic acid (0.5 mmol), and the resulting mixture was stirred at RT for 60 min. The reaction mixture was then charged with solid sodium cyanoborohydride (0.6 mmol), and the stirring was continued at RT for 10 h. To the reaction mixture was then added a few drops of glacial acetic acid, and the mixture was stirred for 30 min. The volatiles were then removed in vacuo, and the residue was suspended in water (10 mL) with vigorous stirring. After 30 min, the solid was filtered, washed with water, and dried under vacuum to afford {4-[6-(1H-indazol-6-ylcarbamoyl)-2-(2-trifluoromethyl-phenylamino)-3H-benzoimidazol-5-yl]-piperazin-1-yl}acetic acid as a white solid. MS: m/z 579 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20]2>ClCCCl>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:20]2[CH:14]=[O:15]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: CN(C=O)c1ccccc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1[nH]c2ccc(Br)cc2c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
In a 1 L round bottom flask 10.5 mL of phosphorus oxychloride was added to 15.5 g of N-methylformanilide at room temperature that resulted in a yellow solid after 15 min. At this time, 170 mL of 1,2-dichloroethane and 20.1 g of ethyl 5-bromoindole-2-carboxylate were added. The resulting suspension was heated under reflux for 4 hours and then concentrated to remove the organic solvent. 75 g of sodium acetate in 750 mL of water were added and the solid suspension was stirred for 30 min at room temperature, filtered and washed 3 times with water. The crude material was dried under vacuum for 1 hour and swished with 500 mL of EtOH to yield 21.2 g of the title compound as off-white solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[O:14][CH2:15][C:16](O)=O>Cl>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:16]=1[CH2:15][O:14][C:13]1[CH:19]=[CH:20][CH:21]=[C:11]([O:10][CH3:9])[CH:12]=1
Reactant: COc1cccc(OCC(=O)O)c1
Reactant: Nc1ccccc1N
Agent: Cl
Product: COc1cccc(OCc2nc3ccccc3[nH]2)c1
Reaction time: 1 h
Yield: 91.9 %

Procedure:
A suspension of phenylenediamine (15.12 g, 0.14 mol) and 3-methoxyphenoxyacetic acid (25.5 g, 0.14 mol) in 4M HCl (150 mL) was refluxed overnight under Ar. The reaction mixture was cooled in an ice bath. The solid was collected and washed with cold H2O (200 mL). To the solid was added CH2Cl2 (150 mL) and saturated NaHCO3 (150 mL). After stirring for 1 hr, the organic phase was separated, washed with brine (75 mL), filtered through phase separation filter paper and concentrated in vacuo to give 32.7 g (92%) of 51 as an oil which solidified. The HPLC analysis showed a purity of 98%. 1H NMR (60 MHz, CDCl3): δ 10.0 (br s, 1H), 6.3-7.9 (m, 8H), 5.0 (s, 2H), 3.7 (s, 3H) ppm.
Reaction SMILES: C(N1[C:12](=[O:13])C2=CC=CC=C2C1=S)C1C=CC=CC=1.CN1CCN([C:26]2[N:30]3[C:31]4[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:32]=4[CH:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[Cl:42])[O:34][CH2:35][C:29]3=[N:28][N:27]=2)CC1>C1C=CC=CC=1.ClCCl>[OH:13][CH2:12][C:26]1[N:30]2[C:31]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:32]=3[CH:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[O:34][CH2:35][C:29]2=[N:28][N:27]=1
Reactant: CN1CCN(c2nnc3n2-c2ccc(Cl)cc2C(c2ccccc2Cl)OC3)CC1
Reactant: O=C1c2ccccc2C(=S)N1Cc1ccccc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)OC2
Yield: 73.6 %

Procedure:
N-Benzylthiophthalimide (1.62 g) is dissolved in benzene (74 ml) under heating. To the resulting solution is added a solution of Compound 18 (1.13 g) prepared in Example 10 in dichloromethane (10 ml), and the mixture is refluxed under heating for 15 hours, and concentrated. The residue is extracted with ethyl acetate and the extract is dried and concentrated. The residue is treated on column chromatography (silica gel/ethyl acetate) to give Compound 23 (0.7 g), which is recrystallized from ethyl acetate. Yield 47%
Reaction SMILES: [CH2:1]1[O:19][C:4]2=[CH:5][C:6]3[O:11][C:10](=[O:12])[C:9]([C:13]([O:15]CC)=[O:14])=[CH:8][C:7]=3[CH:18]=[C:3]2[O:2]1.O.Cl>CO.[OH-].[K+]>[CH2:1]1[O:19][C:4]2=[CH:5][C:6]3[O:11][C:10](=[O:12])[C:9]([C:13]([OH:15])=[O:14])=[CH:8][C:7]=3[CH:18]=[C:3]2[O:2]1
Reactant: CCOC(=O)c1cc2cc3c(cc2oc1=O)OCO3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2cc3c(cc2oc1=O)OCO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
To a suspension of ethyl 6,7-methylenedioxy-2-oxo-1-benzopyran-3-carboxylate (0.26 g) in methanol (20 ml), 2N KOH (1.5 ml) was added, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water and acidified with hydrochloric acid; the resulting crystal was collected by filtration to yield 6,7-methylenedioxy-2-oxo-1-benzopyran-3-carboxylic acid (0.1 g, 44%), which was then recrystallized from N,N-dimethylformamide-water to yield yellow prisms having a melting point of 279°-280° C.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:13]>>[CH:1]1([NH:7][CH2:8][CH2:9][Cl:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OCCNC1CCCCC1
Product: ClCCNC1CCCCC1

Procedure:
2-Hydroxyethylamine and cyclohexanone were reacted according to Method B4a, Step 1 to afford 4-aza-1-oxaspiro[4.5]decane. The oxazolidine was reduced according to method B4a, Step 2 to afford N-cyclohexyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to afford N-cyclohexyl-N-(2-chloroethyl)amine. The amine was reacted with 2-methoxy-4-nitrophenyl isothiocyanate according to Method C1d to afford 2-(2-methyl-4-nitrophenylimino)-3-cyclohexyl-1,3-thiazolidine.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([CH2:12][CH2:13][NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17][CH2:18][C:19](Br)=[O:20].N1C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:18][C:19]([NH:14][CH2:13][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)=[O:20]
Reactant: NCCc1ccc(Oc2ccccc2)cc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CBr)NCCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.2 %

Procedure:
4-phenoxyphenethylamine (213.28 amu, 2.5 g, 1 eq, 10.8 mmol, 1.09 g/mL, 2.3 mL) added to a 3-necked flask. Bromoacetyl bromide (201.86 amu, 1.1 eq, 11.8 mmol, 2.4 g, 2.317 g/mL, 1.03 mL), pyridine (79.10 amu, 5 eq, 4.27 g, 0.978 g/mL, 54 mmol, 4.4 mL) added along with 50 mL CH2Cl2. Reaction stirred for 2 hours at RT. CH2Cl2 removed and mixture taken up in 200 mL EtOAc. Organic layer washed with brine and water (200 mL each). Organics seperated, dried sodium sulfate, and rotovaped to give 1.56 g material. MS [EI+] 334 (M+H)+, MS [EI−] 332 (M−H)+
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[N:20][CH:21]=1>CN(C)C=O>[F:22][C:19]1[N:20]=[CH:21][C:16]([CH2:15][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccc(CBr)cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
tert-Butyl piperazine-1-carboxylate (Aldrich, St. Louis, Mo., 17.77 g, 95 mmol) was added to a stirred solution of 5-(bromomethyl)-2-fluoropyridine (15.11 g, 80 mmol) in N,N-dimethylformamide (120 mL) at 0° C. and the suspension was stirred at room temperature overnight. The resulting thick reaction mixture was quenched with cold water (50 mL), the resulting suspension was stirred for 30 min, and the resulting solid was collected and washed with additional cold water (50 mL). The off-white precipitate was dried under vacuum to give the title compound tert-butyl 4-((6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (19.7494 g, 66.9 mmol, 84% yield) as a white solid. LCMS (API-ES) m/z 296 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 8.13 (s, 1H) 7.90 (td, J=8.02, 1.37 Hz, 1H) 7.15 (dd, J=8.31, 2.05 Hz, 1H) 3.51 (s, 2H) 3.30 (br. s., 4H) 2.10-2.40 (m, 4H) 1.39 (s, 9H).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:15])/[C:11](/[CH3:14])=[CH:12]/[CH3:13])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH:25](=[O:27])[CH3:26]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:27][CH:25]([C:11]([CH3:14])([CH:12]=[CH2:13])[C:10]([N:5]1[C@@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][O:7][C:6]1=[O:9])=[O:15])[CH3:26]
Reactant: CC=O
Reactant: C/C=C(\C)C(=O)N1C(=O)OC[C@@H]1C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(C)(C(=O)N1C(=O)OC[C@@H]1C(C)C)C(C)O
Reaction time: 0.08 h
Yield: 62 %

Procedure:
A cooled (−78° C.) solution of (S)-4-isopropyl-3-((E)-2-methyl-but-2-enoyl)-oxazolidin-2-one (the enantiomer of the previously described compound 77a) (2.316 g, 10.962 mmol) in anhydrous dichloromethane (50 mL) was treated with a solution of titanium(IV) chloride (1 M, 12 mL, 11.510 mmol) in dichloromethane. After stirring the orange solution for 5 minutes, the mixture was treated with N,N-diisopropylethylamine (4.8 mL, 27.405 mmol). After stirring at −78° C. for 2 h, the purple solution was treated with acetaldehyde (4.3 mL, 76.374 mmol). After stirring at −78° C. for 1.5 h and at room temperature for 50 minutes, the reaction was quenched with a saturated solution of ammonium chloride (60 mL). The aqueous layer was extracted with dichloromethane. The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/diethyl ether 1:0 to 1:1 to afford the title compound (1.742 g, 62%) as a 1:1.13:1.85:2.60 mixture of diastereoisomers and as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[C:6]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39].[H-].[Na+].Cl[C:43]1[N:48]=[CH:47][CH:46]=[CH:45][N:44]=1.CN(C=O)C>C1COCC1>[N:44]1[CH:45]=[CH:46][CH:47]=[N:48][C:43]=1[O:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=2)[C:6]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCO
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCOc1ncccn1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
4-i-Propyl-phenyl sulfamic acid-[6-(2-hydroxy-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (60 mg, Example 3) was dissolved in THF (8 ml) and sodium hydride (14 mg, 60% dispersion in mineral oil) was added and stirring continued for 10 min. 2-Chloro-pyrimidine (22 mg) was added and the mixture was heated to 60° C. for 90 min. DMF (0.5 ml) was added and the solution was stirred at r.t. for 48 h. The solvents were evaporated, water (12 ml) and a 10/solution of citric acid was added until the pH was 3. The precipitate was filtered off and washed with water and purified by recrystallization from diethyl ether to give 4-i-propyl-phenyl sulfamic acid-[6-[2-(pyrimidin-2-yloxy)-ethoxy]-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (50 mg). tR=4.80 min, (LC); [M+H]+=630.91 (ES+).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=O>>[CH3:7][C:8](=[CH:9][CH2:10][CH2:1][C:2](=[CH:3][CH:4]=[O:5])[CH3:6])[CH3:12]
Reactant: CC(C)=CC=O
Reactant: CC(C)=CCO
Product: CC(C)=CCCC(C)=CC=O

Procedure:
100 parts of 3-methyl-2-buten-1-ol and 50 parts of 3,3-dimethylacrolein are heated for ninety minutes at 200° C and a pressure of 40 atmospheres in a rocking autoclave having a capacity of 250 parts by volume. The reaction product is worked up by distillation. 12.5 parts of citral is obtained having a boiling pont of 104° C at 12 mm. The yield (based on 3,3-dimethylacrolein) is 53% of theory at a conversion of 26%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])([CH3:4])([CH3:3])[CH3:2].[CH:24](O)([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(C)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][N:10]([CH:24]([CH3:26])[CH3:25])[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])(=[O:12])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)N(CCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 150.5 %

Procedure:
The compound (2.22 g, 6.43 mmol) obtained in step A, isopropanol (0.65 ml, 8.46 mmol), and triphenylphosphine (1.85 g, 7.05 mmol) were dissolved in tetrahydrofuran (50 ml) and the mixture was stirred under ice-cooling. Thereto was slowly added 40% diisopropyl azodicarboxylate-toluene solution (5 ml), and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated under reduced pressure and diluted with diethyl ether, and the precipitated colorless solid was filtered off. The mother liquor was concentrated under reduced pressure and the obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give tert-butyl[2-{isopropyl[(2-nitrophenyl)sulfonyl]amino}ethyl]carbamate (3.75 g) as a colorless crude oil. This was dissolved in dichloromethane (10 ml), 4N hydrochloric acid-dioxane solution 10 ml) was added at room temperature and the mixture was stirred for 1 hr. The reaction mixture was diluted with diethyl ether, and the mixture was extracted with water. The aqueous layer was alkalified with aqueous sodium hydroxide solution, extracted with dichloromethane, dried over sodium sulfate, the insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (1.39 g, yield 75%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:10]#[N:11].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(N(CC)CC)C>ClCCl>[C:10]([C:3]1[CH:4]=[N:5][N:6]([CH:7]([CH3:9])[CH3:8])[C:2]=1[NH:1][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=1)#[N:11]
Reactant: CC(C)n1ncc(C#N)c1N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1ncc(C#N)c1NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A mixture of crude 5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile (0.72 g, 4.5 mmol maximum) and 4-nitrobenzoylchloride (1.3 g, 6.8 mmol) in dichloromethane (20 mL) was treated successively with triethylamine (1.8 mL, 14 mmol) and 4-N,N-dimethylaminoaniline (DMAP, 55 mg, 10 mol %). The mixture was heated to reflux (oil bath) for one hour and then allowed to cool to room temperature. The mixture was then concentrated to dryness under reduced pressure. The residue was dissolved in pyridine (20 mL). Water was added, followed by concentrated aqueous ammonium hydroxide (5 mL). The reaction vessel was swirled manually and then left overnight at room temperature. The mixture was concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed twice with saturated aqueous sodium hydrogen carbonate solution and once each with 0.25 M aqueous hydrochloric acid and saturated aqueous sodium chloride solution. Drying over anhydrous magnesium sulfate was followed by filtration and then concentration under reduced pressure to provide N-(4-cyano-1-isopropyl-1H-pyrazol-5-yl)-4-nitrobenzamide as a dark yellow solid (1.3 g, 100%). MS (ES+): 299.6, 299.9 (M+H)+
Reaction SMILES: C([O:4][C:5]1[C:10]([O:11][CH2:12][CH:13]=[CH2:14])=[C:9]([O:15][CH3:16])[CH:8]=[CH:7][C:6]=1[C:17](=[O:27])[CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=1[Cl:26])C=C.C([O-])([O-])=O.[K+].[K+]>CO.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>[CH2:12]([O:11][C:10]1[C:5]([OH:4])=[C:6]([C:17](=[O:27])[CH2:18][C:19]2[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=2[Cl:26])[CH:7]=[CH:8][C:9]=1[O:15][CH3:16])[CH:13]=[CH2:14]
Reactant: C=CCOc1c(OC)ccc(C(=O)Cc2c(Cl)cncc2Cl)c1OCC=C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CCOc1c(OC)ccc(C(=O)Cc2c(Cl)cncc2Cl)c1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-(2,3-Bis-allyloxy-4-methoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethanone from example 6 (3.9 g, 9.55 mmol) was dissolved in MeOH (96 mL) and cooled to 0° C. under argon. Pd(PPh3)4 (110 mg, 0.0955 mmol) was added followed by K2CO3 (1.3 g, 9.55 mmol). The cooling bath was removed and the reaction mixtured was stirred for 3 hours and then evaporated in vacuo. The crude was redissolved in EtOAc (100 mL) and washed twice with NH4Cl (sat, 50 mL). The organic phase was dried over Na2SO4 and evaporated in vacuo and purified by flash chromatography using a gradient of toluene and 2% EtOAc as eluent. 1-(3-Allyloxy-2-hydroxy-4-methoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethanone was obtained as a white solid. 1H NMR (CDCl3) δ=11.90 (1H, s), 8.53 (2H, s), 7.68 (1H, d), 6.58 (1H, d), 6.10 (1H, m), 5.26 (2H, m), 4.66 (2H, s), 4.59 (2H, d), 3.96 (3H, s). Yield 2.2 g (64%)