Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([Cl:11])[C:3]=1[Cl:12].[C:13](=[O:16])([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:22][C:23]1([CH2:27]Cl)[CH2:26][O:25][CH2:24]1>O.CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:27][C:23]2([CH2:22][O:16][C:13]3[C:6]([Cl:9])=[C:5]([Cl:10])[C:4]([Cl:11])=[C:3]([Cl:12])[C:2]=3[Cl:1])[CH2:24][O:25][CH2:26]2)=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([Cl:11])[C:3]=1[Cl:12]
Reactant: ClCC1(CCl)COC1
Reactant: O=C([O-])[O-]
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1c(Cl)c(Cl)c(OCC2(COc3c(Cl)c(Cl)c(Cl)c(Cl)c3Cl)COC2)c(Cl)c1Cl
Temperature: 140 °C
Reaction time: 3 h

Procedure:
This reaction was carried out similarly to that described in Example 1. Pentachlorophenol (469 g., 1.86 moles), potassium carbonate (262 g., 1.9 moles), potassium iodide (4 g.) and 1.5 liters of dimethyl formamide were charged to a 3 liter reaction flask. The mixture was stirred and heated in a nitrogen atmosphere. When the temperature reached 95° C., 140 g. (0.9 moles) of 3,3-bischloromethyl oxetane was added. The reaction mixture was slowly heated to about 140° C. and held 3 hours. After cooling to 63° C., 700 ml. of water was added to the mixture. After standing overnight, the reaction mixture was filtered. The recovered crystalline 3,3-bis[pentachlorophenoxymethyl]oxetane was washed on the funnel with six portions of water, three portions of ethanol and three portions of 2-butanone. The yield of oven-dried, cream-colored crystals was 480 g. (87%). The compound melted at 229°-230° C. If desired, this compound can be recrystallized from dioxane.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11](C(O)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[NH2:34][C:35]1[C:36]([OH:46])=[C:37]([S:42]([NH2:45])(=[O:44])=[O:43])[C:38]([Cl:41])=[CH:39][CH:40]=1.C[N:48]([CH:50]=[O:51])C>>[Cl:41][C:38]1[C:37]([S:42]([NH2:45])(=[O:44])=[O:43])=[C:36]([OH:46])[C:35]([NH:34][C:50]([NH:48][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:51])=[CH:40][CH:39]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)NC2CCNCC2)c1O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.23 g, 1.0 mmol) in DMF (0.5 mL) was added DPPA (0.215 mL, 1.0 mmol) and TEA (0.139 mL, 1.0 mmol) and the reaction heated at 80° C. After 18 hrs, 3-Amino-6-chloro-2-hydroxy-benzenesulfonamide (1.0 mmol) was added and the reaction heated at 80° C. After 18 hrs, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were dried over anhydrous magnesium sulfate, and concentraed under reduced pressure. The crude residue was purified via HPLC to give 12 mg of 6-Chloro-2-hydroxy-3-(3-piperidin-4-yl-ureido)-benzenesulfonamide. LC-MS (m/z) 349 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1.Cl[CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:10]=[N:11][N:12]=1
Reactant: Cc1ccccc1-c1nnn[nH]1
Reactant: COC(=O)CCl
Product: COC(=O)Cn1nnnc1-c1ccccc1C

Procedure:
Feed materials: 5-(2-methylphenyl)tetrazole and methyl chloroacetate.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OCC)(=O)CC(OCC)=O.[O-:31][CH2:32][CH3:33].[Na+].Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)=[CH:39][CH:38]=1.Cl>C(O)C.O.C(OCC)(=O)CC(OCC)=O>[O:31]=[C:32]1[O:1][C@H:2]([C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH:33]1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CO1
Reactant: BrCc1ccc(-c2ccccn2)cc1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(=O)CC(=O)OCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccn3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-Butyl (1S)-1-[(2R)-oxiran-2-yl]-2-phenylethylcarbamate (10.0 g, 38.0 mmol) and diethyl malonate (5.8 ml, 38.2 mmol) in ethanol (30 mL) at 0° C. was treated with sodium ethoxide (17 mL, 21% in ethanol) over 10 minutes. The reaction was warmed to 25° C. and stirred for 2 hours, treated with additional diethyl malonate (0.58 mL, 3.4 mmol) and stirred for 1 hour. The reaction was cooled to 0° C., and solid 2-[4-(bromomethyl)phenyl]pyridine (9.43 g, 38.0 mmol) was added in four increments over 10 minutes. To this suspension was added ethanol (20 mL) and the mixture was stirred at 25° C. for 16 hours. The reaction mixture was treated with LiOH monohydrate (4.6 g, 109.6 mmol) solution in water (30 mL), stirred at 25° C. for 16 hours, cooled to 0° C., adjusted to pH 5 by addition of 4N HCl and partitioned between dichloromethane and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. A solution of the concentrate in toluene (100 mL) was heated at reflux for 16 hours, cooled to 25° C. and concentrated to afford the title compound (21.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][N:13]=[C:14]=[O:15].[H-].[Na+].[NH2:18][C:19]([C:26]([F:29])([F:28])[F:27])=[CH:20][C:21](OCC)=[O:22]>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][N:13]1[C:21](=[O:22])[CH:20]=[C:19]([C:26]([F:29])([F:28])[F:27])[NH:18][C:14]1=[O:15]
Reactant: O=C=NCc1cc([N+](=O)[O-])cc(Cl)c1Cl
Reactant: CCOC(=O)C=C(N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1Cc1cc([N+](=O)[O-])cc(Cl)c1Cl
Yield: 55.8 %

Procedure:
By the method of Example 1, Step G, 19.67 grams (0.080 mole) of 2,3-dichloro-5-nitrophenylmethyl isocyanate, 2.102 grams (0.088 mole) of sodium hydride, and 14.59 grams (0.080 mole) of ethyl 3-amino-4,4,4-trifluoro-2-butenoate were reacted in 80 mL of N,N-dimethylformamide, yielding 17.14 grams of 3-(2,3-dichloro-5-nitrophenylmethyl)-6-trifluoromethyluracil as a brown solid. The NMR spectrum was consistent with the proposed structure. This reaction was repeated.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])[CH:15]=[CH:16][C:3]1=2.C(O)C.[OH-].[K+].Cl>O>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:23])[C:18]([OH:20])=[O:19])[CH:15]=[CH:16][C:3]1=2
Reactant: CCOC(=O)C(C)c1ccc2c(c1)Sc1ccccc1CC2=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)Sc1ccccc1CC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
The mixture of 83 mg of ethyl 2-(10,11-dihydro-11-oxo dibenzo[b,f]thiepin-3-yl)-propionate, 0.8 ml of ethanol, 120 mg of potassium hydroxide and 0.8 ml of water was stirred at room temperature for 2 hours. The solvent was distilled off to obtain the residue, which was acidified with hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain brown oil, which was chromatographed over silica gel, eluted with chloroform to give 59 mg of 2-(10,11-dihydro-11-oxo dibenzo[b,f]thiepin-3-yl)-propionic acid as pale yellow oil. The result in IR spectrum thereof is in accordance with that of the compound obtained in Example 9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:26]([O-])=O)[CH:5]=[C:6]([Cl:25])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:10]=1>[Pt].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:25])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:10]=1)[NH2:26]
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1Cc1ccc(F)cc1
Agent: [Pt]
Solvent: CCO
Product: COc1ccc(Oc2c(Cl)cc(N)cc2Cl)cc1Cc1ccc(F)cc1

Procedure:
3,5-Dichloro-4-[3'-(4-fluorobenzyl)-4'-methoxyphenoxy]nitrobenzene (3.64 g) and 360 mg of 10% platinum on carbon in 200 ml ethanol is hydrogenated on a Parr shaker. Catalyst is removed by filtration through Celite and the filtrate stripped to afford 3,5-dichloro-4-[3'-(4-fluorobenzyl)-4'-methoxyphenoxy]-aniline. This is redissolved with 1.10 ml ethyl bromoacetate and 1.28 g of diisopropylethylamine in 30 ml dimethylformamide and heated at 140° for 18 hours. Solvent is removed with high vacuum and the residue dissolved in ethyl acetate and extracted twice with water. The ethyl acetate is dried, filtered and stripped to give crude product Chromatography on silica gel with 80:20 to 70:30 hexane:ethyl acetate affords pure ethyl N-[3,5-dichloro-4-[3'-(4-fluorobenzyl)-4'-methoxyphenoxy]-phenyl]aminoacetate; NMR (CDCl3): δ1.3 (3H, t), 3.7 (3H, s), 3.9 (2H, s), 3.9 (2H, s), 4.3 (2H, q), 6.6 (1H, d of d), 6.7 (1H, d), 6.8 (1H, d), 6.9 (2H, m), 7.1 (2H, m), 7.3 (2H, s).
Reaction SMILES: CN(C(O[N:9]1N=[N:16][C:11]2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49](O)=[O:50].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:9][CH2:10][CH2:11][NH:16][C:49]([C:27]1[S:28][C:29]2[N:30]=[CH:31][N:32]=[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)[C:34]=2[C:26]=1[CH3:25])=[O:50]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)NCCN)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
HATU (0.157 g, 0.41 mmol) was added into a mixture of 5-methyl-4-(2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylic acid (0.145 g, 0.38 mmol) and Hünig's base (65 μL, 0.38 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. Tert-butyl-N-(2-aminoethyl) carbamate (296 μL, 1.88 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The solvent was concentrated in vacuo and the crude product dissolved in DCM. The organic layer was washed with water, concentrated in vacuo (10 mL) and trifluoroacetic acid added (3.0 mL). The mixture was stirred at ambient temperature overnight, concentrated in vacuo and purified by ion-exchange chromatography (SCX-2 eluting with hydrochloric acid/MeOH→ammonia/MeOH). Further purification by flash-column chromatography (100% DCM→10% ammonia/MeOH/DCM) yielded the title compound as pale yellow solid (0.063 g, 39%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:12]=[C:11]([CH3:13])[O:10][N:9]=1)=[O:6].C(N(CC)CC)C.[CH3:21][C:22]1[N:23]=[C:24]([NH:38][C:39](N2C=CN=C2)=[O:40])[S:25][C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)=[CH:29][CH:28]=1.O>CN(C=O)C>[CH3:13][C:11]1[O:10][N:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][CH2:3][NH:2][C:39]([NH:38][C:24]2[S:25][C:26]([C:27]3[CH:28]=[CH:29][C:30]([N:33]4[CH:37]=[CH:36][CH:35]=[N:34]4)=[CH:31][CH:32]=3)=[C:22]([CH3:21])[N:23]=2)=[O:40])[CH:12]=1
Reactant: Cc1cc(NC(=O)CCN)no1
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(-n2cccn2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(NC(=O)CCNC(=O)Nc2nc(C)c(-c3ccc(-n4cccn4)cc3)s2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-amino-N-(5-methyl-isoxazol-3-yl)-propionamide hydrochloride (Intermediate B1 produced by HCl deprotection) (0.1 g, 0.49 mmol) and triethylamine (0.164 ml, 1.18 mmol) is stirred in DMF (4 ml). Imidazole-1-carboxylic acid [4-methyl-5-(4-pyrazol-1-yl-phenyl)-thiazol-2-yl]-amide (Intermediate A2) (0.16 g, 0.47 mmol) is added and the mixture stirred at room temperature for 18 h. Water (20 ml) is added and the mixture stirred for 30 min. The solid is filtered off, washed with water and dried in vacuo at 45° C. for 4 h to afford the title compound.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([OH:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:36][C:37]1[O:38][C:39](=[O:43])[O:40][C:41]=1[CH3:42].CCOC(C)=O>CN(C=O)C>[CH3:42][C:41]1[O:40][C:39](=[O:43])[O:38][C:37]=1[CH2:36][O:12][C:11](=[O:13])[C@H:10]([OH:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](O)C(=O)O
Reactant: Cc1oc(=O)oc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(2R,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxypentanoic acid (500 mg, 1.0 mmol, 1.0 eq.) was dissolved in dry DMF (10.0 mL). The solution was cooled to 0° C. and dicesium carbonate (465 mg, 1.4 mmol, 1.1 eq.) was added. The mixture was stirred for 30 minutes and 4-chloromethyl-5-methyl-1,3-dioxol-2-one (212 mg, 1.4 mmol, 1.1 eq.) was added. The resulting mixture was stirred for an additional 1 hour at 0° C., then warmed to room temperature while stirring. The mixture was further stirred overnight. EtOAc (20 mL) was added, followed by washing with saturated aqueous NaCl (100 mL). The product was dried under vacuum and purified using reverse phase chromatography (10-70% MeCN/H2O; 0.05% TFA over 70 minutes) to yield (2R,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxypentanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester. This material was dissolved in 4N HCL in dioxane and stirred for 2 hours at room temperature. The material was dried under vacuum then azeotroped with toluene to yield (2R,4R)-4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8](Cl)=[N:7][CH:6]=1)[CH3:2].C1C=CC(P([C:27]2[CH:32]=[CH:31]C=CC=2)C2C=CC=CC=2)=CC=1.O1CCOC[CH2:34]1>C([O-])([O-])=O.[K+].[K+].CCOCC.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>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH:34]=[C:32]([CH3:31])[CH3:27])=[N:7][CH:6]=1)[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reactant: C1COCCO1
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: CCOCC
Product: CCOC(=O)c1cnc(C=C(C)C)c(Cl)c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5,6-dichloronicotinic acid ethyl ester (2.40 g, 10.9 mmol) and 2,4,6-tris-(2-methyl-propenyl)-cyclotriboroxane pyridine complex (2.02 g, 6.22 mmol, prepared in analogy to a procedure given by F. Kerins, D. F. O'Shea J. Org. Chem. 67 (2002) 4968-4971) in dioxane (40 mL) and 2 M aq. K2CO3 solution (10 mL), PPh3 (114 mg, 0.436 mmol) is added. The mixture is degassed and put under N2 before Pd(PPh3)4 (160 mg, 0.218 mmol) is added. The mixture is stirred at 100° C. for 1.5 h before another portion of 2,4,6-tris-(2-methyl-propenyl)-cyclotriboroxane pyridine complex (1.01 g, 3.11 mmol) is added. Stirring is continued at 100° C. for 3 h before the mixture is cooled to rt, diluted with ether, washed with 1N aq. NaOH solution followed by water, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 5-chloro-6-(2-methyl-propenyl)-nicotinic acid ethyl ester (2.4 g) as an oil; LC-MS: tR=1.05 min, [M+1]+=240.02. To a solution of this material in dioxane (40 mL), 2,4,6-trivinylcyclotriboroxane pyridine complex (1.84 g, 7.63 mmol), Cs2CO3 (4.62 g, 14.2 mmol) followed by tri-tert-butylphosphine (88 mg, 0.436 mmol) is added. The mixture is degassed and put under N2 before Pd2(dba)3 (200 mg, 0.218 mmol) is added. The mixture is stirred at 100° C. for 16 h before another portion of 2,4,6-trivinylcyclotriboroxane pyridine complex (1.84 g, 7.63 mmol) and Pd2(dba)3 (200 mg, 0.218 mmol) is added. Stirring is continued at 100° C. for 24 h before the mixture is diluted with EA, washed with 1N aq. NaOH solution, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 10:1 to give a first portion of 6-(2-methyl-propenyl)-5-vinyl-nicotinic acid ethyl ester. In addition, unreacted 5-chloro-6-(2-methyl-propenyl)-nicotinic acid ethyl ester is isolated. This material is again treated with 2,4,6-trivinylcyclotriboroxane pyridine complex as described before. Work-up, purification and combining the two portions give 6-(2-methyl-propenyl)-5-vinyl-nicotinic acid ethyl ester (1.37 g) as an oil; LC-MS: tR=0.87 min, [M+1]+=232.13.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:13][C:14]#[N:15]>>[CH3:8][O:9][C:10]1[CH:11]=[C:12](/[C:13](=[CH:13]/[C:12]2[CH:16]=[CH:17][C:18]([O:19][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:10][CH:11]=2)/[C:14]#[N:15])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COCCOCCl
Reactant: COc1ccc(CC#N)cc1OC
Product: COCCOCOc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1
Yield: 146.7 %

Procedure:
The hydroxyl group of 4-hydroxybenzaldehyde (24.9 g) was protected by use of 2-methoxyethoxymethyl chloride (24.4 g) in accordance with (production process 1), to thereby produce 4-methoxyethoxymethoxybenzaldehyde (33.5 g, yield: 80%). The thus-produced 4-methoxyethoxymethoxybenzaldehyde (21.0 g) and 3,4-dimethoxybenzyl cyanide (17.7 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce (Z)-2-(3,4-dimethoxyphenyl)-3-[4-(2-methoxy-ethoxymethoxy)-phenyl]acrylonitrile (29.1 g, yield: 86%). Separately, 2-methoxyethoxymethyl chloride (4.1 g), which had been prepared in a manner similar to that described above, and 3,4-dimethoxybenzyl cyanide (3.4 g) were subjected to condensation in accordance with process B of (production process 2), to thereby produce (Z)-2-(3,4-dimethoxy-phenyl)-3-[4-(2-methoxy-ethoxymethoxy)-phenyl]acrylonitrile (5.2 g, yield: 73%). The thus-produced (Z)-2-(3,4-dimethoxy-phenyl)-3-[4-(2-methoxy-ethoxymethoxy)-phenyl]-acrylonitrile (10.2 g) was subjected to deprotection in accordance with (production process 3), to thereby produce the target product (6.22 g, yield: 74%).
Reaction SMILES: CC1(C)COB([C:8]2[CH:31]=[CH:30][C:11]3[C:12]4[N:16]([CH2:17][CH2:18][O:19][C:10]=3[CH:9]=2)[CH:15]=[C:14]([C:20]2[N:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:22]=[CH:23][N:24]=2)[N:13]=4)OC1.Cl.N[OH:35].[OH-].[Na+]>O>[F:28][C:26]([F:27])([F:29])[CH2:25][N:21]1[C:20]([C:14]2[N:13]=[C:12]3[C:11]4[CH:30]=[CH:31][C:8]([OH:35])=[CH:9][C:10]=4[O:19][CH2:18][CH2:17][N:16]3[CH:15]=2)=[N:24][CH:23]=[N:22]1
Reactant: CC1(C)COB(c2ccc3c(c2)OCCn2cc(-c4ncnn4CC(F)(F)F)nc2-3)OC1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.4 %

Procedure:
To a solution of 8-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (1.7 g, 3.8 mmol) in IMS was added hydroxylamine hydrochloride (1.58 g, 22.8 mmol) and sodium hydroxide (1.22 g, 30.4 mmol). The reaction mixture was stirred at RT for 18 h before being diluted with water (100 mL). The reaction mixture was concentrated in vacuo to remove the IMS. The solid which formed was collected by filtration and dried in vacuo to yield 468 as a beige solid (1.1 g, 85%). LCMS: RT=2.81 min, [M+H]+=352
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]1([N:18]2[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]2)[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[CH:15]1([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19]2)[CH2:17][CH2:16]1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NC1CCN(C2CC2)CC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(NC2CCN(C3CC3)CC2)c([N+](=O)[O-])c1

Procedure:
To a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.26 g) and 1-cyclopropylpiperidin-4-amine (0.802 g) in tetrahydrofuran (20 mL) was added N,N-diisopropylethylamine (2.22 g) and 4-dimethylaminopyridine (35 mg). The mixture was heated at reflux for 18 hours and upon cooling was diluted with ethyl acetate (200 mL) and aqueous NaHCO3. The crude product was isolated by concentration of the organic layer and was purified on silica gel, which was eluted with 5% methanolic ammonia in methylene chloride to give the title compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(NC(C)C)(C)C.[I-]>CN(C)C=O.O>[CH:1]1([CH2:7][CH2:8][N:22]2[CH2:23][CH2:24][CH:19]([NH:18][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:20][CH2:21]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCCC1CCCCC1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: O=C(NC1CCN(CCC2CCCCC2)CC1)c1ccccc1
Temperature: 70 °C

Procedure:
2-Cyclohexylethyl bromide (1.9 g.) in dimethylformamide (10 ml.) was added to 4-benzamidopiperidine (2.2 g.), diisopropylamine (4 ml.) and a trace ofsodium iodide in dimethylformamide (10 ml.). The mixture was heated at 70° C for 16 hours, cooled, poured into water, and extracted with methylene chloride. The washed and dried extracts were evaporated and the solid residue was recrystallised from ethanol to give the product (1.25 g.), m.p. 174°-5° C. (Found: C, 76.4; H, 9.5; N, 8.9. C20H30H2O requires C, 76.4; H, 9.6; N, 8.9%).