Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[F:34])[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:24]=2)[N:21]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:28]1([C:26]([NH:25][C:23]2[N:24]=[C:19]3[CH:18]=[CH:17][C:16]([O:15][C:14]4[CH:31]=[CH:32][C:33]([F:34])=[C:12]([NH:11][C:8]([C:4]5[S:3][C:2]([CH3:1])=[N:6][C:5]=5[CH3:7])=[O:10])[CH:13]=4)=[N:21][N:20]3[CH:22]=2)=[O:27])[CH2:29][CH2:30]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cc1nc(C)c(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C)c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)s1
Yield: 32.2 %

Procedure:
In the same manner as in Example 261 and using 2,4-dimethyl-1,3-thiazole-5-carboxylic acid (190 mg, 1.2 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol), 1-hydroxybenzotriazole (170 mg, 1.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (240 mg, 1.2 mmol), N,N-diisopropylethylamine (240 mg, 1.9 mmol) and N,N-dimethylformamide (5 mL) as starting materials, the title compound (93 mg, 32%) was obtained as a pale-yellow solid.
Reaction SMILES: C(C1C(=O)CC[O:6]C1)C=C.C(O)CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:27]([CH:30]1[CH2:39][O:38][CH2:37][CH2:36][C:31]21[O:35][CH2:34][CH2:33][O:32]2)[CH:28]=C.I([O-])(=O)(=O)=O.[Na+]>C1(C)C=CC=CC=1.C1COCC1.O.[Os](=O)(=O)(=O)=O>[O:35]1[C:31]2([CH2:36][CH2:37][O:38][CH2:39][CH:30]2[CH2:27][CH:28]=[O:6])[O:32][CH2:33][CH2:34]1
Reactant: C=CCC1COCCC12OCCO2
Reactant: C=CCC1COCCC1=O
Agent: O=[Os](=O)(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: OCCO
Solvent: O
Solvent: C1CCOC1
Product: O=CCC1COCCC12OCCO2
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(prop-2-en-1-yl)tetrahydro-4H-pyran-4-one (1.00 g, 7.13 mmol), ethylene glycol (0.597 mL, 10.70 mmol) and p-toluenesulfonic acid monohydrate (0.136 g, 0.713 mmol) in toluene (30 mL) was heated to 120° C. overnight. The reaction was then cooled to rt and concentrated. The residue was purified via column chromatography and used in the next step. To a mixture of 6-(prop-2-en-1-yl)-1,4,8-trioxaspiro[4.5]decane (0.840 g, 4.56 mmol) and osmium tetraoxide (2.5 wt % in T-BuOH, 0.551 mL, 0.046 mmol) in THF (15 mL) and water (5 mL) at rt was added sodium periodate (2.15 g, 1.19 mmol) portionwise over 5 min. The mixture was stirred at rt for 2 hr. The reaction was then quenched with sat'd. aq. sodium sulfite. The mixture was extracted 3× with Et2O. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 9.71 (s, 1H), 3.81-3.99 (m, 6H), 3.64-3.70 (m, 1H), 3.47 (dd, 1H, J=8.6 Hz, 11.5 Hz), 2.49-2.57 (m, 2H), 2.18-2.26 (m, 1H), 1.65-1.82 (m, 2H).
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7][C:6]([O-:9])=[C:5](C(OC)=O)[CH2:4]1)#[N:2].[Na+].Cl.C(=O)=O.[OH-].[Na+]>C(O)(=O)C.O>[C:14]1([C:3]2([C:1]#[N:2])[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C1=C([O-])CCC(C#N)(c2ccccc2)C1
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CC1(c2ccccc2)CCC(=O)CC1

Procedure:
In a flask they were introduced successively under nitrogen atmosphere 179.7 g of sodium 4-cyano 4-phenyl 2-methoxy carbonyl cyclohex-1-enolate, 450 ml water, 450 ml acetic acid then 180 ml hydrochloric acid. It appears a milky suspension which is heated to reflux under stirring. After 5 hours heating the evolution of carbon dioxide has ceased and a green homogeneous solution is obtained. After reverting to room temperature this solution is carefully neutralized by adding a 5 N solution of sodium hydroxide while maintaining the inner temperature at about 20° by means of a iced water bath.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([CH:17]=[CH2:18])[N:12]2[C:19](=[O:23])[CH2:20]C=C)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]>C(Cl)Cl.CC1C=C(C)C(N2[CH-]N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]3[N:12]2[C:19](=[O:23])[CH2:20][CH:18]=[CH:17]3)=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: C=CCC(=O)N1[C@H](C=C)CCC[C@@H]1c1ccc(C(=O)OC)cc1
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1cc(C)c(N2[CH-]N(c3c(C)cc(C)cc3C)CC2)c(C)c1
Solvent: ClCCl
Product: COC(=O)c1ccc([C@H]2CCC[C@H]3C=CCC(=O)N32)cc1
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A solution of 1-[(2R*,6S*)-2-(4-carbomethoxyphenyl)-6-vinylpiperidin-1-yl]-3-buten-1-one (281 mg) and tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidene]ruthenium (IV) dichloride (53 mg) in methylene chloride (150 mL) was heated under reflux for 1.5 hours. The reaction solution was left to cool to room temperature and then concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=4:1->ethyl acetate) to obtain 145 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCBr
Product: CCCCCCCOc1ccc(C=O)cc1
Yield: 80.5 %

Procedure:
General procedure K was used to convert 4-hydroxybenzaldehyde (8.2 mmols) and 1-bromoheptane (12.3 mmols) to 6.6 mmols (80%) of the title product was recovered. 1H NMR (300 MHz, CDCl3) δ 9.87 (s, 1H), 7.82 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 4.03 (t, J=6.5 Hz, 2H), 1.81 (quin., J=6 Hz, 1H), 1.24-1.53 (m, 8H), 0.89 (t, J=6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 191.0, 164.4, 132.13, 129.8, 114.9, 68.6, 31.9, 29.18, 29.1, 26.1, 22.7, 14.2.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[OH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:27]([CH2:28][CH2:29][C@:11]12[CH3:12])[C@:24]1([CH2:25][OH:26])[C:19](=[CH:20][C:21](=[O:30])[CH2:22][CH2:23]1)[CH2:18][CH2:17]3.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(O)(C)(C)C>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[OH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:27]([CH2:28][CH2:29][C@:11]12[CH3:12])[C@:24]1([CH2:25][OH:26])[C:19](=[CH:20][C:21](=[O:30])[CH2:22][CH2:23]1)[CH:18]=[CH:17]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O

Procedure:
17β,19-Dihydroxy-4-androsten-3-one diacetate and chloranil are dissolved in t-butanol which is rapidly brought to reflux. The t-butanol is distilled at atmospheric pressure at such a rate that the total reflux and distillation time equals one hour. The dark residue which remains is triturated with hot chloroform and filtered. The filtrate is extracted with water, a 2% sodium hydroxide solution and again with water. The organic layer is dried over magnesium sulfate and the solvent removed to yield 17β,19-dihydroxy-4,6-androstadien-3-one diacetate. The diene so prepared is refluxed with dichlorodicyanobenzoquinone in anhydrous dioxane for a period of about 48 hours. The mixture is cooled, filtered and the filtrate poured onto a mixture of methylenechloride and water. The organic layer is separated, washed with water, dried well over magnesium sulfate and the solvent removed. The dark residue remaining is chromatographed on silica gel and eluted with methylenechloride to yield from the eluate the desired 17β,19-dihydroxy-1,4,6-androstatrien-3-one diacetate.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([S:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)([O-])=O>C(O)C.O.[Fe]>[NH2:2][C:5]1[CH:6]=[C:7]([S:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2ccc3[nH]nc(-c4ccccc4)c3c2)c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cccc(S(=O)(=O)Nc2ccc3[nH]nc(-c4ccccc4)c3c2)c1
Temperature: 20 °C
Yield: 46.4 %

Procedure:
3-Amino-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide can be obtained in the following way: 0.06 ml of an aqueous hydrochloric acid solution is added to a solution of 0.28 g of 3-nitro-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide in 15 ml of absolute ethanol and 0.3 ml of water. The reaction mixture is refluxed, then 0.12 g of powdered iron is added in small portions. The reaction mixture is refluxed for 2 hours and is then cooled to a temperature in the region of 20° C. 30 ml of water are added to the mixture, which is filtered through Celite®, and the solid is washed with water then ethyl acetate. The filtrate is basified with an aqueous 32% ammonium hydroxide solution to a pH in the region of 12, and is then extracted with 3 times 20 ml of ethyl acetate. The organic extracts are pooled, washed with 3 times 10 ml of water, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The solid residue is washed successively with diisopropyl ether then dichloromethane, partially dried and dried. 0.12 g of 3-amino-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide is thus obtained in the form of an off-white powder melting at 205° C.
Reaction SMILES: CCN(CC)CC.[O:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9]1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH3:34])[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:22]([O:26][C:27](=[O:28])[NH:29][C@H:30]([C:31](=[O:32])[NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][CH:10]1[CH2:11][CH2:12][CH2:13][O:8][CH2:9]1)[CH3:34])([CH3:23])([CH3:24])[CH3:25]
Reactant: Nc1ccccc1NC1CCCOC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1NC1CCCOC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
Et3N (1.6 mL, 11.3 mmol) was added to a stirred mixture of N-(tetrahydropyran-3-yl)benzene-1,2-diamine (0.61 g, 3.17 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.78 g, 4.14 mmol), HOAt (0.56 g, 4.14 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.79 g, 4.14 mmol) in anhydrous DCM (20 mL) at 0° C. under a nitrogen atmosphere. Stirring was continued for 10 min at 0° C. then the mixture was slowly warmed to RT and stirred at RT for 3 h. The reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was further extracted with DCM (×2) and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-4% 2M NH3/MeOH in DCM) affording {(S)-1-[2-(Tetrahydropyran-3-ylamino)phenylcarbamoyl]ethyl}carbamic acid tertbutyl ester as a white solid (0.96 g, 70%). LCMS: RT 3.00 min [M+H]+ 364.1.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[S:14]([OH:17])(=O)=[O:15]>CCCCCC>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[S:14]([Cl:3])(=[O:17])=[O:15]
Reactant: COc1cc(C)ccc1S(=O)(=O)O
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Product: COc1cc(C)ccc1S(=O)(=O)Cl
Temperature: 25 °C
Yield: 59 %

Procedure:
Thionyl chloride (350 ml, 2.5 ml/g) was cautiously added to 2-methoxy-4-methylbenzenesulfonic acid (from (b), 140 g, 0.587 moles) over a period of 30 minutes. The mixture was stirred and heated to reflux for 1 hour and at room temperature for 16 hours. The excess thionyl chloride was removed by evaporation under reduced pressure and the residue was partitioned between deionised water (300 ml) and dichloromethane (400 ml). The phases were separated and the organic phase dried (MgSO4), filtered and concentrated to give the crude product (70 g, 54% yield). The crude product was partially dissolved in hexane (490 ml) at reflux, hot filtered to remove insoluble material and allowed to cool. The precipitated product was collected to give the title compound (41.3 g, 59% recovery) as a white crystalline solid (m.p.=81-84° C.).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1.C(OCC)(=O)C.O>[O:13]=[C:8]1[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:11][CH2:10][N:9]1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C1NCCCC1c1ccccc1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCCC(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of the product from Example 91B (1.08 g, 6.16 mmol) in tetrahydrofuran (10 mL) at 0° C. was added potassium tert-butoxide (1.0 Min tetrahydrofuran) (6.78 mL, 6.78 mmol). After stirring for 20 minutes, ethyl 2-bromoacetate (0.750 mL, 6.78 mmol) was added, and the reaction was allowed to warm to room temperature. After stirring for 3 hours, the reaction was poured in ethyl acetate/water (1:1, 200 mL). The organic layer was washed with brine (100 mL), dried over magnesium sulfate and concentrated. Silica gel chromatography using a GraceResolv 80 g silica gel column (Grace Davison Discovery Sciences) eluting with a gradient of 25% ethyl acetate/hexanes to 85% ethyl acetate/hexanes (flow=40 mL/minute) over 30 minutes supplied the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.39-7.14 (m, 5H), 4.45 (d, J=17.2, 1H), 4.23 (q, J=7.1, 2H), 3.91 (d, J=17.2, 1H), 3.78-3.65 (m, 1H), 3.65-3.49 (m, 1H), 3.41 (dt, J=5.7, 11.3, 1H), 2.32-2.12 (m, 1H), 2.12-1.74 (m, 3H), 1.30 (t, J=7.2, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][CH:5]=[CH:6][N:7]=1.N1C=CN=C1.[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[Si:13]([O:1][CH2:2][C:3]1[NH:4][CH:5]=[CH:6][N:7]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1ncc[nH]1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1ncc[nH]1)(c1ccccc1)c1ccccc1
Yield: 82 %

Procedure:
A solution of 2-hydroxymethylimidazole (1.96 g ; 0.02 mole), imidazole (3.4 g; 0.05 mole), tert-butyldiphenylsilyl chloride (6.6 g; 0.024 mole) in DMF (20 ml) was stirred under an argon atmosphere for 16 hours. The mixture was extracted with ethyl acetate and purified by flash column chromatography eluting with a gradient 50-70% ethyl acetate/petroleum ether to give 2-(tert-butyldiphenylsilyloxymethyl)imidazole as a solid.
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:20][C:21]([C:42]([O:44][CH3:45])=[O:43])=[CH:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]([C:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C:34]=2[C:39]([NH2:41])=O)=[O:32])[CH:26]=[CH:27][C:28]=1[Cl:29].O>ClCCl>[Br:20][C:21]([C:42]([O:44][CH3:45])=[O:43])=[CH:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]([C:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C:34]=2[C:39]#[N:41])=[O:32])[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: COC(=O)C(Br)=Cc1cc(NC(=O)C2=C(C(N)=O)CCCC2)ccc1Cl
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: COC(=O)C(Br)=Cc1cc(NC(=O)C2=C(C#N)CCCC2)ccc1Cl
Reaction time: 2 h

Procedure:
2.6 g of pyridine and then, at from 0 to 5° C., 4.6 g of trifluoroacetic anhydride in 10 ml of dichloromethane were added dropwise to a solution of 5 g of N-(3-(2-bromo-2-methoxycarbonylethenyl)-4-chlorophenyl]-cyclohexene-1,2-dicarboxamide in 80 ml of dichloromethane. Stirring was carried out for 1 hour at 5° C. and 2 hours at 25° C., after which 100 ml of water were added and stirring was carried out for a further 30 minutes. The organic phase was then separated off and dried. After removal of the solvent, the crude product was dissolved in 50 ml of diethyl ether. The product which had crystallized out was separated off from the cooled solution, the melting point of said product being 123-125° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>CN(C)C=O>[C:37]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4ccccc4)cc3)cc21
Yield: 58.4 %

Procedure:
In a similar manner to that described in Example 47, a reaction was carried out using 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}thiazolidine-2,4-dione dihydrochloride (400 mg), benzoylchloride (126 mg), triethylamine (263 mg) and anhydrous N,N-dimethylformamide (8 ml) and the reaction mixture was purified to give the title compound (247 mg).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:32]=[CH:31][C:9]2[N:10]3[C:28]([C:29]#[N:30])=[CH:27][CH:26]=[C:11]3[C:12]3([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[O:13][C:8]=2[CH:7]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[CH:32]=[CH:31][C:9]2[N:10]3[C:28]([C:29]#[N:30])=[CH:27][CH:26]=[C:11]3[C:12]3([CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[O:13][C:8]=2[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)c1ccc(C#N)n1-2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCc1ccc2c(c1)OC1(CCNCC1)c1ccc(C#N)n1-2
Yield: 62 %

Procedure:
tert-Butyl 7′-(bromomethyl)-1′-cyano-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (33.0 mg, 0.0720 mmol) and potassium acetate (35.3 mg, 0.360 mmol) were combined in DMF (0.5 mL) and the mixture was stirred at 80° C. for 18 hours. The mixture was taken up in NH4Cl (10 mL) and was extracted with CH2Cl2 (10 mL). Solvent was removed under reduced pressure and the residue was purified by column chromatography (0-10% EtOAc/CH2Cl2) to obtain tert-butyl 7′-(acetoxymethyl)-1′-cyano-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (19.5 mg, 62%) as a clear oil. ESI-MS m/z calc. 437.2. found 438.5 (M+1)+; Retention time 2.05 minutes (3 min run). tert-Butyl 7′-(acetoxymethyl)-1′-cyano-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate was dissolved in CH2Cl2 (10 mL) before TFA (5.0 mL, 65 mmol) was added. The solvent was removed under reduced pressure to give (1′-cyanospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-7′-yl)methyl acetate (15 mg, 62%). ESI-MS m/z calc. 337.1. found 338.3 (M+1)+; Retention time 1.16 minutes (3 min run).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])=[CH:6][C:5]=1[C:11]([F:12])([F:13])[F:14])([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
To a stirred, cooled solution of 100 g. of 4-nitro-3-trifluoromethylaniline in 400 ml. of pyridine, slowly and in a dropwise fashion, add 54 g. of isobutyrylchloride and then heat the reaction mixture on a steam bath for 1.5 hours. Cool and pour the resulting mixture into ice-water, filter and water-wash the crude anilide, crystallize the product of this example from benzene to obtain analytically pure material, m.p. 111.5°-112.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:30]([NH:29][C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:28][CH:27]=2)=[O:31])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccc(C(F)(F)F)cc2)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (45.8 mg, 0.167 mmol) in CH2Cl2 (2 mL) was added 4-(trifluoromethyl)phenyl isocyanate (0.28 μL, 0.196 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH, in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 137 as a colorless solid (25.1 mg, 33%). LCMS m/z (%)=462 (MH+) (100), 1H NMR (400 MHz, DMSO-d6) δ: 9.11 (bs, 1H), 8.75 (bs, 1H), 7.65 (d, J=9.08 Hz, 2H), 7.62 (d, J=9.35 Hz, 2H), 7.47 (dd, J=9.09, 2.78 Hz, 1H), 7.45 (d, J=1.77 Hz, 1H), 7.39 (d, J=2.78 Hz, 1H), 7.10 (d, J=8.84 Hz, 1H), 6.24 (d, J=1.77 Hz, 1H), 3.98 (t, J=6.32 Hz, 2H), 3.66 (s, 3H), 2.19 (t, J=7.07 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[F-:12].[K+].CN(C=O)C>[Cl-].[Na+].O>[I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([F:12])=[N:6][CH:7]=1
Reactant: [F-]
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(I)cnc1F
Yield: 47.5 %

Procedure:
5-iodo-3-nitro-2-chloropyridine (0.624 g, 2.19 mmol), KF (265 mg, 58.1 mmol), and DMF (3 mL) were stirred at 120 degrees Celsius for 24 h. The mixture was poured into saturated brine, extracted with ethyl acetate, dried over sodium sulfate, then concentrated. The crude residue was purified by flash chromatography using 4-1 hexane:ethyl acetate to yield 5-iodo-3-nitro-2-fluoropyridine (279 mg, 47%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[C:15]([OH:20])=[N:16][O:17][C:18]=1[CH3:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)=[O:60])[CH2:55][CH2:56][CH3:57]>CN(C=O)C>[CH2:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][N:64]([C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:14]2[C:15]([OH:20])=[N:16][O:17][C:18]=2[CH3:19])[CH2:63][CH2:62]1)=[O:60])[CH2:55][CH2:56][CH3:57]
Reactant: Cc1onc(O)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCOC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](Cc2c(O)noc2C)NC(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To a solution of 110 mg (S)-2-tert-Butoxycarbonylamino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)-propionic acid in 2 ml DMF were added 0.07 ml DIPEA, 107 mg HATU and 50 mg Piperazine-1-carboxylic acid butyl ester. After stirring for 2 h the reaction mixture was concentrated, diluted with DCM and washed with aqueous LiCl (4%). The crude product obtained was used without further purification. Yield: 146 mg.