Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[S:32][CH:33]=[CH:34][N:35]=1)CCC>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1>[CH:21]([N:18]1[CH2:19][CH2:20][N:15]([C:13]([C@H:10]2[CH2:11][CH2:12][C@H:7]([O:6][C:5]3[CH:24]=[CH:25][C:2]([C:31]4[S:32][CH:33]=[CH:34][N:35]=4)=[CH:3][CH:4]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:16][CH2:17]1)([CH3:23])[CH3:22]
Reactant: CC(C)N1CCN(C(=O)C2CCC(Oc3ccc(I)cc3)CC2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(-c4nccs4)cc3)CC2)CC1

Procedure:
To a mixture of 1.04 g (4.09 mmol) of cis-(4-isopropyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone, 1.50 g (6.82 mmol) of 4-iodephenol, 1.25 g (4.77 mmol) of triphenylphisphine in 5 ml THF, 1.1 g (4.78 mmol) of di-tert-butyl azodicarboxylate was added at 0° C., and stirred for 12 h at room temperature. After evaporation, the residue was purified by column chromatography on silica gel eluting with cyclohexane and ethyl acetate=from 100:0 to 2:1. The combined product fractions were evaporated to dryness to yield 0.67 g (14% yields, about 67% purity) of [4-(4-iodo-phenoxy)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone. A mixture 100 mg (0.15 mmol) of [4-(4-iodo-phenoxy)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone, 88 mg (0.24 mmol) of 2-tributylstannylthiazole, 15 mg (0.02 mmol) of bis(triphenylphosphine) palladium(II) dichloride and 2 ml of THF was refluxed for 8 hr under Ar. The mixture was evaporated. The residue was purified by column chromatography on silica eluting with cyclohexane and ethyl acetate=from 100:0 to 2:1. The combined product fractions were evaporated to dryness to yield 33 mg (36%) of the title compound. MS (m/e): 414.2 (MH+).
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=3)=[N:33][CH:32]=2)=[CH:27]1.Cl.Cl[CH2:46][CH2:47][N:48]([CH:52]([CH3:54])[CH3:53])[CH:49]([CH3:51])[CH3:50]>C(Cl)Cl.CO>[CH:49]([N:48]([CH:52]([CH3:54])[CH3:53])[CH2:47][CH2:46][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]2[S:35][C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)=[CH:32][N:33]=2)=[CH:38][CH:39]=1)([CH3:51])[CH3:50]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)N(CCOc1ccc(Nc2ncc(-c3ccsc3)s2)cc1)C(C)C

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol (Example 12) and using (2-chloroethyl)-diisopropyl-amine hydrochloride. Title compound: ES-MS: 402.0 [M+H]+; single peak at tR=6.53 min (System 1); Rf=0.50 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[OH-].[Na+].[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:26]2[CH:27]=[CH:28][C:23]([Br:22])=[CH:24][CH:25]=2)([CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(O)CCN(Cc2ccccc2)CC1
Reactant: Brc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: CC1(c2ccc(Br)cc2)CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a solution of 1-benzyl-4-methyl-piperidin-4-ol (0.4 g, 1.95 mmol) in bromobenzene (1.2 mL) was added aluminium trichloride (0.39 g, 2.9 mmol). The mixture was then heated to 100° C. for 14 hours and left standing at room temperature for 48 hours. Aqueous sodium hydroxide (1 N, 30 mL) was added and the products extracted into ethyl acetate, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 0-25% ethyl acetate/hexane. The fractions containing the desired product were concentrated under vacuum to give the title compound as a brown oil (0.5 g). LCMS m/z 344.5 [M+H]+. R.T.=3.13 min (Analytical Method 4).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]([CH:15]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17][CH2:16]2)[OH:14])[CH2:9]1)=O)(C)(C)C.C1C=NC2C3N=CC=CC=3C=CC=2C=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:43][C:44]1[CH:49]=[C:48](I)[CH:47]=[C:46]([Cl:51])[CH:45]=1.C1(C)C=CC=CC=1.Cl.CCO>[Cu]I>[Cl:43][C:44]1[CH:49]=[C:48]([CH:47]=[C:46]([Cl:51])[CH:45]=1)[O:14][CH:13]([CH:15]1[CH2:16][CH2:17][C:18]([F:21])([F:22])[CH2:19][CH2:20]1)[CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]([C@@H](O)C2CCC(F)(F)CC2)C1
Reactant: Clc1cc(Cl)cc(I)c1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: FC1(F)CCC(C(Oc2cc(Cl)cc(Cl)c2)C2CCNC2)CC1
Temperature: 105 °C
Reaction time: 8 h

Procedure:
(R)-3-[(S)-(4,4-Difluorocyclohexyl)hydroxymethyl]pyrrolidine-1-carboxylic acid t-butyl ester (44.0 mg, 138 μmol), copper(I) iodide (7.9 mg, 41 μmol), o-phenanthroline (15 mg, 83 μmol) and cesium carbonate (89.8 mg, 276 μmol) were combined. 1,3-Dichloro-5-iodobenzene (75.2 mg, 276 μmol) was added, followed by the addition of toluene (220 μL, 2.1 mmol). Air was bubbled through the mixture, the vessel was sealed, and the mixture was heated at 105° C. for 48 hours. The mixture was filtered, rinsed with DCM, and concentrated. The crude material was treated with 1.25M HCl in EtOH (5.8 mL, 7.2 mmol) and stirred overnight. The mixture was concentrated, redissolved in 1:1 AcOH:H2O and purified by preparative HPLC to yield the title compound as a mono-TFA salt (1.5 mg, 96% purity). MS m/z: [M+H]+ calcd for C17H21Cl2F2NO, 364.10. found 364.0.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([Br:21])[CH:19]=2)[NH:14][CH:13]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([Br:21])[CH:19]=2)[NH:14][CH:13]=1)=[S:31]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(Nc1cccc(F)c1F)c1c[nH]c2ncc(Br)cc12
Solvent: Cc1ccccc1
Product: Fc1cccc(NC(=S)c2c[nH]c3ncc(Br)cc23)c1F

Procedure:
To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (2,3-difluoro-phenyl)-amide (300 mg, 0.85 mmol) in toluene (6 mL) was added Lawesson's reagent (210 mg, 0.52 mmol). The suspension was heated under reflux for 14 h. The solvent was removed by evaporation and the residue was dried on the pump for the next reaction. MS (ES+): m/e=368 (M+H); LC: 3.6 min.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[CH:35]=[CH:34][C:15]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[N:19][N:18]=2)=[CH:14][CH:13]=1.[F:36]N1C(C)(C)C2C=CC=CC=2S1.C([O-])(O)=O.[Na+]>C1COCC1.C(O)(=O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[F:36])=[N:19][N:18]=2)=[CH:34][CH:35]=1
Reactant: CC1(C)c2ccccc2SN1F
Reactant: Clc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: FC(c1ccncc1)c1nnc(Nc2ccc(Cl)cc2)c2ccccc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under N2-atmosphere, 7.02 ml (4.65 mmol; 15% in toluene) of potassium bis(trimethylsilyl)amide are dissolved in 78 ml THF and then cooled to −78° C. A solution of 537.5 mg (1.55 mmol) of 1-(4-chlor-anilino)-4-(pyridin-4-yl-methyl)-phthalazine (see WO 98/35958) in 30 ml THF is added dropwise. The resulting black solution is stirred for additional 30 min, then 1.00 g (4.65 mmol) of 2-fluoro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole (Fluka; Buchs, Switzerland) in 30 ml THF are added slowly. The reaction solution slowly turns to yellow-orange. After 3 h at −78° C., a solution of 1 ml acetic acid in 5 ml of THF is added. The reaction mixture is poured into a diluted NaHCO3-solution and extracted three times with ethyl acetate. The organic layers are washed with 2 portions of water and brine, dried (Na2SO4) and concentrated. Chromatography (SiO2: EtOAc/dichloromethane 2:1 to EtOAc to EtOAc/EtOH 9:1 to 4:1) and crystallization from acetonitrile/acetone finally gave the title compound: 1H NMR (DMSO-d6) δ 9.50 (s, HN), 8.65 (d, 1H), 8.61 (d, 2H), 8.16 (d, 1H), 8.03 (t, 1H), 7.99 (t, 1H), 7.96 (d, 2H), 7.43 (d, 2H), 7.40 (d, 2H), 7.34 (s, 1H); 19F NMR (DMSO-d6) δ −50.7; FAB-MS (M+H)+=365.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].[C:9]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1)([O:11][CH3:12])=[O:10].N1C=CN=C1.CC([O-])=O.[Na+].C=O>CC(O)=O>[CH2:1]([C:3]1[N:4]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([C:9]([O:11][CH3:12])=[O:10])=[CH:14][CH:15]=2)[CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCc1nc(C)c[nH]1
Agent: C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1nc(C)cn1Cc1ccc(C(=O)OC)cc1
Reaction time: 2 h

Procedure:
Methyl 4-[[2-ethyl-4-methyl-1H-imidazol-1-yl]methyl]benzoate compound was prepared from 2-ethyl-4-methyl-imidazole and (4-carbmethoxy) benzylbromide in an analogous fashion as described in Example 11. A solution of the above imidazole (2.17 g, 8.14 mmol), NaOAc (1.17 g), 37 % HCHO (10 mn) , and AcOH (1.2 mn) was heated under reflux for 22 hours. The solution was evaporated under vacuo, and the residue was stirred with 10 mL of 20% NaOH solution for 2 hours. It was diluted with water and the solution was extracted with CH2Cl2. The extract was washed with water, dried, and evaporated to an oil. It was chromatographed (CH2Cl2 /MeOH, 2-5%) to give 1.0 g of the desired hydroxymethyl compound as a foam. MS (CI 288 (m).
Reaction SMILES: Cl.[OH:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[N+:9]([O-])([OH:11])=[O:10].O.[OH-].[Na+]>S(=O)(=O)(O)O.C(O)(C)C>[OH:2][C:3]1[N:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][N:4]=1
Reactant: Oc1ncccn1
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc(O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
With reference to Scheme 3, to a solution of 2800 g (21.13 mol) of 2-hydroxypyrimidine hydrochloride in 8400 mL of concentrated sulfuric acid was added dropwise 3434 g (52.83 mol) of fuming nitric acid. The solution was heated at reflux for 16 h, then it was allowed to cool to room temperature and was poured slowly into cold water (30 L). The mixture was basified with 50% NaOH to pH 2.5. Isopropyl alcohol (16 L) was added and the mixture was stirred for 60 minutes after which the layers were allowed to separate. The organic layer was diluted with ethyl acetate (16 L) and washed with brine. The organics were concentrated under reduced pressure to yield 2689 g of crude product, which was used in the next step without purification.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=O.[C:13](CC(OC)=O)#N.[OH-].[Na+].Cl>O.CN(C=O)C.C(N(CC)CC)C>[OH:12][C:5]1[CH:13]=[C:2]([OH:4])[C:1]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: COC(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cc(O)c2ccccc2n1
Reaction time: 1 h

Procedure:
Into a 150 ml three neck flask, equipped with an agitator, a reflux condenser sealed on its upper end with a gas bubbler, a thermometer and an electric heating mantle were charged 16.3 g pure isatoic anhydride (M.W. 163) 10.1 g triethylamine (M.W. 101), 9.9 g methyl cyanoacetate (M.W. 99) and 2 ml DMF. The reaction mixture, under agitation, was kept at a temperature within the range of 25° to 30° C. for approximately 1 hour. During this period a constant evolution of gas was observed. The temperature of the reaction mixture was then elevated to and maintained at 78° to 80° C. for approximately 2 hours. At the end of this heating period the evolution of gas practically stopped and the reaction mixture turned into a slightly yellow, good stirrable oil. A minimum of water (approximately 40 ml) and the still hot oil were transferred to a 300 ml stainless steel autoclave, equipped with an anchor agitator, a pressure gauge, a thermocouple and a vent-valve. A charge of 14.7 g sodium hydroxide (MW 40) pellets was added to the reaction mixture and the autoclave was closed. The contents of the autoclave, under agitation, were heated to and maintained at a temperature in the range of 150° to 155° C. for 3 hours. The pressure in the autoclave reached 275 to 280 psig during the heating; after cooling to 50° to 60° C. hot water was added to the autoclave and approximately 600 ml of a brownish colored solution was removed therefrom and treated with 1 g activated charcoal at 60° C. A slightly yellowish colored solution which resulted was then acidified with concentrated hydrochloric acid to a pH of approximately 2. White, slightly creamy colored precipitate which formed was recovered by filtration; the precipitate was then reslurried in 200 ml water, refiltered and dried at 110° C. The yield was 14.17 g (87.9 percent of theory based upon the isatoic anhydride charged) 2,4-dihydroxyquinoline, melting point 350°-355° C. Examination of the product by infrared spectroscopy and nuclear magnetic resonance indicated that it was of high purity.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:7]([O:15][C:16]2[CH:23]=[CH:22][C:19](C=O)=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].[C:30](O)(=O)[CH2:31][C:32]([OH:34])=[O:33].CO>N1CCCCC1.N1C=CC=CC=1>[CH2:1]([C:5]1[C:6]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:7]([O:15][C:16]2[CH:23]=[CH:22][C:19](/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCc1cc2ccccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Solvent: CO
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCCCc1cc2ccccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Yield: 53.3 %

Procedure:
4-[(3-Butyl-2-phenyl-1-naphthalenyl)oxy]benzaldehyde (173) (0.14 g, 0.36 mmol) was heated with malonic acid (0.12 g, 1.09 mmol) and 1 drop of piperidine in pyridine at 85° C. overnight to give the crude product as a light yellow viscous oil, which upon trituration with 1% MeOH in hexanes, yielded 81 mg (53%) of the title compound (174) as a white solid. mp 160-161° C. 1H NMR (400 MHz, CH3OH-d4): δ 0.76 (t, J=7.3 Hz, 3H), 1.15-1.30 (m, 2H), 1.40-1.55 (m, 2H), 2.60 (t, J=7.9 Hz, 2H), 6.26 (d, J=16.0 Hz, 1H), 6.56 (d, J=8.6 Hz, 2H), 7.14-7.19 (m, 2H), 7.20-7.30 (m, 3H), 7.35 (d, J=8.6 Hz, 2H), 7.37-7.42 (m, 1H), 7.46-7.56 (m, 2H), 7.70-7.77 (m, 2H), 7.91 (d, J=8.2 Hz, 1H). LCMS (APCI): m/z 423 (M+H)+, m/z 421 (M−H)−. Anal. Calc for C29H26O3.⅙H2O: C, 81.86; H, 6.24. Found: C, 81.86; H, 6.25.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[S:19]1[CH:23]=[CH:22][C:21]2[C:24](=O)[C:25]3[S:26][CH:27]=[CH:28][C:29]=3[C:30](=O)[C:20]1=2.Cl[Sn]Cl>C1COCC1.[Cl-].[Na+].O>[C:13]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:24]2[C:25]3[S:26][CH:27]=[CH:28][C:29]=3[C:30]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:20]3[S:19][CH:23]=[CH:22][C:21]=23)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCCCCCCCCCc1ccccc1
Reactant: O=C1c2ccsc2C(=O)c2ccsc21
Agent: Cl[Sn]Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CCCCCCCCCCc2c3ccsc3c(CCCCCCCCCCc3ccccc3)c3ccsc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a 100 mL flask under nitrogen was added magnesium (486 mg, 20 mmol) and anhydrous THF (10 mL). The mixture was heated under reflux and 10-bromodecylbenzene (5.95 g, 20 mmol) was added dropwise. The reaction mixture was kept under reflex temperatures until all magnesium was consumed. Subsequently, 4,8-dihydrobenzo[1,2-b:4,5-b′]dithiophene-4,8-dione (1.1 g, 5.0 mmol) suspended in anhydrous THF (10 ml) was added dropwise. After refluxing for 3 hours more, it was cooled down to room temperature. SnCl2 solution (7.5 g in 19 mL 10% HCl) was slowly added dropwise and then the mixture was kept at 60° C. overnight. After cooling down, brine (25 mL) was added. The organic phase was separated and dried over Na2SO4. The residue after vacuum evaporation was purified by column chromatography with hexane/AcOEt 50:1 as eluent and gave a pale yellow oil (466 mg, yield 15%), which turned into a solid upon standing for a few days. 1H NMR (CDCl3, 500 MHz) δ=7.48 (d, J=6.0 Hz, 2H), 7.46 (d, J=5.0 Hz, 2H), 7.27-7.32 (m, 4H), 7.19 (d, J=7.0 Hz, 6H), 3.19 (t, J=8.0 Hz, 4H), 2.61 (t, J=7.5 Hz, 4H), 1.75-1.86 (m, 4H), 1.58-1.67 (m, 4H), 1.42-1.51 (m, 4H), 1.15-1.41 (m, 20H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:12](N)(N)(=[O:14])=[O:13]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][NH:11][S:12]1(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCNCc1ccccc1
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Product: O=S1(=O)NCCN1Cc1ccccc1
Yield: 40 %

Procedure:
To a solution of N-benzylethane-1,2-diamine (1.00 g, 6.65 mmol) in pyridine (10 mL) was added sulfamide (0.77 g, 7.98 mmol). The mixture was refluxed for 16 hours. The solvent was removed in vacuo. The residue was diluted with ethyl acetate (100 mL), washed with water (200 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (1/4) to afford the title compound as an oily solid in 40% yield (0.57 g): 1H NMR (300 MHz, CDCl3) δ 7.35-7.27 (m, 5H), 4.59 (br s, 1H), 4.15 (s, 2H), 3.48-3.42 (m, 2H), 3.27-3.22 (m, 2H); MS (ES+) m/z 213.2 (M+1).
Reaction SMILES: [Cl-].[CH2:2]([O:4][CH:5]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:3].C1CCN2C(=NCCC2)CC1.[CH2:41]([O:48][C:49]1[C:56]([F:57])=[CH:55][C:52]([CH:53]=O)=[CH:51][C:50]=1[F:58])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1>[CH2:41]([O:48][C:49]1[C:56]([F:57])=[CH:55][C:52](/[CH:53]=[C:5](\[O:4][CH2:2][CH3:3])/[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:51][C:50]=1[F:58])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/c1cc(F)c(OCc2ccccc2)c(F)c1)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (1,2-diethoxy-2-oxoethyl)triphenylphosphonium chloride (679) (1.61 g, 3.76 mmol) in tetrahydrofuran (56 mL) was added DBU (0.67 ml, 4.51 mmol) and the reaction was stirred for 10 minutes at room temperature. 4-(benzyloxy)-3,5-difluorobenzaldehyde (1.40 g, 5.64 mmol) was added in one portion and the reaction was stirred at room temperature for 18 hours. The solvent was removed in vacuo, diethyl ether was added and the solids filtered. The filtrate was concentrated in vacuo and the residue oil was purified by flash column chromatography (0-30% EtOAc in hexanes) to provide (Z)-ethyl 3-(4-(benzyloxy)-3,5-difluorophenyl)-2-ethoxyacrylate (680).
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH:71]1[N:75]=[C:74]([NH2:76])[S:73][CH:72]=1>CN(C=O)C>[CH2:38]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([NH:76][C:74]2[S:73][CH:72]=[CH:71][N:75]=2)=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:39]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)Nc3nccs3)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 2-aminothiozole (8.26 mg, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (15.6 mg, 46%). LC-MS m/z 622 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH:18]=[O:19])[CH:15]=[N:14]1.[OH2:20]>S(=O)(=O)(O)O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[N:14]1
Reactant: O
Reactant: O=Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Product: O=C(O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1

Procedure:
2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-carboxaldehyde (1 g) was oxidised using chromium trioxide (26.67 g) in water (40 ml) and concentrated sulphuric acid (23 ml), made up to 100 ml. The product was extracted with ether and worked up in conventional manner to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-carboxylic acid, m.p. 155°-157°.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[NH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>C(O)C>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([N:13]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])=[CH:15][CH:16]=1)#[N:19]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: N#Cc1ccc(N)cc1
Solvent: CCO
Product: N#Cc1ccc(N2CCC(C(=O)O)C2=O)cc1
Yield: 35.5 %

Procedure:
A mixture of 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g, 2.94 mmol) and 4-aminobenzonitrile (1.04 g, 8.82 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. The solution was concentrated under reduced pressure and the residue was dissolved in a solution of sodium hydroxide 6N, washed with dichloromethane, acidified with a solution of sodium hydrogen phosphate (1M) to pH=2, extracted with ethyl acetate dried and concentrated under reduced pressure to yield 0.240 g (36%) of a brown solid, which was used in the next step without further purification.