Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][C:21]([CH2:29][OH:30])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1.[C:41]1([N:47]2[CH:51]=[C:50](B3OC(C)(C)C(C)(C)O3)[CH:49]=[N:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:50]3[CH:49]=[N:48][N:47]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:51]=3)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][C:21]([CH2:29][OH:30])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1
Reactant: CCOC(=O)C1(CO)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Reactant: CC1(C)OB(c2cnn(-c3ccccc3)c2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1(CO)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnn(-c5ccccc5)c4)c3n2)CC1
Temperature: 90 °C
Yield: 72.4 %

Procedure:
A mixture of ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylate (270 mg, 0.383 mmol), 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (135 mg, 0.498 mmol), PdCl2(dppf)CH2Cl2 (31.3 mg, 0.038 mmol), and K3PO4 (244 mg, 1.15 mmol) in dioxane/H2O (3/0.3 mL) was degassed and then heated at 90° C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc and washed with H2O and brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-40% EtOAc/Hexanes, Rf=0.55 in 50% EtOAc) to afford ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylate as a pale yellow solid (200 mg). HPLC-MS TR=3.06 min (UV 254 nm, 5 min method); mass calculated for formula C37H56N6O5Si2 720.4, observed LCMS m/z 721.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH:17]=[CH2:18]>CC(C)=O>[CH2:18]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:17]=[CH2:16]
Reactant: Oc1ccc(F)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(F)cc1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a solution of 4-fluorophenol (1p) (30 g, 268.0 mmol) in acetone (250 mL), anhydrous K2CO3 (65 g, 468.3 mmol) was added followed by 3-bromo-propene (2p) (28 mL, 321.1 mmol). The resulting mixture was refluxed for 16 hours, cooled to room temperature and then poured onto ice water (500 mL). The aqueous layer was extracted with ether (3×250 mL) and the combined organic layers were washed with 2 M NaOH (2×150 mL) and dried over a mixture of anhydrous K2CO3 and Na2SO4. The solvent was removed under vacuum to afford the desired product (3p) (40.4 g, 99%) as light yellow oil. 1H NMR (400 MHz, CDCl3) δ7.01-6.92 (m, 2H), 6.89-6.82 (m, 2H), 6.10-6.82 (m, 1H), 5.44-5.41 (m, 1H), 5.39-5.37 (m, 1H), 4.51-4.448 (m, 2H).
Reaction SMILES: CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@@H](C/C=C/C)C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C[CH:81]([CH3:83])C)N(C)C(=O)CN(C)C1=O.FC(F)(F)S([O:91][Si:92]([CH2:97][CH3:98])([CH2:95][CH3:96])[CH2:93][CH3:94])(=O)=O.O>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:93]([Si:92]([O:91][Si:92]([CH2:81][CH3:83])([CH2:95][CH3:96])[CH2:93][CH3:94])([CH2:97][CH3:98])[CH2:95][CH3:96])[CH3:94]
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: C/C=C/C[C@@H](C)[C@@H](O)[C@H]1C(=O)N[C@@H](CC)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC[Si](CC)(CC)O[Si](CC)(CC)CC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Cyclosporin A (3.606 g, 3 mmol) was dissolved in dry pyridine (8 mL) and then DMAP (122 mg, 1 mmol) was added. The reaction mixture was cooled to 0° C. and then triethylsilyl trifluoromethanesulfonate (3.6 mmol) added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was then poured slowly into water with stirring. The precipitated triethylsilyl ether was filtered off and washed with water. The collected cake was dissolved in a minimum volume of methanol and added to a 5% citric acid solution and stirred for 30 minutes. The precipitated product was collected by filtration and washed with water until the pH of the filtrate reached that of the water. The solid triethylsilyl ether was dried at 50° C. under vacuum to give a colorless solid. Triisopropylsilyl and tert-butyldimethylsilyl protecting groups were also introduced by following an analogous procedure.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:28][CH:29]=[C:30]([Cl:32])[CH:31]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:36]3[CH2:37][CH2:38][N:33]([C:27]4[C:26]([Cl:25])=[CH:31][C:30]([Cl:32])=[CH:29][N:28]=4)[CH2:34][CH2:35]3)=[O:16])[N:12]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cnc(N2CCNCC2)c(Cl)c1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Product: O=C(C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1)N1CCN(c2ncc(Cl)cc2Cl)CC1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 1-(3,5-dichloro-2-pyridinyl)piperazine to give the title compound as a colorless solid. MS: 566.3 ([M+H]+)
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH2:20])=[O:19])C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH2:20])=[O:19]
Reactant: NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 0.75 h
Yield: 119.3 %

Procedure:
445 mg of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide was dissolved in methanol (16 mL), and 80 mg of 10% palladium-carbon (50% water content) was added, followed by stifling for 0.75 hours under hydrogen atmosphere. The catalyst of the reaction mixture was filtered through celite, and the solvent was concentrated under reduced pressure and dried under vacuum to afford 357 mg of the title compound as a colorless solid (quantitative).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:50])[C:5]([CH3:49])([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[C:18](=[O:32])[N:17]2CC2C=CC(OC)=CC=2)=[CH:9][CH:8]=1)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O.O>[CH2:1]([O:3][C:4](=[O:50])[C:5]([CH3:49])([O:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[C:18](=[O:32])[NH:17]2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc4ccccc4c3)C(=O)N2Cc2ccc(OC)cc2)cc1)Oc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc4ccccc4c3)C(=O)N2)cc1)Oc1ccccc1
Yield: 98.8 %

Procedure:
A solution of 3-(4-{2-[3-(4-methoxy-benzyl)-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (1.54 g, 2.29 mmol) and triethylsilane (0.53 g, 4.56 mmol) in trifluroacetic acid (40 mL) is stirred at room temperature under N2 for 4 hours. The reaction mixture is diluted with water and extracted with EtOAc. The organic layer is dried and the solvent removed in vacuo to afford crude product that is purified by flash chromatography using 3:1 then 1:1 hexanes:acetone to afford 1.25 g (100%) 2-methyl-3-{4-[2-(1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl]-ethoxy)-phenyl}-2-phenoxy-propionic acid ethyl ester. The diastereomeric mixture could be separated by chiral HPLC (2:3 IPA:heptane mobile phase, 14 mL/min, 225 nm) to afford >99% de 2-methyl-3-{4-[2-(1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl esters. Rf=0.19 (1:1 acetone:hexanes). 1H NMR. MS (ES+) Calc'd for C34H37N2O5 (M+1) 553. Found m/z 553 (100%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([I:9])=[CH:4][N:3]=1.Cl.C([N:14]([CH2:18][CH3:19])[CH:15]([CH3:17])C)(C)C>O1CCCC1.N1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:14]2[CH2:15][CH2:17][CH2:19][CH2:18]2)[C:5]([I:9])=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ncc(I)c(Cl)n1
Agent: Cl
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: Clc1ncc(I)c(N2CCCC2)n1
Reaction time: 3 h

Procedure:
To a solution of 2,4-dichloro-5-iodopyrimidine (5.00 g) synthesized according to the method described in WO2008/155140 A1 in tetrahydrofuran (50 mL), N,N-diisopropylethylamine (3.49 mL) and pyrrolidine (1.65 mL) were added under ice cooling, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture, 1.0 mol/L aqueous hydrochloric acid was added. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain 2-chloro-5-iodo-4-(pyrrolidin-1-yl)pyrimidine (H1, 4.49 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=O.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[O:5]=[C:4]1[O:6][C:20]([C:19]2[CH:23]=[CH:24][CH:25]=[C:17]([C:16]([F:15])([F:26])[F:27])[CH:18]=2)=[N:1][C:2]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]1=2
Reactant: COC(=O)c1cccc(C(=O)O)c1N
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1cccc2c(=O)oc(-c3cccc(C(F)(F)F)c3)nc12
Reaction time: 16 h
Yield: 69.9 %

Procedure:
To a solution of 2-amino-3-(methoxycarbonyl)benzoic acid 20 (1.16 g, 5.94 mmol) in pyridine (10 mL) was added 3-trifluoromethylbenzoyl chloride 2 (0.90 mL, 5.94 mmol). The reaction was stirred for 16 h, poured into sat. aq NaHCO3 (50 mL), extracted with dichloromethane (3×50 mL) and the combined organic layers were dried (MgSO4) and concentrated. Toluene (10 mL) was added and the solution was concentrated in vacuo. The crude residue was purified by MPLC eluting with pentane/EtOAc (10-50%) to give 42 (1.45 g, 70% yield).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC#N)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#CCc1cccc(O)c1
Temperature: 25 °C
Yield: 54.7 %

Procedure:
To a solution of (3-methoxyphenyl)acetonitrile (150 g, 1.03 mol) in CH2Cl2 (1000 mL) was added BBr3 (774 g, 3.09 mol) dropwise at −70° C. The mixture was stirred and warmed to room temperature slowly. Water (300 mL) was added at 0° C. The resulting mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The crude residue was purified by column (Petroleum Ether/EtOAc 10:1) to give (3-hydroxyphenyl)acetonitrile (75.0 g, 55%). 1H NMR (CDCl3, 300 MHz) δ 7.18-7.24 (m, 1 H), 6.79-6.84 (m, 3 H), 3.69 (s, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:13][C:14]2[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cc(C(=O)Nc3ccccc3)ccc2OC)cc1
Yield: 91 %

Procedure:
A mixture of 4-methoxybenzenesulfonyl chloride (2.21 g, 10.0 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10.0 mmol) and pyridine (25 mL) was allowed to stand at room temperature until thin layer chromatography indicated the reaction to be complete. The mixture was then partitioned between water (400 mL) and ethyl acetate (400 mL). The layers were separated and the organic layer washed with water (2×400 mL), 1N HCL (100 mL), and brine (100 mL), dried (magnesium sulfate), filtered and stripped of solvent. Trituration of the residue in hexanes/ethyl acetate (1:1) and filtration afforded the product (3.754 g); m.p. 184-186° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([O:29][C:30]([N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([CH:42]([CH:48]=O)[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:40]=2)[C:35]([CH3:51])([CH3:50])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([O:29][C:30]([N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([CH:42]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:48]=[C:1]([Br:5])[Br:2])[CH:40]=2)[C:35]([CH3:50])([CH3:51])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCCCCC(C=O)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCC(C=C(Br)Br)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31.5 %

Procedure:
To a solution of carbon tetrabromide (0.32 g, 0.96 mmole) in 5 mL of dichloromethane, at −20° C., was added triphenyl phosphine in 5 mL of dichloromethane. After stirring at 0° C. for 15 minutes reaction mixture was treated with a solution of 7-(1-formyl-hexyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (0.18 g, 0.48 mmole, from Example 5 step 8) in 2 mL of dichloromethane. The reaction mixture was stirred at room temperature for 4 hours, quenched by the successive addition of 5 mL of water and 1.5 mL of saturated sodium bicarbonate. The phases were separated and aqueous phase was extracted with two 25 mL portions of dichloromethane. Organic phase was dried over MgSO4, filtered and concentrated in vacuo affording a brownish thick oil. The product was purified by flash chromatography (SiO2, 20% ethyl acetate in hexanes) to yield 0.08 g of 7-(3,3-dibromo-1-pentyl-allyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as a colourless oil.
Reaction SMILES: [F:1][C:2]1([F:18])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C:14](=[CH2:16])[S:13][C:12]3=[NH:17])=[CH:10][C:4]=2[O:3]1.[C:19](N1C=CN=C1)([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:20]>C(#N)C.C(Cl)Cl>[F:18][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C:14](=[CH2:16])[S:13]/[C:12]/3=[N:17]\[C:19]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)=[O:20])=[CH:10][C:4]=2[O:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)C(=N)S1
Solvent: ClCCl
Solvent: CC#N
Product: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)/C(=N/C(=O)n2ccnc2)S1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-methylenethiazolidin-2-imine (Example 115, 0.2 g, 0.74 mmol) and carbonyldiimidazole (0.14 g, 0.92 mmol) in dry acetonitrile (5 mL) was stirred at 70° C. for 16 hours. After cooling down, the mixture was diluted with 150 mL of CH2Cl2 and washed successively with saturated sodium bicarbonate (75 mL), water (75 mL) and brine (75 mL). The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was chromatographed over silica using 100% CH2Cl2 to CH2Cl2:MeOH 95:5 as mobile phase to give the titled compound. 1H NMR (CD3OD) δ ppm 5.00 (2H), 5.40 (1H), 5.50 (1H), 6.90 (1H), 7.35 (2H), 7.44 (1H), 7.50 (1H), 8.05 (1H); MS (ESI) m/z 365(M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6](N)=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11])[CH3:2].N([O-])=O.[Na+].[BrH:17]>O>[Br:17][C:6]1[CH:8]=[CH:9][C:3]([CH2:1][CH3:2])=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=1
Reactant: CCc1ccc(N)cc1[N+](=O)[O-]
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(Br)cc1[N+](=O)[O-]
Temperature: -5 °C

Procedure:
Hydrobromic acid (48% wt. in water, 240 ml) is added dropwise to a suspension of 4-ethyl-3-nitroaniline (20 g, 0.12 mol) in water (80 ml), and the mixture is stirred until the solid dissolves. The mixture is cooled to −5° C. and a solution of sodium nitrite (19.8 g, 0.28 mol) in water (100 ml) is added dropwise, maintaining the temperature at 0-5° C. Once the addition is complete, the cooling bath is removed and the reaction mixture is stirred for one hour at room temperature. The mixture is added dropwise to a pre-cooled solution of cuprous bromide (22.4 g, 0.16 mol) in hydrobromic acid (48% wt. in water) at 0° C. The reaction mixture is stirred and allowed to warm to room temperature over three hours. The mixture is extracted with diethyl ether, and the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is further purified by column chromatography on silica gel, eluting with hexane to give 4-bromo-1-ethyl-2-nitrobenzene.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]([NH:9][C:10]1[C:11]2[S:19][CH:18]=[C:17]([CH3:20])[C:12]=2[N:13]=[C:14](Cl)[N:15]=1)([CH3:8])([CH3:7])[CH3:6]>O>[CH2:1]([NH:4][C:14]1[N:15]=[C:10]([NH:9][C:5]([CH3:8])([CH3:7])[CH3:6])[C:11]2[S:19][CH:18]=[C:17]([CH3:20])[C:12]=2[N:13]=1)[CH:2]=[CH2:3]
Reactant: Cc1csc2c(NC(C)(C)C)nc(Cl)nc12
Reactant: C=CCN
Solvent: O
Product: C=CCNc1nc(NC(C)(C)C)c2scc(C)c2n1
Temperature: 140 °C
Yield: 89.4 %

Procedure:
In 2.28 g (40.0 mmol) of allylamine was dissolved 250 mg (1.0 mmol) of 4-t-butylamino-2-chloro-7-methylthieno[3,2-d]pyrimidine, and the resulting solution was heated in a sealed tube at 140° C. for 24 hours. After the reaction mixture was cooled, 100 ml of water was added thereto, followed by extraction with ethyl acetate (20 ml×3). The organic layer was washed with 20 ml of water and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane=1/4) to give 247 mg (yield: 91.5%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11](OC)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11]([C:23]2[CH:24]=[CH:25][C:20]([S:19][CH3:18])=[CH:21][CH:22]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: COc1cnn(Cc2ccccc2)c(=O)c1Cl
Product: CSc1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Cl)cc1

Procedure:
2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33, 1579-1582) was converted to the 5-hydroxy-analog according to the method of Example 7 and then to the 5-trifluoromethylsulfonyloxy-analog according to the method of Example 8. Subsequent coupling to 4-(methylthio)phenylboronic acid, according to the method of Example 9, provided 2-benzyl-4-chloro-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone. This intermediate was coupled with 4-chlorophenylboronic acid according to the method of Example 6. This product was N-debenzylated according to the method of Example 11 and N-alkylated with 2-iodo-1,1,1-trifluoroethane according to the method of Example 20. The resulting sulfide was oxidized to the corresponding sulfoxide with one equivalent of meta-chloroperoxybenzoic acid, according to the method of Example 5 to provide the title compound (yield: 130 mg, 70%). mp 154-155° C. 1H NMR (300 MHz, CDCl3) δ 2.74 (s, 3H), 4.88 (q, J=9 Hz, 2H), 7.14 (d, J=9 Hz, 2H), 7.26 (d, J=9 Hz, 2H), 7.31 (d, J=9 Hz, 2H), 7.61 (d, J=9 Hz, 2H), 7.82 (s, 1H). MS (DCI/NH3) m/z 427 (M+H)+. Anal. calc. for C19H14ClF3N2O2S: C, 53.46; H, 3.3; N, 6.56. Found: C, 53.58; H, 3.34; N, 6.42.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[N+:9]([O-])([OH:11])=[O:10].C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:9]([N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccn([N+](=O)[O-])n1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a stirred mixture of 3-nitro-1H-pyrazole (3.16 g, 27.9 mmol) in glacial acetic acid (20 mL) at 0° C. was added fuming nitric acid (2.6 mL, 58.69 mmol) dropwise, followed by acetic anhydride (6.6 mL, 69.87 mmol). The mixture was stirred and allowed to warm to rt over 3 h, then poured into ice water (50 mL) and stirred for 20 h. The mixture was extracted with EtOAc combined organic layers were dried over MgSO4, filtered and concentrated to dryness to afford 1,3-dinitro-1H-pyrazole (4.3 g, 97%). 1H NMR (300 MHz, DMSO-d6) δ 8.00 (br s, 1H), 6.44 (br s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH:4]([OH:13])[C:5]([CH3:12])([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:3].[CH:14](O)=[O:15]>>[CH:14]([O:13][CH:4]([C:5]([CH3:11])([CH3:12])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH:2]([CH3:1])[CH3:3])=[O:15]
Reactant: CC(C)=CCC(C)(C)C(O)C(C)C
Reactant: O=CO
Product: CC(C)=CCC(C)(C)C(OC=O)C(C)C

Procedure:
52 g of 2,4,4,7-tetramethyl-oct-6-en-3-ol and 65 g of formic acid are stirred at 40° C. for 8 hours. The formic acid is then distilled off and the product is purified by cracking tube distillation.
Reaction SMILES: [NH2:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH3:13][C:14]([CH2:16][CH2:17][C:18]([CH3:20])=O)=O>C(O)(=O)C.C(Cl)Cl>[CH3:20][C:18]1[N:1]([N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])[C:14]([CH3:13])=[CH:16][CH:17]=1
Reactant: NN1C(=O)c2ccccc2C1=O
Reactant: CC(=O)CCC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(C)n1N1C(=O)c2ccccc2C1=O
Yield: 98 %

Procedure:
A mixture of N-amino-phthalimide (50 g) and 2,5-hexadione (35.2 g) in 400 ml acetic acid was refluxed for 48 hours, stripped of solvent, slurried in methylene chloride and filtered. The filtrate was washed with saturated sodium bicarbonate solution, dried and stripped to yield N-(2,5-dimethylpyrrol-1-yl)-phthalimide (98%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([S:24][CH2:25][C:26]3[C:35]([F:36])=[CH:34][C:29]([O:30][CH2:31][CH2:32][NH2:33])=[CH:28][C:27]=3[F:37])=[N:14][CH:13]=2)([CH3:11])[CH3:10])=[CH:5][C:4]=1[O:38][CH3:39].[N-:40]([C:43]#[N:44])[C:41]#[N:42]>C(O)(C)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([S:24][CH2:25][C:26]3[C:27]([F:37])=[CH:28][C:29]([O:30][CH2:31][CH2:32][NH:33]/[C:43](/[NH2:44])=[N:40]/[C:41]#[N:42])=[CH:34][C:35]=3[F:36])=[N:14][CH:13]=2)([CH3:11])[CH3:10])=[CH:5][C:4]=1[O:38][CH3:39]
Reactant: N#C[N-]C#N
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCN)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCN/C(N)=N/C#N)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Yield: 57.1 %

Procedure:
To a solution of 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethanamine hydrochloride (100 mg, 0.167 mmol) in isopropylalcohol (5 mL) was added dicyanamide (19.3 mg, 0.217 mmol) and the reaction mixture was heated at reflux for 24 h. Solvent was evaporated in vacuo and the residue was purified by column chromatography (CH2Cl2/MeOH=20:1) to give the title compound (60 mg, 57%) as an ivory solid. 1H NMR (400 MHz, CD3OD) δ 7.22 (s, 1H), 7.17 (d, J=8.2 Hz, 1H), 6.77 (t, J=8.43 Hz, 2H), 6.60-6.42 (m, 5H), 6.25 (dd, J=7.8, 4.7 Hz, 2H), 4.02 (t, J=4.54 Hz, 2H), 3.83 (s, 2H), 3.71 (s, 3H), 3.56 (t, J=4.65 Hz, 2H), 3.51-3.41 (m, 1H), 1.49 (s, 6H), 1.20 (d, J=44.2 Hz, 3H), 0.93-0.80 (m, 1H); MS (EI) m/z 629 (MH+).