Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][C:25](=[O:27])[CH3:26])[CH:6]=1)(=[O:3])[CH3:2].[C:28](OC(C)=C)(=[O:30])[CH3:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16]([O:23][C:28](=[O:30])[CH3:29])=[CH:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][C:25](=[O:27])[CH3:26])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C=C(C)OC(C)=O
Reactant: CC(=O)Oc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@H]1CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)OC1=CC[C@H]2[C@H]3CCc4cc(OC(C)=O)cc(OC(C)=O)c4[C@H]3CC[C@]12C
Temperature: 125 °C

Procedure:
A mixture of 5 g. of 1,3-diacetoxy-8α-estra-1,3,5(10)-trien-17-one, 100 ml. of isopropenyl acetate, and 14.4 g. of p-toluenesulfonic acid is heated for 21 hours to 105° C. under a slight N2 stream. After heating to 125° C., 50 ml. of iospropenyl acetate is gradually distilled off. After cooling, 10 ml. of pyridine is added, the mixture is diluted with methylene chloride, washed with saturated sodium bicarbonate solution and water, and dried over sodium sulfate. The solvent is evaporated under vacuum. After chromatography on 260 g. of SiO2, 3 g. of 1,3,17-triacetoxy-8α-estra-1,3,5(10),16-tetraene is obtained as an oil, which is further processed in the form of the crude product.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)(C)C.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O.CCCCCC.Cl>CO.ClCCl>[C:6]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C#Cc1ccc2ccccc2n1
Temperature: 25 °C

Procedure:
2-((Trimethylsilyl)ethynyl)quinoline (1.289 g, 5.72 mmol), and K2CO3 (0.792 g, 5.73 mmol) were dissolved in a mixture of methanol (3 mL) and dichloromethane (1.5 mL), followed by stirring at room temperature. The completion of the reaction was confirmed by TLC (EtOAc/Hexane=1:4). When the reaction was completed, the pH of the reactant was adjusted to 10 by addition of an aqueous solution of 1 M HCl and extracted with dichloromethane, to thereby separate an organic layer. The organic layer was dried over anhydrous MgSO4 and filtered. The thus obtained filtrate was concentrated under reduced pressure and purified by column chromatography (EtOAc/Hexane=1:4, R.f: 0.3), to thereby obtain 2-ethynylquinoline (0.742 g, 85%) as brown oil.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:6]1[CH:7]=[CH:8][C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH:16]=[O:17])[CH:10]=2)([CH3:5])[CH3:4].CC(C)=O>CO>[CH:3]([C:6]1[CH:7]=[CH:8][C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH2:16][OH:17])[CH:10]=2)([CH3:5])[CH3:4]
Reactant: CC(C)c1ccc2cc(C=O)cc-2cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)c1ccc2cc(CO)cc-2cc1
Reaction time: 1 h
Yield: 81.3 %

Procedure:
Sodium borohydride (0.26 g) was added to a solution of 6-isopropylazulene-2-carboaldehyde (1.4 g) in methanol (30 ml) at 0° C. and the mixture was stirred for one hour. Acetone was added to the reaction mixture and the mixture was stirred for 15 minutes. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (6-isopropylazulen-2-yl)methanol (1.15 g).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17]CC)=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([OH:17])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCCN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Ethyl 1-benzoyl-3-piperidinecarboxylate (431.4 mg; 1.65 mmol) was dissolved in absolute ethanol (10 ml), and after addition of 1 N sodium hydroxide (20 ml), the mixture was allowed to stir at ambient temperature for approximately 1 hour. It was then poured into 1 N hydrochloric acid and extracted with dichloromethane. The dichloromethane was dried with anhydrous magnesium sulfate and then evaporated at ambient temperature under reduced pressure, giving 1-benzoyl-3-piperidine carboxylic acid (327.3 mg) as a white solid without further purification. MS m/z (negative ion) 232 (M-H; 100), 188 (M-CO2H; 90).
Reaction SMILES: [I:1][CH:2]=[CH:3][C:4]([CH3:11])([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C=O>[I:1][CH:2]=[CH:3][C:4]([O:10][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])([CH3:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(C)(O)C=CI
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCCCC(C)(C=CI)O[Si](C)(C)C(C)(C)C

Procedure:
A solution of 2.625 g. of dl-1-iodo-3-methyl-1-octen-3-ol, 3.2 g. of imidazole and 3.6 g. of t-butyldimethylsilyl chloride in 10 ml. of dimethylformamide is stirred at 60° C. for 35 hours under nitrogen. After vacuum evaporation of the solvent, the residue is extracted with hexane and chromatogaphed on neutral alumina (Activity 3). Elution with hexane gives the title product as an oil, 2.15 g.
Reaction SMILES: BrCC=CC1C=CC(C(OC)=O)=C(C2C=CC(F)=CC=2)C=1.IC1N(C)C=NC=1.[C:29]([N:48]1[C:52]([CH2:53]/[CH:54]=[CH:55]/[C:56]2[CH:65]=[CH:64][C:59]([C:60]([O:62][CH3:63])=[O:61])=[C:58]([C:66]3[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=3)[CH:57]=2)=[CH:51][N:50]=[CH:49]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:29][N:48]1[C:52]([CH2:53][CH:54]=[CH:55][C:56]2[CH:65]=[CH:64][C:59]([C:60]([O:62][CH3:63])=[O:61])=[C:58]([C:66]3[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=3)[CH:57]=2)=[CH:51][N:50]=[CH:49]1
Reactant: COC(=O)c1ccc(/C=C/Cc2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(F)cc1
Agent: COC(=O)c1ccc(C=CCBr)cc1-c1ccc(F)cc1
Agent: Cn1cncc1I
Product: COC(=O)c1ccc(C=CCc2cncn2C)cc1-c1ccc(F)cc1
Yield: 59 %

Procedure:
Methyl 4-[3-(1-methylimidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate was prepared from methyl 4-(3-bromoprop-1-en-1-yl)-2-(4-fluorophenyl)benzoate and 5-iodo-1-methyl-imidazole using a similar method to that described for methyl 4-[(E)-3-(1-tritylimidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate in Example 37.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([CH2:16][C:17]([O:19][CH2:20][CH2:21][C:22]#[N:23])=[O:18])(=[O:15])[CH2:13][CH3:14]>CC(O)C.N1CCCCC1.C(O)(=O)C>[C:22]([CH2:21][CH2:20][O:19][C:17](=[O:18])[C:16](=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:12](=[O:15])[CH2:13][CH3:14])#[N:23]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCC(=O)CC(=O)OCCC#N
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CCC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)OCCC#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.9 %

Procedure:
A suspension of 4-nitrobenzaldehyde (18.3 g, 0.118 mol), 2-cyanoethyl propionylacetate (20.0 g, 0.118 mol), piperidine (503 mg, 5.91 mmol) and acetic acid (355 mg, 5.91 mmol) in 230 ml of 2-propanol was stirred at r.t. for 48 hrs. Reaction mixture was filtered, the solid collected was dried in air to give 2-[(4-nitrophenyl)methylene]-3-oxopentanoic acid 2-cyanoethyl ester as a white powder (31.7 g, 89%). A solution of 2-[(4-nitrophenyl)methylene]-3-oxopentanoic acid 2-cyanoethyl ester (14.72 g, 48.7 mmol) and benzyl 3-aminocrotonate (10.00 g, 48.7 mmol) in 150 ml of EtOH was refluxed for 36 hrs. After solvent was removed, the residue was dissolved in 250 ml of CHCl3 washed with water (2×100 ml) and dried over Na2SO4. After filtration and removal of solvent, 3-benzyloxycarbonyl-5-(2-cyanoethoxy)carbonyl-2,6-diethyl-1,4-dihydro-4-(4-nitrophenyl)pyridine was obtain as a yellow oil (23.0 g, 96%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:24])[NH2:23])[C:16]=3[N:17]=2)=[CH:9][CH:8]=1)(=O)=O.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C.O>[C:7]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:16](=[C:18]([C:22]([NH2:23])=[O:24])[CH:19]=[CH:20][CH:21]=3)[N:17]=2)=[CH:9][CH:8]=1
Reactant: NC(=O)c1cccc2sc(-c3ccc(OS(=O)(=O)C(F)(F)F)cc3)nc12
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: NC(=O)c1cccc2sc(-c3ccc(-c4ccccc4)cc3)nc12
Temperature: 0 °C

Procedure:
A mixture of EXAMPLE 1G (25 mg), dichlorobis(triphenylphosphine) palladium(II) (4.36 mg), phenylboronic acid (8.33 mg), 1M sodium carbonate (0.087 mL) and 7:2:3 dimethoxyethane/ethanol/water (1 mL) was heated in a microwave at 160° C. for 10 minutes. The mixture was concentrated and diluted with 1:1 dimethylsulfoxide/methanol. The solid was filtered, dissolved in N,N-dimethylformamide, cooled at 0° C. for 18 hours and filtered to afford the title compound. 1H NMR (DMSO-d6) δ 9.24 (d, J=2.1 Hz, 1H), 8.40 (dd, J=7.9, 1.2 Hz, 1H), 8.27 (d, J=8.2 Hz, 2H), 8.23 (dd, J=7.6, 1.2 Hz, 1H), 8.00 (s, 1H), 7.94 (d, J=8.2 Hz, 2H), 7.79 (d, J=7.0 Hz, 2H), 7.62 (t, J=7.8 Hz, 1H), 7.54 (t, J=7.6 Hz, 2H), 7.46 (t, J=7.3 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[C:6](=[O:20])[NH:7][C:8](=[O:19])[N:9]([CH:18]=1)[C@@H:10]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[CH2:11]1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.N>C1COCC1>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:1][CH2:2][C:3]#[C:4][C:5]2[C:6](=[O:20])[NH:7][C:8](=[O:19])[N:9]([CH:18]=2)[C@@H:10]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[CH2:11]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C#CCO
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C#CCOc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C

Procedure:
A solution of pre-dried 5-(3-hydroxy-1-propynyl)-2′-deoxyuridine (“Nucleic Acid Compounds. 39. Efficient Conversion of 5-Iodo to 5-Alkynyl and Derived 5-Substituted Uracil Bases and Nucleosides” Robins and Barr, (1983) supra) (565 mg, 2 mmol) in 40 mL of anhydrous THF under argon was treated with 4-nitrophenol (696 mg, 5 mmol), triphenylphosphine (787 mg, 3 mmol), and diisopropyl azodicarboxylate (590 L, 3 mmol), and the reaction mixture heated at 60° C. until the solution was clear, and then 1 h longer. The mixture was allowed to cool to 23° C. and then it was evaporated onto SiO2 and purified by chromatography using MeOH/CH2Cl2 as eluent to afford 107 mg (13%) of the desired ether product: mp 112-118° C. 1H NMR((CD3)2SO) δ 11.65 (s, exchanges with D20, 1, NH), 8.29 (s, 1, H6), 8.24 (d, J=9.3 Hz, 2, m-ArH), 7.23 (d, J=9.3 Hz, 2, o-ArH), 6.09 (pseudo-t, 1, H1′), 5.17 (s, 2, propargyl-CH2), 4.22 (m, 1, H3), 3.80 (m, 1, H4′), 3.59 (m, 2,5′-CH2), 2.13 (pseudo-t, 2,2′-CH2). Low-resolution mass spectrum (DCI-NH3) on per-trimethylsilyated material, m/z 547 [M(TMS)2H+], 565 [M(TMS)2NH4+], 620 [M(TMS)3H+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:30][CH2:31][CH3:32].O>CN(C)C=O>[N:17]1([S:14]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([O:1][CH2:30][CH2:31][CH3:32])[CH:3]=3)[NH:7][C:6]=2[C:11]([NH2:13])=[O:12])(=[O:16])=[O:15])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CCCI
Reactant: NC(=O)c1[nH]c2ccc(O)cc2c1S(=O)(=O)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 50 (29 mg, 0.089 mmol) in 1 mL of dimethylformamide was added cesium carbonate (86 mg, 0.27 mmol) and 1-iodopropane (0.0094 mL, 0.096 mmol). After one hour, another portion (0.005 mL) of 1-iodopropane was added. After an additional hour, 0.5 mL of water was added to solubilize the material, and the resulting mixture was purified by preparative reversed phase HPLC to provide the titled product as a white solid. HRMS (ES) exact mass calculated for C16H22N3O5S (M+H+): 368.1275. Found 368.1291.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[C:19]1([CH3:32])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH:26][CH:27]=[CH:28][C:29](=[O:31])[CH3:30]>>[C:29]([C:28]1[CH:15]([CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:16]=[CH:17][N:26]([CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH3:32])[CH:27]=1)(=[O:31])[CH3:30]
Reactant: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O
Reactant: CC(=O)C=CNCc1ccccc1C
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3ccccc3C)C=C1C(C)=O)C2=O

Procedure:
The title compound 59 is prepared according to the procedure reported in step D of Example 8 with aldehyde 54 (100 mg, 0.41 mmol) and enamine 60 (110 mg, 0.57 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=2:1) afford the title compound 59 as a yellow oil. (Yield 100 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([CH2:22][N:11]([C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18](=[O:19])[NH2:20])[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])=[CH:24][CH:25]=1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(CN([C@@H]2CCCC[C@@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 61 %

Procedure:
The titled compound (90 mg) was prepared in 61% yield from cis-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide and methyl 4-(bromomethyl)benzoate according to the procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.83 (m, 4 H), 7.64 (d, 2 H, J=8.0 Hz), 7.42 (d, 2 H,J=8.0 Hz), 7.28 (s, 1 H), 6.61 (s, 1 H), 4.64 (AB2,2 H,Δv=20,Jab=72 Hz), 3.85 (m, 4 H), 2.79 (m, 1 H), 2.42 (m, 1 H), 1.78 (m, 1 H), 1.63 (m, 2 H), 1.28 (m, 3 H), 0.90 (m, 1 H); MS m/e 464.98 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH:3]=[CH:2]1.C(=O)=O.C(N(CC)CC)C.C12(Cl)CC3CC(CC(C3)C1)C2.[Li+].[Cl-].[O:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35]>C(O)CO.CN(C)C1C=CN=CC=1.C1COCC1>[CH:1]1([C:4]([N:32]2[CH2:33][CH2:34][O:30][C:31]2=[O:35])=[O:6])[CH:3]=[CH:2]1
Reactant: O=C1NCCO1
Reactant: O=C(O)C1C=C1
Agent: CN(C)c1ccncc1
Agent: ClC12CC3CC(CC(C3)C1)C2
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: O=C1OCCN1C(=O)C1C=C1
Reaction time: 1 h

Procedure:
A flame-dried 100 mL round bottomed flask containing 6 (84 mg, 1.0 mmol), 20 mL of THF was chilled by a cold bath at −30° C. (dry ice/30% ethanol in ethylene glycol). The mixture was allowed to stir under nitrogen atmosphere. Distilled triethylamine (0.36 g, 0.50 mL, 3.5 mmol), 1-adamantyl chloride (238 mg, 1.2 mmol) were added sequentially, and stirring at −30° C. was continued for one hour. LiCl (0.21 g, 5.0 mmol) was added. After five minutes, oxazolidinone (131 mg, 1.50 mmol), and 4-dimethylamino pyridine (13 mg, 0.10 mmol) were added. The whole reaction mixture was allowed to stir overnight at room temperature. The solvents were removed under reduced pressure, and the residue was partitioned between 20 mL of CH2Cl2 and 20 mL water. The aqueous layer was extracted twice with 20 mL portions of CH2Cl2, and the combined organics were dried (Na2SO4), filtered, and concentrated. The residue was chromatographed on silica gel. The eluent was 1:3:6 CH2Cl2:ethyl acetate:hexane. The yield of 8 was 115 mg (0.752 mmol, 75%). Compound 8 is a semi-solid.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[C:18](OC1C=CC(Cl)=C(Cl)C=1Cl)(=[O:23])[CH2:19][C:20]([O-])=[O:21]>C1(C)C(C)=CC=CC=1>[OH:23][C:18]1[N:17]=[C:13]2[CH:12]=[C:11]([O:10][CH2:9][C:6]3[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)[CH:16]=[CH:15][N:14]2[C:20](=[O:21])[CH:19]=1
Reactant: CC(C)c1csc(COc2ccnc(N)c2)n1
Reactant: O=C([O-])CC(=O)Oc1ccc(Cl)c(Cl)c1Cl
Solvent: Cc1ccccc1C
Product: CC(C)c1csc(COc2ccn3c(=O)cc(O)nc3c2)n1
Temperature: 140 °C
Yield: 63.6 %

Procedure:
4-[(4-Isopropyl-1,3-thiazol-2-yl)methoxy]-2-pyridinamine (378 mg, 1.52 mmol) dissolved in xylene (15 ml) was added with trichlorophenyl malonate (750 mg, 1.62 mmol) and refluxed by heating at 140° C. for 1 hour and 30 minutes. The reaction solution was returned to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=100:1→80:1→50:1) to obtain 307 mg (64%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)\[C:10]#[N:11])=[CH:4][C:3]=1[O:22][CH3:23].[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[OH:1][C:2]1[C:7]([N+:24]([O-:26])=[O:25])=[CH:6][C:5](/[CH:8]=[C:9](/[C:12]2[CH:13]=[N:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)\[C:10]#[N:11])=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(/C=C(\C#N)c2ccc(C(F)(F)F)nc2)ccc1O
Solvent: CC(=O)O
Product: COc1cc(/C=C(\C#N)c2ccc(C(F)(F)F)nc2)cc([N+](=O)[O-])c1O
Temperature: 25 °C

Procedure:
To a solution of (Z)-3-(4-hydroxy-3-methoxyphenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)acrylonitrile (0.858 g, 2.68 mmol) in acetic acid (20 mL) was added 60% nitric acid (0.23 mL, 2.95 mmol) dropwise. The resulting mixture was allowed to stir at room temperature for thirty minutes then poured onto ice-water (100 mL). The yellow precipitate was filtered off, washed with water and dried. Recrystallisation from isopropanol afforded (Z)-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)acrylonitrile as a yellow solid, 0.597 g, (61%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([C:27]#[N:28])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[CH3:2].C(OC(C1CC(C(OCC)=O)=C(C)NC=1C)=O)C>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([C:27]#[N:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C#N)=Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A mixture of 2-cyano-3-{4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl}acrylic acid ethyl ester (described in Example 6) (1.69 g; 4.07 mmole) and diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate (2.06 g; 8.14 mmole) was slowly heated to more than 190° C. under vacuum and thereafter allowed to cool to room temperature. The crude product was purified by chromatography on silica gel using heptane:ethyl acetate (gradient 2:1 to 1:1) as eluant to give 1.55 g (yield 91%) of 2-cyano-3-{4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([S:18][C:19]2[N:23]4[CH:24]=[C:25]([C:28](=O)[CH3:29])[CH:26]=[CH:27][C:22]4=[N:21][N:20]=2)=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.[NH2:31][O:32][CH2:33][CH2:34][OH:35].Cl>CO>[OH:35][CH2:34][CH2:33][O:32]/[N:31]=[C:28](/[C:25]1[CH:26]=[CH:27][C:22]2[N:23]([C:19]([S:18][C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[N:10]=[CH:9][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[CH:17]4)=[N:20][N:21]=2)[CH:24]=1)\[CH3:29]
Reactant: NOCCO
Reactant: CC(=O)c1ccc2nnc(Sc3ccc4ncc(N5CCC(O)CC5)cc4c3)n2c1
Agent: Cl
Solvent: CO
Product: C/C(=N\OCCO)c1ccc2nnc(Sc3ccc4ncc(N5CCC(O)CC5)cc4c3)n2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To the solution of (76.3) (30 mg, 0.072 mmol) and 2-(aminooxy)ethanol (6.06 mg, 0.079 mmol) in MeOH (3 ml) was added a drop of 2 N HCl, sealed the tube and stirred at 50° C. for overnight. The solvent was evaporated under reduced pressure to give crude desired product as orange oil which was purified by chromatography and eluent with DCM/MeOH (30:1-20:1) to obtained pure desired product as yellow solid (25 mg, 69.4%).
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[N:55]=[C:54]([S:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([F:64])[C:59]=2[F:65])[N:53]=[C:52]([O:66][CH2:67][CH2:68][OH:69])[CH:51]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:65][C:59]1[C:60]([F:64])=[CH:61][CH:62]=[CH:63][C:58]=1[CH2:57][S:56][C:54]1[N:55]=[C:50]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:51]=[C:52]([O:66][CH2:67][CH2:68][OH:69])[N:53]=1
Reactant: NS(=O)(=O)N1CCC1
Reactant: OCCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(OCCO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Temperature: 100 °C

Procedure:
A mixture of azetidine-1-sulfonamide (0.33 g, prepared according to patent WO2004/011443), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.585 g) and 2-({6-chloro-2-[(2,3-difluorobenzyl)thio]pyrimidin-4-yl}oxy)ethanol ((the product from example 112 step ii), 0.400 g) in dioxane (20 ml) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 30 mins. The reaction mixture was then reduced in vacuo and the residue separated between DCM (150 ml) and H2O (150 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting residue purified by prep HPLC to give the title compound as a white solid. Yield: 0.13 g
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[C:27]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([O:14][CH3:27])[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C#N
Temperature: 25 °C

Procedure:
A mixture of 0.34 g (0.92 mMol) of 1,2-dihydro-6-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-2-oxo-pyridine-3-carbonitrile (Step 3) in 10 ml of DMF and 0.33 g of K2CO3 and 2 ml of iodomethane, was stirred at room temperature over the weekend. The reaction mixture was diluted with 75 ml of water and extracted with dichloromethane (4×25 ml). The combined organic layers were extracted once with 50 ml of 10% NaOH solution then once with brine, dried over MgSO4 and evaporated to dryness. The residue was purified by HPLC to give two fractions. The first fraction was the desired product: m.p. 202.5-204° C.