Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Br)C.[CH2:5]([C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)[CH3:6].[CH2:14]=[O:15].CN(C)P(N(C)C)(N(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:14]=[O:15])=[C:9]([OH:13])[CH:8]=1)[CH3:6]
Reactant: CCc1cccc(O)c1
Reactant: C=O
Agent: CC[Mg]Br
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1ccc(C=O)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A stirred solution of 200 mL (0.20 mole) of 1.0M of ethylmagnesium bromide (in tetrahydrofuran) in 100 mL of tetrahydrofuran was cooled in an ice-bath and 25.0 grams (0.21 mole) of 3-ethylphenol was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 30 minutes. After this time, 15.4 grams (0.51 mole) of paraformaldehyde, 36.7 grams (0.21 mole) of hexamethylphosphoramide, and 350 mL of toluene were added. Upon completion of addition, the reaction mixture was heated to 80° C. where it stirred for about 18 hours. The reaction mixture was then cooled and concentrated under reduced pressure to a residue. The residue was taken up in diethyl ether and 200 mL of an aqueous 10% hydrochloric acid solution was added. The aqueous layer was separated and extracted with diethyl ether. The extract was combined with the organic layer, and the combination was washed with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduce pressure to a residue. The residue was subjected to column chromatography on silica gel, using 1:1 hexane and methylene chloride as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 21.8 grams of 5-ethyl-2-formylphenol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:38][O:39][C:40]([C:42]1[C:50]2[N:49]=[C:48]([NH2:51])[NH:47][C:46]=2[CH:45]=[C:44]([C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)[CH:43]=1)=[O:41]>>[CH3:38][O:39][C:40]([C:42]1[C:50]2[NH:49][C:48]([NH:51][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])=[N:47][C:46]=2[CH:45]=[C:44]([C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)[CH:43]=1)=[O:41]
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: COC(=O)c1cc(-c2ccncc2)cc2[nH]c(N)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1cc(-c2ccncc2)cc2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12
Yield: 75 %

Procedure:
0.3 g (75%) of 2-[(isoquinoline-3-carbonyl)-amino]-6-pyridin-4-yl-3H-benzoimidazole-4-carboxylic acid methyl ester was synthesized from 0.16 g (0.09 mmol) of isoquinoline-3-carboxylic acid, 0.4 g (1 mmol) of HBTU, and 0.25 g (0.09 mmol) of the above synthesized 2-amino-6-pyridin-4-yl-1H-benzoimidazole-4-carboxylic acid methyl ester as described in general procedure A. LCMS: 424 (M+1)+.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:5]=1[CH2:6]Cl)([CH3:3])[CH3:2].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K].CN(C)C=O>O>[CH:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:5]=1[CH2:6][N:19]1[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[C:15]1=[O:25])([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)c1cccc(C(C)C)c1CCl
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1CN1C(=O)c2ccccc2C1=O
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 71.4 %

Procedure:
A mixture of 0.92 g (4.4 mmol) of 2, 6-diisopropylbenzyl chloride, 0.97 g (5.24 mmol) of potassium phthalimide and 8 ml of N, N-dimethylformamide was stirred at 70° C. for 1.5 hours. After cooling, the reaction mixture was mixed with water and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The residue was mixed with 15 ml of hexane and 2 ml of ethyl acetate, stirred at room temperature, and the precipitated crystals were filtered to give 1.01 g of N-(2, 6-diisopropylbenzyl)-phthalimide.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[C:9]12(O)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH:10]1O)[CH2:16]2.[OH2:21]>CS(O)(=O)=O>[OH:2][C:1]1[CH:8]=[C:7]([C:11]23[CH2:12][CH:13]4[CH2:14][CH:15]([CH2:16][C:9]([C:7]5[CH:6]=[CH:5][C:3]([OH:21])=[C:1]([OH:2])[CH:8]=5)([CH2:18]4)[CH2:10]2)[CH2:17]3)[CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: Oc1ccccc1O
Reactant: OC1C2CC3CC(C2)CC1(O)C3
Reactant: O
Agent: CS(=O)(=O)O
Product: Oc1ccc(C23CC4CC(C2)CC(c2ccc(O)c(O)c2)(C4)C3)cc1O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
According to the method described by Lu a solution of catechol (1.0 g) and adamantane diol (0.5 g) in methanesulfonic acid (2 ml) was heated to 80° C. for 3 hours, then left at room temperature overnight. Water was added and the mixture extracted into 10% methanol in chloroform which was dried and evaporated in vacuo to give a white solid. Purification by column chromatography over silica gel eluting with 0-20% methanol in chloroform gave the product as a white solid. Crystallisation from diethyl ether/40% petroleum ether then gave the pure product 10 as a white crystalline solid (210 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:14]([O:16]CC)=O)[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1.[C:20]([NH:29][NH2:30])(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:14]([NH:30][NH:29][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:16])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ccc(Cl)cc2n(C)c1=O
Reactant: CCCCCCCC(=O)NN
Product: CCCCCCCC(=O)NNC(=O)c1c(O)c2ccc(Cl)cc2n(C)c1=O

Procedure:
Reagents: Comp 39 (0.36 mmols, 0.1 g); octanoyl hydrazine (0.39 mmols, 0.063 g). Yield: 0.07 g (50%), white solid, m.p.=164° C.-165° C.
Reaction SMILES: [N:1]1C=CC=CC=1.[CH3:7][C:8]1[C:13](=O)[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH2:18][C:19]([CH3:21])=[CH2:20].N[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>ClCCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[CH3:7][C:8]1[C:9]([CH2:18][C:19]([CH3:21])=[CH2:20])=[C:10]([O:17][NH2:1])[C:11]([CH3:16])=[C:12]([CH3:15])[C:13]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccncc1
Reactant: C=C(C)CC1=C(C)C(=O)C(C)=C(C)C1=O
Reactant: Nc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: C=C(C)Cc1c(C)c(-c2ccccc2)c(C)c(C)c1ON
Temperature: 90 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
Titanium tetrachloride (2.58 ml, 23.4 mmol) was added dropwise to a solution of pyridine (7.60 ml, 93.6 mmol) in 1,2-dichloroethane (40 ml) and, after completion of the addition, the reaction mixture was heated under reflux for 30 minutes in an argon atmosphere. After cooling of the reaction mixture, a solution of 3,5,6-trimethyl-2-(2-methyl-2-propenyl)-1,4-benzoquinone (2.40 g, 11.7 mmol) and aniline (3.35 ml, 35.1 mmol) in 1,2-dichloroethane (5 ml) was added thereto and the mixture was stirred at 90° C. for 2 hours in an argon atmosphere. The reaction mixture was cooled and filtered through Cerite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 98:2). The resulting compound was dissolved in tetrahydrofuran (10 ml) and to the solution was added a solution of sodium hydrosulfite (12 g, 69 mmol) in water (30 ml). The mixture was stirred at room temperature for 30 minutes. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The extract was combined with the organic phase and the mixture was washed with water and dried and the solvent was distilled oil under reduced pressure. The residue was purified by silica gel chromatography (hexaneethyl acetate, 95:5) to obtain the desired compound as oil (1.41 g, yield: 42.8%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([NH:10][C:11]1[N:12]=[C:13](C2N=CNN=2)[C:14]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[CH:18]=[CH:17][C:15]=2[N:16]=1)(=[O:9])[CH3:8]>O1CCOCC1>[C:7]([NH:10][C:11]1[N:12]=[C:13]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:14]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[CH:18]=[CH:17][C:15]=2[N:16]=1)(=[O:9])[CH3:8]
Reactant: COc1ccc(-c2ccc3nc(NC(C)=O)nc(-c4nc[nH]n4)c3n2)cc1OC
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3nc(NC(C)=O)nc(N4CCNCC4)c3n2)cc1OC
Yield: 78.8 %

Procedure:
Piperazine (430 mg, 5 mmole) was added to a stirred suspension of 2-acetamido-6-(3,4-dimethoxyphenyl)-4-(1,2,4-triazolyl)pyrido[3,2-d]pyrimidine (977 mg, 2.5 mmole) in dioxane (70 ml). The reaction mixture was refluxed for 16 hours. The precipitate was filtered off and washed with a small amount of dioxane. The filtrate was evaporated to dryness and the residue washed with diethyl ether. Both fractions (the precipitate and the washed filtrate) were combined, resulting in the pure title compound (805 mg, yield 79%) which was characterized by its mass spectrum as follows: MS (m/z): 409 ([M+H]+, 100).
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][O:6][CH2:7][CH2:8]Br.[F:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:18][C:19]#[N:20]>CN1C(=O)CCC1.CCOCC>[F:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[C:18]1([C:19]#[N:20])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: BrCCOCCBr
Reactant: N#CCc1cccc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: N#CC1(c2cccc(F)c2F)CCOCC1
Temperature: 0 °C
Yield: 73.4 %

Procedure:
A mixture of sodium hydride (2 mL, 88 mmol) in 120 mL NMP was stirred at 0° C. and treated with a mixture of bis(2-bromoethyl)ether (9 mL, 40 mmol) and 2-(2,3-difluorophenyl)acetonitrile (6.12 g, 40 mmol) in 20 mL ether. The reaction was stirred at room temperature for 4 hours, carefully quenched with 20 mL H2O, and neutralized to pH=5 with concentrated HCl. The mixture was further diluted with 200 mL water, and the precipitate was collected by filtration. The solid was redissolved in 200 mL ether, washed with 20 mL saturated NaCl, dried over anhydrous Na2SO4, and concentrated to give 6.55 g of the title compound as a white solid. MS m/e: (M+H)+ 224.
Reaction SMILES: [Cl:1][C:2]1[C:7](/[C:8](/O)=[CH:9]\[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])(=[O:21])=[O:20].[CH3:30][C:31]([CH3:36])([CH3:35])[C:32](=[S:34])[NH2:33]>>[Cl:1][C:2]1[C:7]([C:8]2[N:33]=[C:32]([C:31]([CH3:36])([CH3:35])[CH3:30])[S:34][C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])(=[O:21])=[O:20]
Reactant: CC(C)(C)C(N)=S
Reactant: O=S(=O)(Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)c(-c2ccnc(Cl)n2)s1
Yield: 43.7 %

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step A using N-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (4.03 g, 8.80 mmol) and 2,2-dimethylpropanethioamide (1.03 g, 8.80 mmol), the title compound was obtained as a bright yellow solid (2.25 g; 43.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 8.54 (d, J=5.3 Hz, 1H), 7.63-7.73 (m, 1H), 7.42-7.57 (m, 3H), 7.22 (t, J=9.2 Hz, 2H), 6.53 (d, J=5.3 Hz, 1H), 1.42 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH2:18]([NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([OH:43])([C:39]([F:42])([F:41])[F:40])[C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)[CH3:19].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl.ClCCl.CO>[CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:20]([CH2:18][CH3:19])[CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([C:34]([OH:43])([C:35]([F:38])([F:36])[F:37])[C:39]([F:40])([F:41])[F:42])=[CH:32][CH:33]=4)[CH2:23][CH2:22]3)=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: CCNC1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 24 h
Yield: 53.3 %

Procedure:
To a mixture of 4-(3-(cyclopropylmethyl)ureido)benzoic acid (0.781 mmol, 183 mg), 2-(4-((4-(ethylamino)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.781 mmol, 300 mg) and triethylamine (1.873 mmol, 0.261 mL, 190 mg) in dichloromethane (50 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.937 mmol, 180 mg). The reaction was stirred for 24 hours. Chromatography on silica eluting with dichloromethane to dichloromethane/methanol (10%) gave the title compound (250 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=2)[NH:14][CH:13]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[CH2:1]([N:8]([CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=2)[N:14]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH:13]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(I)cc1
Reactant: CN(CCc1c[nH]c2ccc(Cl)cc12)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN(CCc1cn(-c2ccc(F)cc2)c2ccc(Cl)cc12)Cc1ccccc1
Temperature: 165 °C

Procedure:
A mixture of N-benzyl-N-methyl-2-(5-chloro-3-1H-indolyl)ethylamine (16 g, 0.054 mol), 4-fluoro-iodobenzene (14.3 g, 0.064 mol), K2CO3 (11.1 g, 0.080 mol) and 1-methyl-2-pyrrolidinone (200 mL) was heated at 165° C. for 8 h. After cooling to room temperature water (250 mL) was added and the thus formed mixture was extracted with diethyl ether (2×300 mL). The combined organic phases were washed with brine (3×500 mL) and dried (Na2SO4). Evaporation of the solvent afforded an oil that was purified by column chromatography (eluted with ethyl acetate/heptane 1:3) affording pure title compound as an oil: 13.7 g (26%) 1H NMR (CDCl3) δ 2.35 (s, 3 H), 2.70-2.80 (m, 2 H), 2.90-3.00 (m, 2 H), 3.60 (s, 2 H), 7.05-7.40 (m, 12 H), 7.55 (broad s, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH2:13][O:14][CH3:15])[C:5]([O:8][CH2:9][O:10][CH3:11])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[SH:67][CH2:68][CH2:69][C:70]([O:72][CH3:73])=[O:71]>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]>[CH3:15][O:14][CH2:13][O:12][C:4]1[CH:3]=[C:2]([S:67][CH2:68][CH2:69][C:70]([O:72][CH3:73])=[O:71])[CH:7]=[N:6][C:5]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: COCOc1cc(Br)cnc1OCOC
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(SCCC(=O)OC)cnc1OCOC
Temperature: 25 °C
Yield: 72.3 %

Procedure:
A solution of 5-bromo-2,3-bis(methoxymethoxy)pyridine (Intermediate 41; 2 g, 7.19 mmol) in dioxane 40.0 ml) was degassed and to this was added DIPEA (2.51 ml, 14.38 mmol), Xantphos (0.333 g, 0.575 mmol) and Pd2(dba)3 (0.263 g, 0.288 mmol). Methyl 3-mercaptopropanoate (0.951 g, 7.91 mmol) was then added as a solution in dioxane (4 mL) and the reaction was heated under reflux for 1 hour before being cooled to room temperature and filtered through a pad of celite, washing with ethyl acetate. The combined organics were washed with water and then brine, dried (MgSO4) and then concentrated in vacuo. The crude product was purified by column chromatography (SiO2; 0-50% ethyl acetate/petrol) to yield methyl 3-{[5,6-bis(methoxymethoxy)pyridin-3-yl]sulfanyl}propanoate (1.65 g, 72%).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:16]=[CH:15][C:8]2[O:9][CH:10]=[C:11]([CH2:12][C:13]#[N:14])[C:7]=2[CH:6]=1)#N.[CH2:17](O)COCCOCCO>>[C:11]1([CH2:12][C:13]#[N:14])[C:7]2=[C:6]3[C:5](=[CH:16][CH:15]=[C:8]2[O:9][CH:10]=1)[O:4][CH2:3][CH:1]=[CH:17]3
Reactant: N#CCOc1ccc2occ(CC#N)c2c1
Reactant: OCCOCCOCCO
Product: N#CCc1coc2ccc3c(c12)C=CCO3

Procedure:
A mixture of 0.03 mol (6 g) of compound obtained in stage D in 170 ml of triethyleneglycol is refluxed 5 minutes. The reaction is then cooled at room temperature and hydrolysed by a mixture water/ice. The precipitate thus formed is filtrated and recrystallized in isopropanol to yield the title product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[O:9]1[C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:16]2[CH2:17][CH2:18][C:13]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(N2CCC3(CC2)OCCO3)nn1
Temperature: 80 °C

Procedure:
To a mixture of 3,6-dichloropyridazine (2.98 g, 20 mmol) in DMSO (10 mL) was added 1,4-dioxa-8-azaspiro[4.5]decane (3 g, 21 mmol) and DIPEA (4.18 mL, 24 mmol). The resulting mixture was heated at 80° C. for 4 h and was then poured into H2O (300 mL). The resulting solid was washed with H2O (10 mL×3) and hexane (10 mL×3) and then dried to yield 8-(6-chloropyridazin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane.
Reaction SMILES: C(O[I:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC(=O)C)(=O)C.[Si]([O:20][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])(C)(C)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>>[F:25][C:24]([F:27])([F:26])[S:21]([O-:23])(=[O:22])=[O:20].[F:25][C:24]([F:27])([F:26])[S:21]([O-:23])(=[O:22])=[O:20].[C:10]1([I:5]([N+:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)[N+:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Reactant: COc1ccncc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Product: COc1cc[n+](I(c2ccccc2)[n+]2ccc(OC)cc2)cc1
Product: O=S(=O)([O-])C(F)(F)F
Yield: 97.3 %

Procedure:
Based on a reported procedure: All manipulations were carried out in a dry box under a N2 atmosphere. To (diacetoxyiodo)benzene (3.00 g, 9.31 mmol, 1.00 equiv) dissolved in CH2C12 (100 mL) in a round-bottom flask was added TMSOTf (4.14 g, 18.6 mmol, 2.00 equiv) dropwise over 1 minute at 23 ° C. 4-Methoxypyridine (2.03 g, 18.6 mmol, 2.00 equiv) in CH2C12 (15 mL) was added to the solution dropwise over 5 minutes. The reaction mixture was concentrate until a white solid was observed. To the reaction mixture was added 100 mL of Et2O and the resulting solid was collected on a frit. The solid was washed with Et2O (3 x 10 mL) and subsequently dried under vacuum to afford 6.52 g of the title compound as a colorless solid (97%). NMR Spectroscopy: c 1H NMR (500 MHz, CD3CN, 23 ° C., δ): 8.77 (d, J=7.5 Hz, 4H), 8.60 (d, J=8.5 Hz, 2H), 7.79 (t, J=7.5 Hz, 1H), 7.64 (t, J=8.5 Hz, 2H), 7.19 (d, J=7.5 Hz, 4H), 3.99 (s, 3H). 13C NMR (125 MHz, CD3CN, 23 ° C., δ): 172.1, 149.9, 136.1, 135.7, 134.2, 121.9 (q, J=319 Hz, triflate), 115.3, 58.5. 19F NMR (375 MHz, CD3CN, 23 ° C., δ): −77.5. Anal: calcd for C20H19F6IN2O8S2: C, 33.34; H, 2.66; N, 3.89; found: C, 33.05; H, 2.59; N, 3.73.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCO[C:23]([CH3:25])=O>C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][CH:25]3[CH2:23][CH2:15][CH2:16][NH:8][CH2:6]3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)n1ncc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ncc2cc(NC3CCCNC3)ccc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of 5-nitro-indazole-1-carboxylic acid tert-butyl ester (300 g, 1.1 mol, 1.0 eq) in THF (3 L) was added Pd/C (30 g). The reaction mixture was stirred at 40° C. for 16 hours under pressure of H2 (50 psi). TLC (PE:EtOAc=4:1) showed complete conversion. After uptake of H2, the catalyst was filtered off and the filtrate was evaporated to afford the crude 5-amino-indazole-1-carboxylic acid tert-butyl ester (252 g, 95%) which was used directly for next step without purification.
Reaction SMILES: CN(OC)[C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH:13]([Mg]Br)=[CH2:14].[NH4+].[Cl-]>C1COCC1>[CH:5]1([C:3](=[O:4])[CH:13]=[CH2:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CON(C)C(=O)C1CCCCC1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(=O)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the stirring solution of N-methyl-N-methoxy-cyclohexanecarboxamide (0.05 mol, 8.5 g) in 150 ml anhydrous THF at −10-0° C. (ice-NaCl bath) the solution of vinyl magnesium bromide (1M in THF, 0.1 mol, 100 ml) was added dropwise. The resulting mixture was stirred at 0° C. for 1 h (white solid formed), then at rt for 4 h (the solid dissolved). The resulting solution was added slowly by cannula into a well-cooled Erlenmeyer flask equipped with magnetic stirrer and thermometer, containing 0.5 L saturated aqueous NH4Cl, with such speed that the temperature stays between 0° C. and +10° C., at vigorous stirring. At higher temperatures oligomerization of the product occurs. The phases were separated; the aqueous one extracted with EtOAc (3×100 ml), and the combined organic extracts were washed with sat. aq. NH4Cl until pH<7 (5×50 ml, carefully removing all the N,O-dimethylhydroxylamine product), then washed with brine (100 ml), dried with Na2SO4, and concentrated under vacuum >80 mbar (taking care not to evaporate the volatile product). Yield 11.8 g of yellow oil containing pure vinylcyclohexylketone. Used in the next reaction without purification as 0.05 mol. 1H NMR (400 MHz, CDCl3) δ 6.41 (dd, 1H, 17.5 Hz, 10.3 Hz, Z—H—CH═C), 6.25 (dd, 1H, 17.5 Hz, 1.4 Hz, E-H—CH═C), 5.74 (dd, 1H, 10.3 Hz, 1.4 Hz, CO—CH═C), 2.60 (m, 1H, cyclohexyl CH—CO), 1.9-1.7 (m, 3H, cyclohexyl), 1.7-1.5 (m, 2H, cyclohexyl), 1.4-1.2 (m, 5H, cyclohexyl).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:17])C(=O)C1.F[C:19]([F:25])(F)S(O)(=O)=O>>[F:25][C:19]1[CH:3]=[C:2]([CH:7]=[C:6]([I:17])[C:5]=1[CH3:4])[C:1]([OH:9])=[O:8]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: O=C(O)c1ccccc1
Reactant: O=C1CCC(=O)N1I
Product: Cc1c(F)cc(C(=O)O)cc1I
Temperature: 0 °C

Procedure:
The benzoic acid (1.54 g, 0.01 mol) is dissolved in trifluoromethanesulfonic acid (10 mL) and cooled to about 0° C. NIS (2.25 g. 0.01 mol) is added in several portions over a 6 h period while maintaining the reaction temperature at about 0° C. The mixture is allowed to warm to rt. overnight. The reaction mixture is then poured over ice and extracted with ethyl acetate (3×). The organic layers are washed (Na2S2O5) and concentrated. The material is carried on crude.