Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][SiH:10]([Cl:12])[Cl:11].NC(N)=O.C(O)C>[Pt].C1(C)C=CC=CC=1>[CH2:1]([CH2:9][SiH:10]([Cl:12])[Cl:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[SiH](Cl)Cl
Reactant: C=Cc1ccccc1
Agent: [Pt]
Agent: NC(N)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cl[SiH](Cl)CCCc1ccccc1
Yield: 61 %

Procedure:
Reaction between styrene and methyldichlorosilane with platinum catalyst in the presence of urea. 0.384 g Styrene and 0.435 g methyldichlorosilane were introduced into a glass tube, and an ethanol solution containing 0.255 mg urea (5.1 wt %) was added with a microsyringe. 1 mg Of a toluene solution of 0-valent platinum complex of divinylsiloxane (0.04 wt % platinum content) was added. The reaction tube was sealed with Teflon tape and a septum and placed in a 100° C. oil bath where it was heated for 20 minutes. After cooling, the tube contents were analyzed by gas chromatography revealing a styrene conversion of 64% and a phenethylmethyldichlorosilane yield of 61%. The ratio between the phenethylmethyldichlorosilane and the (α-methylbenzyl)methyldichlorosilane was 102:1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:14]([CH3:16])[CH3:15])[C:5]([O:12][CH3:13])=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:7]=1.[C:17](=O)([O-])O.[Na+].O>CO.Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([O:11][CH3:17])([CH3:9])[CH3:10])[C:5]([O:12][CH3:13])=[C:4]([N:14]([CH3:16])[CH3:15])[CH:3]=1
Reactant: O=C([O-])O
Reactant: COc1c(N(C)C)cc(Br)cc1C(C)(C)O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(N(C)C)cc(Br)cc1C(C)(C)OC
Temperature: 25 °C

Procedure:
After dissolving 2-[5-bromo-3-(dimethylamino)-2-methoxyphenyl]-2-propanol (410 mg) in 100 mL of methanol-hydrochloric acid, the solution was heated to reflux for 14 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added for neutralization, water was added and extraction was performed with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (370 mg) as an oil. 1H-NMR (CDCl3) δ: 1.57(3H, s), 1.60(3H, s), 2.77(6H, s), 3.40(3H, s), 3.77(3H, s), 6.95(1H, d, J=2 Hz), 7.16(1H, d, J=2 Hz).
Reaction SMILES: [CH3:1][S:2][C:3]([S:11][CH3:12])([CH2:7][CH2:8][S:9][CH3:10])[C:4]([OH:6])=[O:5].C([O-])(=O)C.[Ca+2:17].C([O-])(=O)C>O.CC(C)=O>[CH3:12][S:11][C:3]([S:2][CH3:1])([CH2:7][CH2:8][S:9][CH3:10])[C:4]([O-:6])=[O:5].[Ca+2:17].[CH3:12][S:11][C:3]([S:2][CH3:1])([CH2:7][CH2:8][S:9][CH3:10])[C:4]([O-:6])=[O:5]
Reactant: CSCCC(SC)(SC)C(=O)O
Agent: CC(=O)[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CC(C)=O
Product: CSCCC(SC)(SC)C(=O)[O-]
Yield: 98.4 %

Procedure:
16.6 g of 2,2,4-tris(methylthio)butanoic acid (4) (73.3 mmol) were dissolved in a mixture of 140 ml of H2O and 35 ml of acetone. Subsequently, a solution of 6.2 g of calcium acetate (93%) and 22 ml of H2O was slowly added dropwise at 20° C. with vigorous stirring. After a short time a white solid precipitated out which was filtered off after 30 minutes. The resulting white solid was washed twice with 200 ml of H2O each time, then with 200 ml of acetone and 200 ml of diethyl ether, and dried in a drying cabinet. A total of 17.7 g of calcium 2,2,4-tris(methylthio)butanoate (5) (M=490.8 g/mol, yield=98%) were isolated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([Cl:11])(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.N1CCOCC1>>[N:6]1[CH:7]=[CH:2][CH:3]=[C:4]([S:8]([Cl:11])(=[O:10])=[O:9])[CH:5]=1
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Solvent: C1COCCN1
Product: O=S(=O)(Cl)c1cccnc1
Yield: 13 %

Procedure:
Using an analogous method to that described in the portion of Example 8 that is concerned with the preparation of starting materials, 5-bromopyridine-3-sulfonyl chloride was reacted with morpholine to give the required starting material (90 mg, 13% yield from the pyridine-3-sulfonyl chloride); Mass Spectrum: M+H+ 350 and 352.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([NH:12][N+:13]([O-:15])=[O:14])=[NH:11])=[CH:4][N:3]=1.Cl[CH2:17][N:18]([CH2:20]Cl)[CH3:19].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:19][N:18]([CH3:20])[CH2:17][NH:11][C:10]2=[N:12][N+:13]([O-:15])=[O:14])=[CH:4][N:3]=1
Reactant: N=C(NCc1ccc(Cl)nc1)N[N+](=O)[O-]
Reactant: CN(CCl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CNC(=N[N+](=O)[O-])N(Cc2ccc(Cl)nc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
0.6 g of 1-(2-chloro-5-pyridylmethyl)-3-nitroguanidine and 0.4 g of bis(chloromethyl)methylamine were suspended in dried THF. To the suspension, a solution of 0.52 g of triethylamine in THF was added dropwise with cooling. The reaction mixture was stirred for 1 hour, and then poured into ice water. The mixture was extracted with dichloromethane. After the extract was dried over anhydrous magnesium sulfate, dichloromethane was distilled off. The residue was recrystallized from methanol to obtain 0.78 g of the title compound. This compound is No. 1 in Table 1. m.p.: 150-154° C.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[O:12][C:13]([N:15]3[CH2:19][CH2:18][C@H:17](O)[CH2:16]3)=[O:14])[CH2:3]1)[CH2:9]2.[O:21]=[C:22]1[CH2:27][C:26]([C:28]#[N:29])=[CH:25][CH2:24][NH:23]1>>[OH:1][C:2]12[CH2:3][CH:4]3[CH2:10][CH:8]([CH2:7][CH:6]([CH:5]3[O:12][C:13]([N:15]3[CH2:19][CH2:18][C@@H:17]([N:23]4[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:22]4=[O:21])[CH2:16]3)=[O:14])[CH2:11]1)[CH2:9]2
Reactant: N#CC1=CCNC(=O)C1
Reactant: O=C(OC1C2CC3CC1CC(O)(C3)C2)N1CC[C@H](O)C1
Product: N#Cc1ccn([C@@H]2CCN(C(=O)OC3C4CC5CC3CC(O)(C5)C4)C2)c(=O)c1
Yield: 2 %

Procedure:
The title compounds were prepared from (S)-3-hydroxy-pyrrolidine-1-carboxylic acid 5-hydroxy-adamantan-2-yl ester (ca. 1:1 mixture of cis- and trans-isomer) and 2-oxo-1,6-dihydro-pyridine-4-carbonitrile following a procedure analogous to that described in Example 77. The isomers were separated by HPLC on reversed phase (acetonitrile/water containing 1.36% trifluoroacetic acid).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=O)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][NH:24][CH3:25].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:24]([CH2:23][CH2:22][N:21]([CH3:26])[CH3:20])[CH3:25])[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(C=O)cc(Cl)c1F
Reactant: CNCCN(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)CCN(C)Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1

Procedure:
was prepared according to Scheme C2 (step C) from (3-chloro-2-fluoro-5-formyl-benzyl)-carbamic acid tert-butyl ester (200 mg, 0.59 mmol), N,N,N′-trimethyl-ethylendiamine (71 mg, 0.70 mmol), acetic acid (0.06 mL, 1.0 mmol) and sodium triacetoxyborohydride (368 mg, 1.7 mmol) in THF (8 mL). MS (LC-MS): 374.0 [M]+; tR (HPLC conditions c): 3.53 min.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=4[F:50])[CH:34]=3)[O:32][C@@:10]1([CH:51]=[O:52])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:53][Mg]Br>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=4[F:50])[CH:34]=3)[O:32][C@@:10]1([CH:51]([OH:52])[CH3:53])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cc2cc([C@]34OC[C@](C=O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6,8-dioxa bicyclo[3.2.1]octane-1-carbaldehyde 21p (0.50 g, 0.69 mmol) in dry tetrahydrofuran (10 mL) was added dropwise methylmagnesium bromide (0.46 mL, 1.38 mmol, 3M in ethyl ether) under N2 at 0° C. The mixture was stirred at room temperature for 2 hours and quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (15 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=15/1 to give the title compound 21q as a white solid (0.14 g, 19%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.41 (s, 3H), 7.31 (m, 9H), 7.21 (m, 4H), 6.98-6.86 (m, 2H), 6.68 (m, 1H), 6.53 (m, 1H), 4.96 (m, 2H), 4.80 (m, 2H), 4.34-4.24 (m, 2H), 4.16-4.05 (m, 4H), 3.98 (m, 2H), 3.85 (s, 3H), 3.82 (dd, 1H), 3.70 (m, 1H), 1.27 (d, 3H).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:3]=1[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Mg]Cl)(C)C.[Li+].[Cl-].[CH:28]1([CH:34]=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[Si:6]([O:5][CH2:4][C:3]1[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:2]=1[CH:34]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[OH:35])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C(F)(F)F)ccc1Br
Reactant: O=CC1CCCCC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cc(C(F)(F)F)ccc1C(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
To a solution of (2-bromo-5-(trifluoromethyl)benzyloxy)(tert-butyl)dimethylsilane (1.3 g, 3.5 mmol) in THF at 0° C. was added i-PrMgCl/LiCl in THF (3.5 mL, 4.5 mmol). The mixture was stirred at 0° C. for 4 hours and cyclohexanecarboxaldehyde (0.61 g, 0.65 mL, 5.4 mmol) was added. The mixture was stirred at 0° C.-room temperature for 1 hour, quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+M Biotage silica column (eluted with 0-20% ethyl acetate in heptane) to afford the title compound (1.27 g, 90%). 1H NMR (400 MHz, CDCl13) δ ppm 0.13 (s, 6H) 0.94 (s, 9H) 0.96-1.38 (m, 7H) 1.63-1.73 (m, 2H) 1.77-1.83 (m, 1H) 2.06(d, J=13.28 Hz, 1H) 2.28 (d, J=3.73 Hz, 1H) 4.58 (dd, J=7.68, 3.94 Hz, 1H) 4.75 (d, J=13.28 Hz, 1H) 4.85 (d, J=13.28 Hz, 1H) 7.53 (s, 2H) 7.68 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[C:23]([CH3:24])=[C:22](/[CH:25]=[C:26]3\[C:27](=[O:47])[NH:28][C:29]4[C:34]\3=[CH:33][C:32]([S:35]([CH2:38][C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:46])(=[O:37])=[O:36])=[CH:31][CH:30]=4)[NH:21][C:20]=2[CH3:48])=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[C:23]([CH3:24])=[C:22](/[CH:25]=[C:26]3\[C:27](=[O:47])[NH:28][C:29]4[C:34]\3=[CH:33][C:32]([S:35]([CH2:38][C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:46])(=[O:37])=[O:36])=[CH:31][CH:30]=4)[NH:21][C:20]=2[CH3:48])=[O:18])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[2-({5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (370 mg, 0.52 mmol) and TFA (3 mL) in DCM (20 mL) was stirred at rt for overnight. The reaction was concentrated and purified to give 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-piperazin-1-yl-ethyl)-amide.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[O:22][C:21]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]4)=[CH:20][C:9]=3[N:10]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=3)[N:12]=2)[CH2:3][CH2:2]1.ClS([N:38]=[C:39]=[O:40])(=O)=O.[OH-].[Na+]>C(#N)C>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[O:22][C:21]([CH2:23][N:24]4[CH2:25][CH2:26][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:28][CH2:29]4)=[CH:20][C:9]=3[N:10]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:39]([NH2:38])=[O:40])=[N:17][CH:18]=3)[N:12]=2)[CH2:5][CH2:6]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3o2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(NC(N)=O)nc4)nc(N4CCOCC4)c3o2)CC1
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
To a solution of 236 (1.0 eq) in acetonitrile (0.1M) at r.t. was added chlorosulfonyl isocyanate (10 eq) dropwise. The reaction was stirred for 40 minutes, then concentrated. To the residue was added 2N HCl and mixture was heated to 80° C. for 20 minutes. Reaction mixture was allowed to cool down to room temperature, and was neutralized with NaOH 6M. Mixture was then concentrated. The crude product was purified by reverse phase HPLC to give 6 mg of 247. MS (Q1) 517 (M+
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[CH:10]1([Mg]Br)[CH2:12][CH2:11]1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:9][C:4]1[CH:3]=[C:2]([CH:10]2[CH2:12][CH2:11]2)[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: Br[Mg]C1CC1
Reactant: Clc1cc(Br)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1cc(Br)cc(C2CC2)c1
Temperature: 70 °C
Yield: 63.5 %

Procedure:
To a solution of 1,3-dibromo-5-chlorobenzene (500 mg, 1.85 mmol) in THF (1 ml) was added cyclopropylmagnesium bromide (3698 μl, 0.5M solution in THF, 1.85 mmol) in a sealed tube and the reaction mixture was degassed with argon for 5 min before tetrakis(triphenylphosphine)palladium (0) (107 mg, 0.09 mmol) was added. The resulting solution was heated to 70° C. overnight, cooled to RT and then quenched with sat. NH4Cl solution and extracted with pentane. The organic phases were combined, washed with water and brine, dried over MgSO4 and filtered through a short pad of silica gel to give the desired product (272 mg, 64%) which did not require further purification. 1H NMR (CDCl3, 300 MHz): 7.28 (aptt, J=2.0 Hz, 1H), 7.08 (aptt, J=1.5 Hz, 1H), 6.97 (aptt, J=1.5 Hz, 1H), 1.83 (m, 1H), 1.04-0.97 (m, 2H), 0.72-0.67 (m, 2H).
Reaction SMILES: [O-]Cl=O.[Na+].[Cl:5][C:6]1[N:7]=[C:8]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:10]=1[CH:11]=[O:12].CC(=CC)C.CC([OH:39])(C)C>O.C1COCC1>[Cl:5][C:6]1[N:7]=[C:8]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:10]=1[C:11]([OH:39])=[O:12]
Reactant: CC(C)(C)O
Reactant: CC(C)(C)[Si](C)(C)OCc1nc(Cl)c(C=O)n1COCC[Si](C)(C)C
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1nc(Cl)c(C(=O)O)n1COCC[Si](C)(C)C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of NaClO2 (1.55 g, 17 mmol) and NaH2PO4 H2O (1.42 g, 10.3 mmol) in H2O was added to a mixture of 4-chloro-2-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carbaldehyde (694 mg, 1.7 mmol), 2-methyl-2-butene (10.8 mL, 21.5 mmol, 2 M in THF), and tBuOH (1.33 mL) in THF (5.5 mL) at room temperature. The mixture was stirred overnight and separated and the aqueous layer was extracted with EtOAc. The combined extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography (0-80% 0.1%) formic acid solution of EtOAc in DCM) to give the title compound (740 mg, >99%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.83 (2H, s) 4.80 (2H, s) 3.56 (2H, t, J=8.1 Hz) 0.83-0.91 (11H, m) 0.08 (6H, s) −0.04 (9H, s). LCMS: m/z 421 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:3]=1.[NH2:26][CH2:27][C:28]([NH2:30])=[O:29].C(N(CC)C(C)C)(C)C>O1CCOCC1>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:4]2[N:5]=[C:6]([CH2:8][C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[N:7]=[C:2]([NH:26][CH2:27][C:28]([NH2:30])=[O:29])[N:3]=2)=[CH:25][CH:24]=1)#[N:23]
Reactant: N#Cc1ccc(Nc2nc(Cl)nc(Cc3c(Cl)cccc3Cl)n2)cc1
Reactant: NCC(N)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Nc2nc(Cc3c(Cl)cccc3Cl)nc(NCC(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
Intermediate (27) (0.00423 mol), 2-amino-acetamide (0.00431 mol), 1,4-dioxane (20 ml) and N,N-diisopropylethylamine (0.00862 mol) were combined and stirred at RT for 16 hours under argon. The reaction mixture was quenched with H2O and filtered. The residue was washed with H2O, filtered and recrystallized from ACN (200 ml). The precipitate was filtered off and dried, yielding 0.75 g (41.4%) of [N-[4-[(4-cyano-phenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]]aminoacetamide (compound 14).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[N+:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1F)([O-:18])=[O:17]>C(O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([S:13][C:20]2[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: Cc1c(S)cnn(C(C)(C)C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(Sc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cnn(C(C)(C)C)c1=O
Temperature: 25 °C

Procedure:
To a solution of 2.0 g (0.01 mol) of the crude product of 2-tert.-butyl-5-mercapto-4-methyl-3(2H)-pyridazinone dissolved in 15 ml of ethanol was added 1.5 ml of 20% sodium hydroxide under stirring at room temperature. After stirring for additional 15 minutes at room temperature, the resulting mixture was added dropwise with a solution of 1.4 g of 2,4-dinitrofluorobenzene dissolved in 5 ml of ethanol and stirred for 10 minutes at room temperature. Crystalline precipitates were collected by filtration, washed with 50 ml of water and 50 ml of ethanol and then recrystallized from 50 ml of benzene to give 2.0 g of 2-tert.-butyl-4-methyl-5-(2',4'-dinitrophenylthio)-3(2H)-pyridazinone.
Reaction SMILES: [C:1]1([C:6]([NH:8][NH:9][C:10]([NH:12][CH3:13])=[S:11])=O)[S:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].Cl>>[CH3:13][N:12]1[C:6]([C:1]2[S:5][CH:4]=[CH:3][CH:2]=2)=[N:8][NH:9][C:10]1=[S:11]
Reactant: CNC(=S)NNC(=O)c1cccs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1c(-c2cccs2)n[nH]c1=S

Procedure:
1-(2-Thenoyl)-4-methylthiosemicarbazide (7.1 g, 3.3×10-1 mole) and 1 molar aqueous NaHCO3 (330 ml, 3.30×10-1 mole) were stirred and heated to reflux. After refluxing about 14 hours the reaction was filtered while hot and the filtrate was then cooled in an ice bath. Acidification by the dropwise addition of concentrated HCl (28 ml, 3.4×10-1 mole) gave a colorless precipitate which was collected by filtration, washed with a little cold H2O, and dried by suction. Crystallization from isopropanol gave colorless spears: 5.0 g (77%), mp 155°-157° C.
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=O.CN1C=CN=C1.[F:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=O.[NH2:28][C:29]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[C:34]([CH2:40][CH3:41])[C:30]=1[C:31](O)=[O:32]>C(Cl)Cl>[CH2:40]([C:34]1[C:30]2[C:31](=[O:32])[O:23][C:21]([C:20]3[C:19]([F:18])=[N:27][CH:26]=[CH:25][CH:24]=3)=[N:28][C:29]=2[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=1)[CH3:41]
Reactant: O=C(O)c1cccnc1F
Reactant: CCc1cc(OC)cc(N)c1C(=O)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cn1ccnc1
Solvent: ClCCl
Product: CCc1cc(OC)cc2nc(-c3cccnc3F)oc(=O)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
TsCl (275 mg, 1.44 mmol) and N-methylimidazole (285 uL, 3.60 mmol) were added at 0° C. to a suspension of 2-fluoro-nicotinic acid (169 mg, 1.20 mmol) in CH2Cl2 (3 mL) under Ar atmosphere. The mixture was stirred at 0° C. for 1 hour. Compound R (195 mg, 1.00 mmol) was added to the mixture at 0° C. over 5 minutes and the mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. N-methylimidazole (47.5 uL, 0.60 mmol) and TsCl (114 mg, 0.60 mmol) were added at 0° C. to the mixture, and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with saturated NaHCO3 (aq.), water (5 times) and brine. The organic phase was then dried over anhydrous Na2SO4 and concentrated in vacuo to afford compound S (300 mg, 1.00 mmol) as a white powder.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[N:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[C:51]1[O:55][N:54]=[CH:53][C:52]=1[C:56](O)=[O:57]>CN(C=O)C>[C:1]1([C@@H:7]2[CH2:11][N:10]([C:56]([C:52]3[CH:53]=[N:54][O:55][C:51]=3[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][N:45]=3)=[O:57])[CH2:9][CH:8]2[CH2:12][OH:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cnoc1-c1ccccn1
Reactant: OCC1CNCC1c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cnoc1-c1ccccn1)N1CC(CO)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
A solution of (4-phenylpyrrolidin-3-yl)methanol (7 mg, 0.033 mmol), TBTU (13 mg, 0.039 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (11 μL, 0.066 mmol, 2 equ.) in DMF (0.3 mL) was added to 5-pyridin-2-ylisoxazole-4-carboxylic acid (6 mg, 0.033 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound (3 mg). MS (ESI, pos. ion) m/z calcd for C20H19N3O3: 349.1426, found 349.1427.