Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][S:16][CH2:15][CH2:14]3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:27])=[CH:29][CH:30]=2)[C:8]2[CH:12]=[C:11]([CH:13]3[CH2:14][CH2:15][S:16][CH2:17][CH2:18]3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1sc(C2CCSCC2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(C3CCSCC3)sc2CC)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a mixture of 4-({cyclohexyl[2-ethyl-5-(tetrahydro-2H-thiopyran-4-yl)thiophen-3-yl]methyl}amino)benzoic acid (1.00 g) synthesized above, ethyl β-alaninate hydrochloride (415 mg), 1-hydroxybenzotriazole monohydrate (414 mg) and triethylamine (376 μL) in N,N-dimethylformamide (20 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (518 mg), and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title compound (1.06 g, 87%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1.[CH2:20]([OH:23])[CH2:21][OH:22]>O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([O:22][CH2:21][CH2:20][OH:23])=[O:18])=[CH:12][CH:11]=1
Reactant: OCCO
Reactant: COC(=O)CCCCCOc1ccc(N=C=O)cc1
Solvent: O
Product: COC(=O)CCCCCOc1ccc(NC(=O)OCCO)cc1
Reaction time: 16 h
Yield: 84 %

Procedure:
6-(4-Isocyanatophenoxy)-hexanoic acid methyl ester 18 (15 g, 57 mmol) was added to ethylene glycol (50 ml) at room temp. The reaction was exothermic and the temp. rose to 46° C. Stirring at room temp. for 16 h. was followed by addition of water (150 ml), after which crude 19 was filtered, dried and recrystallised from toluene to get pure 19 (12 g, 84%) as a white powder with an m.p. between 69.5-71.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([OH:16])=O.Cl.Cl.[N:19]1([CH:24]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=2)[CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20]1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C=O)C>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[S:4][C:3]=1[C:14]([NH:34][CH2:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([CH:24]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH3:25])=[CH:31][CH:30]=1)=[O:16]
Reactant: Nc1cc(-c2ccc(F)cc2)sc1C(=O)O
Reactant: CC(c1ccc(CCN)cc1)N1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(c1ccc(CCNC(=O)c2sc(-c3ccc(F)cc3)cc2N)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a mixture of 3-amino-5-(4-fluorophenyl)thiophene-2-carboxylic acid (0.20 g), 2-[4-(1-pyrrolidin-1-ylethyl)phenyl]ethanamine dihydrochloride (0.22 g), 1-hydroxybenzotriazole (0.16 g), N,N-diisopropylethylamine (0.30 ml) and DMF (3.0 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.15 g), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=9:1 (volume ratio)→1:2 (volume ratio)) using NH-silica gel to give 3-amino-5-(4-fluorophenyl)-N-{2-[4-(1-pyrrolidin-1-ylethyl)phenyl]ethyl}thiophene-2-carboxamide (0.15 g).
Reaction SMILES: [CH3:1][I:2].[CH3:3][N:4]([CH2:6][C:7]1[NH:8][CH:9]=[CH:10][CH:11]=1)[CH3:5]>CCOCC>[I-:2].[NH:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[CH2:6][N+:4]([CH3:1])([CH3:5])[CH3:3]
Reactant: CN(C)Cc1ccc[nH]1
Reactant: CI
Solvent: CCOCC
Product: C[N+](C)(C)Cc1ccc[nH]1
Product: [I-]

Procedure:
To a cold solution of 67 g (0.47 mole) of methyliodide in 150 ml of anhydrous ether was added slowly a dry ether solution of 50 gm of 2-(N,N-dimethylaminomethyl)pyrrole (0.37 mole). A white solid begain to precipitate out of solution. The mixture was heated to 30° for 1.5 hours, filtered and washed with 2/×30 ml of ether to obtain 59 gm of 2-pyrryl)methyltrimethylammonium iodide which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12](=[CH2:16])[C:13]([OH:15])=O)=[CH:7][CH:6]=1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[C:48]([Br:49])=[CH:47][CH:46]=[CH:45][N+:44]=1[O-:50].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:49][C:48]1[C:43]([NH:42][C:13](=[O:15])[C:12](=[CH2:16])[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)[CH3:17])=[N+:44]([O-:50])[CH:45]=[CH:46][CH:47]=1
Reactant: C=C(C(=O)O)C(C)c1ccc(C(=O)OC)cc1
Reactant: Nc1c(Br)ccc[n+]1[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=C(C(=O)Nc1c(Br)ccc[n+]1[O-])C(C)c1ccc(C(=O)OC)cc1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(4-(methoxycarbonyl)phenyl)-2-methylenebutanoic acid (1.0 g, 4.2 mmol), HATU (1.9 g, 5.1 mmol), 2-amino-3-bromopyridine 1-oxide (0.88 g, 4.6 mmol) and diisopropyl ethylamine (2.22 mL, 12.5 mmol) in anhydrous DMF (10 mL) was stirred at 23° C. for 1 h, then concentrated. The residue was partitioned between ethyl acetate and brine (2×). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated. The residue was triturated with acetonitrile (20 mL). The solid was filtered and dried under vacuum to give the title compound. MS: m/z=406.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)=[CH:10][N:4]2[N:3]=1.[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].N1C=CC=CC=1>CC#N>[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:21])[CH3:22])[CH:16]=3)=[CH:10][N:4]2[N:3]=1)=[O:30]
Reactant: Cc1ccc(-c2cn3nc(N)ccc3n2)cc1NC(=O)C(C)(C)C
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1ccc(-c2cn3nc(NC(=O)c4cccc(Br)c4)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.8 %

Procedure:
An 8-mL vial is charged with N-[5-(6-aminoimidazo[2,1-f]pyridazin-2-yl)-2-methyl-phenyl]-2,2-dimethyl-propanamide (0.097 g, 0.3 mmol), 3-bromobenzoyl chloride (0.059 mL, 0.45 mmol), pyridine (0.073 mL), and MeCN (1.0 mL). The mixture is stirred at room temperature for 16 hours, concentrated onto celite and purified by silica gel chromatography (0-100% 1:0.1 EtOAc:MeOH in CH2Cl2) to give the title compound (0.065 g). LCMS (m/z)=506.4 and 508.4 [M+H]+, tR=2.96 min.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH:20][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[CH:8]=3)[N:3]=2)=[CH:16][CH:15]=1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: Cc1ccc(CN)o1
Reactant: NCc1ccncc1
Product: Cc1ccc(CNc2ccc3cc(NCc4ccncc4)ccc3n2)o1

Procedure:
The title compound, MS: m/e=345.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 4-(aminomethyl)pyridine.
Reaction SMILES: [Si:1]([C:8]1[S:9][C:10]([C:13]2([OH:29])[CH2:18][CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15][CH2:14]2)=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>CO.[C].[Pd]>[Si:1]([C:8]1[S:9][C:10]([C:13]2([OH:29])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)c1ncc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)c1ncc(C2(O)CCNCC2)s1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of benzyl 4-(2-(tert-butyldimethylsilyl)thiazol-5-yl)-4-hydroxypiperidine-1-carboxylate (as prepared in the previous step) (3 g, 6.94 mmol, 1.00 equiv) in methanol (20 mL) and Palladium carbon (0.3 g). Hydrogen was introduced into the above mixture. Under H2 atmosphere, the resulting solution was stirred overnight at 50° C. in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The title compound was obtained as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=O.[C:12]([CH2:14][C:15]([NH2:17])=[S:16])#[N:13]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:17]=[C:15]([CH2:14][C:12]#[N:13])[S:16][CH:2]=2)=[CH:6][CH:7]=1
Reactant: N#CCC(N)=S
Reactant: O=C(CBr)c1ccc(Cl)cc1
Product: N#CCc1nc(-c2ccc(Cl)cc2)cs1
Yield: 75 %

Procedure:
This compound was synthesized from 2-bromo-1-(4-chlorophenyl)ethanone and 2-cyanothioacetamide as described in example 1 step 1 (1.51 g, yield 75%). 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J=8.8 Hz, 2H), 7.49 (s, 1H), 7.43 (d, J=8.8 Hz, 2H), 4.18 (s, 2H). MS (ESI) m/z: Calculated for C11H7ClN2S: 234.00. found: 235.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][C@@H:13]3[C@H:8]([CH2:9][CH2:10][CH2:11][N:12]3[C:15](=[O:18])[CH2:16][CH3:17])[CH2:7][C:6]=2[CH:19]=1.[CH:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])[CH3:21].Cl.C(OCC)C>N1C=CC=CC=1>[CH:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:14][C@@H:13]4[C@H:8]([CH2:9][CH2:10][CH2:11][N:12]4[C:15](=[O:18])[CH2:16][CH3:17])[CH2:7][C:6]=3[CH:19]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])[CH3:21]
Reactant: CCC(=O)N1CCC[C@@H]2Cc3cc(N)ccc3C[C@H]21
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCC(=O)N1CCC[C@@H]2Cc3cc(NS(=O)(=O)c4ccc(C(C)C)cc4)ccc3C[C@H]21
Reaction time: 1 h
Yield: 70.5 %

Procedure:
1.21 g of trans-1-(7-amino-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinolin-1-yl)propan-1-one (0.38 mmol) were dissolved in 2 ml of pyridine. At 0-4° C., 0.08 g of 4-isopropyl-benzene sulfonylchloride (0.4 mmol) were added, and the reaction stirred for 1 h under cooling. 40 ml of aqueous 1 N hydrochloride acid and diethyl ether were added, the phases separated, and the aqueous layer extracted twice with diethyl ether. The organic phases were combined, washed three times with water acidified with 1 N aqueous hydrochloric acid, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield 0.118 g of the product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:15])[C:8](O)=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=[O:18])C.[BrH:22]>C(Cl)(Cl)Cl.[Cu](Br)Br>[Br:22][CH2:12][C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:18])=[C:7]([CH3:15])[CH:8]=1)=[O:13]
Reactant: CC(=O)c1cc(C(C)(C)C)cc(C)c1O
Reactant: Br
Reactant: CCOC(C)=O
Agent: Br[Cu]Br
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
A solution of 82.5 g (0.4 mol) of 1-(5-tert.butyl-3-methyl-hydroxyphenyl)-ethanone in 360 ml of chloroform was added dropwise while stirring to a suspension, heated to boiling, of 179 g (0.8 mol) of copper(II) bromide in 360 ml f ethyl acetate. The mixture was subsequently refluxed for 4 hours until the evolution of hydrogen bromide was complete. After the mixture had been cooled to room temperature, the copper salts were filtered off under suction, the filter residue was washed repeatedly with ethyl acetate, the filtrate was evaporated under reduced pressure, the solid residue was recrystallized from cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15]([CH2:23][C:24]#[N:25])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>C(O)C>[NH2:25][C:24]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:23]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(-c2ccccc2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (0.245 g) in ethanol (2 ml) was added to a stirred solution of benzoylacetonitrile (0.145 g) in ethanol (8 ml) and the resulting solution heated under reflux for 6 hours. Glacial acetic acid (1 ml) was added and the resulting mixture heated under reflux for a further 6 hours and then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (10 g), using dichloromethane as eluant, followed by reverse phase HPLC on C18 silica, using acetonitrile:methanol:water (50:10:40) as eluant, to afford the title compound as a white solid, m.p. 141.5-142.5° C. δ(CDCl3): 3.60 (br.s,2H), 6.08 (s,1H), 7.30-7.45 (m,3H), 7.80 (s,2H), 7.80-7.85 (m,2H). MS (thermospray): M/Z [M+H] 372.1; C16H10Cl2F3N2 +H requires 372.03.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:11]=1)[C:9]#[N:10].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:16]Br.C(OCC)(=O)C>CC(N(C)C)=O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:16][O:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: N#Cc1cncc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1cncc(OCc2cc(F)cc(F)c2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
876 mg (2 eq) of sodium hydride is added gradually at 0° C. under nitrogen to a solution of 865 mg of 5-hydroxynicotinonitrile (7.2 mmol) in 15 mL of dimethylacetamide. The mixture is stirred 10 min at 0° C. before adding 2.24 g (1.5 aq) of 3,5-difluorobenzyl bromide. The mixture is placed under stirring for 2.5 additional hours before being diluted in an ethyl acetate fraction and being washed with aqueous fractions. The organic phases are isolated, dried and concentrated. The solid residue obtained is recrystallized in methanol to yield 1.1 g (68% of 5-(3,5-difluorobenzyloxy) nicotinonitrile in the form of a beige powder.
Reaction SMILES: [CH:1]1[C:7](=[O:8])[NH:6][C:4](=[O:5])[N:3]([CH:9]2[O:13][CH:12]([CH2:14][O:15][P:16]([O:19][P:20]([O:23][P:24]([O-:27])([OH:26])=[O:25])([O-:22])=[O:21])([O-:18])=[O:17])[CH:11]([OH:28])[CH:10]2[OH:29])[CH:2]=1.[Na+].[Na+].[Na+].[CH2:33]([N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36]>O>[CH:1]1[C:7](=[O:8])[NH:6][C:4](=[O:5])[N:3]([C@@H:9]2[O:13][C@H:12]([CH2:14][O:15][P:16]([O:19][P:20]([O:23][P:24]([OH:26])([OH:27])=[O:25])([OH:22])=[O:21])([OH:18])=[O:17])[C@@H:11]([OH:28])[C@H:10]2[OH:29])[CH:2]=1.[CH2:42]([N:37]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:43][CH2:44][CH3:45]
Reactant: O=c1ccn(C2OC(COP(=O)([O-])OP(=O)([O-])OP(=O)([O-])O)C(O)C2O)c(=O)[nH]1
Agent: [Na+]
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1

Procedure:
UTP trisodium salt (1.00 g, 1.82 mmol) was dissolved in deionized water (13 mL), and the solution was caused to pass through a strong cation-exchange column (PK 216, proton-type, 10 cc). The eluate was mixed with a column wash solution, and the mixture was neutralized with tributylamine (1.75 mL, 7.35 mmol). The resultant solution was concentrated under reduced pressure, and the residue was co-boiled four times with dioxane (10 mL). The residue was dissolved in dimethylformamide (10 mL), to thereby yield a 0.133 M dimethylformamide solution of UTP tributylamine salt.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]3[CH2:12][CH:13]([CH3:16])[CH2:14][CH2:15][C:9]=3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([CH3:19])[CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:1][C:2]1[C:11]2[C:10]3[CH2:12][CH:13]([CH3:16])[CH2:14][CH2:15][C:9]=3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([CH3:19])[CH:3]=1)(=[O:22])[CH3:21]
Reactant: Cc1cc(O)c2c(c1)OC(C)(C)C1=C2CC(C)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C)cc2c1C1=C(CCC(C)C1)C(C)(C)O2
Temperature: 25 °C

Procedure:
A solution of 1-hydroxy-7,8,9,10-tetrahydro-3,6,6,9-tetramethyl-6H-dibenzo[ b,d]pyran (9.07 g., 0.035 mole) and acetic anhydride (7.1 g., 0.07 mole) in 25 ml. of pyridine was warmed over a steam bath for 2 hours. The reaction mixture was allowed to cool to room temperature and pyridine was removed by evaporation under reduced pressure. Water was added to the residue and the aqueous mixture was extracted with three portions of ether. The ethereal extracts were combined, washed with water, 6N HCl, again with water, dried over Na2SO4 and concentrated under reduced pressure to 9.5 g. (90%) of a colorless solid, m.p. 115°-119° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]([OH:17])(=O)[CH3:15].Cl[C:19]1[N:20]=C(NC2C=C(C=CC=2)C(O)=O)C2[S:27][CH2:26][CH2:25][C:23]=2[N:24]=1>O>[OH:13][C:10]1[CH:9]=[CH:8][C:7]([N:1]2[CH2:2][CH2:3][N:4]([C:19]3[N:20]=[C:14]([OH:17])[C:15]4[S:27][CH2:26][CH2:25][C:23]=4[N:24]=3)[CH2:5][CH2:6]2)=[CH:12][CH:11]=1
Reactant: CC(=O)O
Reactant: O=C(O)c1cccc(Nc2nc(Cl)nc3c2SCC3)c1
Reactant: Oc1ccc(N2CCNCC2)cc1
Solvent: O
Product: Oc1ccc(N2CCN(c3nc(O)c4c(n3)CCS4)CC2)cc1
Temperature: 180 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
1.70 g (9.54 mmol) of 4-piperazin-1-ylphenol is placed in 0.55 mL (9.62 mmol) of glacial acetic acid and heated to 180° C. in the heating block. 0.800 g (3.73 mmol) of 2-ethylsulfanyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (I) is added, then the mixture is left to stand for 1.5 hours at 180° C. and 16 hours at ambient temperature. Then the reaction mixture is combined with water and treated in the ultrasound bath. The precipitate is suction filtered, washed, and dried. 1.1 g of product II is obtained as a powder.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]3[C:14](=[CH2:28])[CH2:15][N:16]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:17][CH2:18][N:19]([S:20]([CH3:23])(=[O:22])=[O:21])[C:10]3=[N:9][C:8]=2[O:7][C:6]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:4]>CO.CCOC(C)=O.O[Pd]O>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]3[CH:14]([CH3:28])[CH2:15][N:16]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:17][CH2:18][N:19]([S:20]([CH3:23])(=[O:21])=[O:22])[C:10]3=[N:9][C:8]=2[O:7][C:6]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:4]
Reactant: C=C1CN(S(C)(=O)=O)CCN(S(C)(=O)=O)c2nc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc21
Agent: O[Pd]O
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc3c(cc12)C(C)CN(S(C)(=O)=O)CCN3S(C)(=O)=O
Reaction time: 8 h
Yield: 4.6 %

Procedure:
To 2-(4-Fluoro-phenyl)-7,10-bis-methanesulfonyl-5-methylene-5,6,7,8,9,10-hexahydro-1-oxa-7,10,11-triaza-cycloocta[f]indene-3-carboxylic acid methylamide (3 mg, 5.74 umol) dissolved in MeOH:EtOAc (1:1 1 mL) was added Dihydroxypalladium (0.5 mg, 2.87 umol). The reaction was fitted with a balloon of H2 and then stirred overnight. The mixture was filtered through a bed of celite and washed with additional MeOH (10 mL) and EtOAc (10 mL) and then concentrated and purified by HPLC CH3CN/H2O/0.1% TFA) to provide 2-(4-Fluoro-phenyl)-7,10-bis-methanesulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-1-oxa-7,10,11-triaza-cycloocta[f]indene-3-carboxylic acid methylamide (140 ug, 3%). MS-ES [M+H]+=525.2.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@:10]1([N:43]2[CH:51]=[C:49]([CH3:50])[C:47](=[O:48])[NH:46][C:44]2=[O:45])[O:42][C@H:22]([CH2:23][O:24][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.F>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][CH2:9][C@@:10]1([N:43]2[CH:51]=[C:49]([CH3:50])[C:47](=[O:48])[NH:46][C:44]2=[O:45])[O:42][C@H:22]([CH2:23][OH:24])[C@@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](OC(=O)c3ccccc3)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](OC(=O)c3ccccc3)[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 96.8 %

Procedure:
The silyl ether 4 (96.0 g, 136.4 mmol) in THF (600 mL) was treated with hydrogen fluoride-pyridine (70% HF in pyridine, 30 mL) at 0° C. for 4 h under a N2 atmosphere. The resultant mixture was diluted with AcOEt (600 mL) and washed with H2O (2×300 mL). the organic layer was dried (MgSO4) and concentrated at reduced pressure. The residue was purified by silica gel column chromatography (CH2 Cl2 /AcOEt 10:1) to give 61.6 g (97%) of 5 as a white solid. Rf (CH2Cl2 /AcOEt 10:1) 0.29.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl:6][C:7]1[C:8]([O:30][CH3:31])=[N:9][C:10]([C:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26][CH:27]3[CH2:29][CH2:28]3)=[CH:22][CH:21]=2)=[CH:14][C@H:15]2[CH2:19][CH2:18][NH:17][CH2:16]2)=[CH:11][CH:12]=1.C(N(CC)CC)C.O>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:20]2[CH:21]=[CH:22][C:23]([S:26][CH:27]3[CH2:28][CH2:29]3)=[CH:24][CH:25]=2)=[CH:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:16]2)=[N:9][C:8]=1[O:30][CH3:31]
Reactant: COc1nc(C(=C[C@H]2CCNC2)c2ccc(SC3CC3)cc2)ccc1Cl
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)N1CC[C@H](C=C(c2ccc(SC3CC3)cc2)c2ccc(Cl)c(OC)n2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Propionyl chloride (58 μL) was added to a solution of 3-chloro-6-{1-[4-(cyclopropylsulfanyl)phenyl]-2-[(3R)-pyrrolidin-3-yl]ethenyl}-2-methoxypyridine (EZ mixture) (235 mg) and triethylamine (83 μL) in tetrahydrofuran (6 mL) under ice-cooling, and the mixture was stirred at room temperature for four hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:5) to give 1-[(3R)-3-{2-(5-chloro-6-methoxypyridin-2-yl)-2-[4-(cyclopropylsulfanyl)phenyl]ethenyl}pyrrolidin-1-yl]propan-1-one (EZ mixture) as a crude product (363 mg).