Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(C(C)=O)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=1
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 13.8 g (0.1 mole) potassium carbonate, 11.3 g (0.01 mole) 4-fluorophenol and 13.0 ml (19.6 g [0.22 mole]) ethyl bromoacetate in 100 ml methyl ethyl ketone were stirred overnight at room temperature and then heated at reflux for 5 hours. After the reaction mixture cooled to room temperature, it was filtered. The filtrate was concentrated to remove solvent. The concnetrate was used as a whole without further isolation in Example 2.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[CH:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]=[O:13])(=[O:7])=[O:6].CC(C)=[O:26]>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[CH:11]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:12]([OH:26])=[O:13])(=[O:7])=[O:6]
Reactant: CC(C)(COS(=O)(=O)CCCCl)C(C=O)OCc1ccccc1
Reactant: CC(C)=O
Product: CC(C)(COS(=O)(=O)CCCCl)C(OCc1ccccc1)C(=O)O
Yield: 96 %

Procedure:
Following the general procedure of the oxidation of aldehydes to carboxylic acids of Description 13, (3R/S)-2,2-dimethyl-4-oxo-3-(phenylmethoxy)butyl (3-chloropropyl)sulfonate (12b) (7.6 g, 21 mmol) dissolved in 100 mL of acetone was reacted with 10.5 mL of Jones-reagent (2.0 M in water). After work-up, 7.6 g (96% yield) of the title compound (12) was obtained as a colorless oil. The analytical data was consistent with the proposed structure and with the data obtained for the enantiopure compound (11).
Reaction SMILES: C([SiH](C(C)C)C(C)C)(C)C.[CH2:11]([O:18][C@@H:19]1[C@@H:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:24]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:23]([CH2:42][O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[O:22][C:20]1([C:51]1[CH:56]=[C:55]([CH3:57])[CH:54]=[CH:53][C:52]=1[O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>>[CH2:11]([O:18][C@@H:19]1[C@@H:25]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@H:24]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:23]([CH2:42][O:43][CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[O:22][C@H:20]1[C:51]1[CH:56]=[C:55]([CH3:57])[CH:54]=[CH:53][C:52]=1[O:58][CH2:59][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(OCc2ccccc2)c(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Agent: CC(C)[SiH](C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
1.56 Moles of n-hexane solution of n-butyllithium (50 ml) were added dropwise to a solution of 1-(benzyloxy)-2-bromo-4-methylbenzene (20 g) in tetrahydrofuran (250 ml) at −78° C. in an argon atmosphere, and the mixture was stirred for one hour at the same temperature. To the reaction mixture was added dropwise a solution of 2,3,4,6-tetra-0-benzyl-D-(+)-glucono-1,5-lactone (35.0 g) in tetrahydrofuran (200 ml) at −78° C., and the resulting mixture was stirred for one hour at the same temperature. Aqueous solution of 1M hydrochloric acid (10 ml) was added to the mixture, and the temperature was raised to room temperature. Then, anhydrous magnesium sulfate (50 g) was added to the mixture, and the mixture was stirred for one hour at room temperature. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 2,3,4,6-tetra-0-benzyl-1-C-[2-(benzyloxy)-5-methylphenyl]-D-glucopyranose (37 g). Triisopropylsilane (31 ml) and borontrifluoride diethylether complex (12.6 ml) were added to a solution of 2,3,4,6-tetra-O-benzyl-1-C-[2-(benzyloxy)-5-methylphenyl]-D-glucopyranose in dicyclomethane-acetonitrile (1:3) (400 ml) under cooling with ice in an argon atmosphere, and the mixture was stirred for one hour at the same temperature. The reaction mixture was poured into saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtrated, and then the solvent was evaporated from the filtrate under reduced pressure to give the residue. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-methylphenyl]-D-glucitol (16.9 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[C:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)#[N:17]>>[CH3:1][C:2]1[C:3]([C:11]2[S:12][C:13]([C:22]([C:21]3[CH:25]=[CH:26][C:18]([C:16]#[N:17])=[CH:19][CH:20]=3)=[O:23])=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: Cc1c(-c2cccs2)noc1C(F)(F)F
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: Cc1c(-c2ccc(C(=O)c3ccc(C#N)cc3)s2)noc1C(F)(F)F
Yield: 36 %

Procedure:
Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and 4-cyanobenzoyl chloride by the method described in Example 3. Crude product was chromatographed on silica gel with EtOAc/hexanes (10 then 20%) as eluant to afford product as a colorless solid (130 mg, 36%). 1H NMR (CDCl3) 2.42 (d, J=1.3, 3 H), 7.62 (d, J=4.0, 1 H), 7.67 (d, J=4.0, 1 H), 7.85 (d, J=8.3, 1 H), 7.98 (d, J=7.9, 1 H). 13C NMR 8.0, 114.9, 116.3, 118.7 (q, J=271), 118.0, 129.1, 129.8, 132.7, 135.3, 137.6, 141.1, 144.6, ˜155 (q, obscured due to baseline noise), 157.7, 186.4. 19F NMR −63.1. LC/MS 7.08 min, [M+1]+ 363.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([OH:14])=[CH:3][CH:2]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.ClCCl>[CH3:15][O:14][C:4]1[C:5]2[S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=[CH:2][CH:3]=1
Reactant: Oc1cccc2c1sc1ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1cccc2c1sc1ccccc12
Reaction time: 16 h

Procedure:
To a solution of dibenzothiophen-4-ol (i)(14.2 g, 71.0 mmol) in acetone (500 ml) was added powdered potassium carbonate (14.72 g, 106.5 mmol) and methyl iodide (4.43 ml, 71 mmol). The mixture was heated to reflux and stirred like this for 16 hours. The mixture was then cooled and filtered through a Celite™ pad. The resulting filtrant was concentrated in vacuo to give an oily residue that was diluted in dichloromethane (100 ml) and washed with 1M NaOH and saturated brine solution. The organic layer was dried using MgSO4, filtered and concentrated in vacuo to give a buff coloured solid that corresponded to the title compound and was used without any further purification. (15.2 g, 100%) m/z (LC-MS, ESP), RT=4.22 min, (M+H)=215.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:12])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.CC1C=CC(S(O[CH2:24][C@@H:25]2[O:27][CH2:26]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:12])[C:5]([O:11][CH2:24][CH:25]2[CH2:26][O:27]2)=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CC(=O)c1cc(Br)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc(Br)cc(Cl)c1OCC1CO1
Temperature: 60 °C
Yield: 74.7 %

Procedure:
A mixture of 1-(5-bromo-3-chloro-2-hydroxyphenyl)ethanone (5.5 g, 21.9 mmol), (2R)-(−)Glycidyltosylate (10 g, 43.8 mmol) and K2CO3 (4.5 g, 32.9 mmol) in DMF (25 ml) was heated at 60° C. for 25 h. The solution was brought to ambient temperature and water and EtOAc was added. The water phase was extracted with EtOAc. The combined organic phases were washed with LiCl (5%), HCl (1 N) and brine and then dried (Na2SO4) and evaporated to dryness. Purification on flash column chromatography (isooctane/EtOAc) gave the title compound (5.0 g). MS m/z (rel. intensity, 70 eV) 250 (30), 248 (M+, 26), 235 (bp), 233 (85), 57 (90), 306 (M+, 9).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2[CH2:13][CH2:14][CH2:15][CH2:16][C:8]1=2.C(N(CC)CC)C.CO>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:5]([O:4][C:2]([N:11]1[C:10](=[O:12])[C:9]2[CH2:13][CH2:14][CH2:15][CH2:16][C:8]=2[C:7]1=[O:17])=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: O=C1NC(=O)C2=C1CCCC2
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)N1C(=O)C2=C(CCCC2)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 42 %

Procedure:
Ethyl chloroformate (0.38 ml, 4.3 mmol) was added dropwise to a stirred solution of 3,4,5,6-tetrahydrophthalimide (0.5 g, 3.3 mmol) and triethylamine (0.53 ml, 3.8 mmol) in dimethylformamide (6 ml) at 0-5° C. The reaction mixture was allowed to warm to room temperature and stand for 4 h. Methyl alcohol (3 ml) was added, diluted with chloroform (50 ml) and washed with water (3×150 ml). The chloroform solution was dried (Na2SO4) and concentrated in vacuum to give N-ethoxycarbonyl-3,4,5,6-tetrahydrophthalimide (yield 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][NH:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=2)=[CH:5][CH:4]=1.[C:25]([OH:31])([C:27](F)(F)F)=[O:26]>>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([N:12]([CH2:11][CH2:10][O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:27][C:25]([O:31][C:15]([CH3:21])([CH3:16])[CH3:14])=[O:26])=[CH:14][C:15]=1[C:21]([F:22])([F:23])[F:24])#[N:18]
Reactant: COc1ccc(OCCNc2ccc(C#N)c(C(F)(F)F)c2)cc1
Reactant: O=C(O)C(F)(F)F
Product: COc1ccc(OCCN(CC(=O)OC(C)(C)C)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 70B from 4-[(2-{[4-(methyloxy)phenyl]oxy}ethyl)amino]-2-(trifluoromethyl)benzonitrile, excluding TFA deprotection of tert-butyl ester. Purified by flash chromatography (EtOAc/hexanes), obtained as a colorless gum: MS (APCI) m/z 451 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[CH3:33][C:34]1[CH:35]=[N:36][NH:37][CH:38]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:36]2[CH:35]=[C:34]([CH3:33])[CH:38]=[N:37]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reactant: Cc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1cnn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)c1
Yield: 62.6 %

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.3 g, degreased with hexane), 4-methylpyrazole (0.48 g) and dimethylformamide (25 ml), the title compound (0.74 g) was obtained as an amorphous solid, MS, m/z: 403.2 (M+H)+, 425.2 (M+Na)+, 805.3 (2M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[C:6]([O:8]C)=O.[CH2:17]([NH2:19])[CH3:18]>C(Cl)Cl>[CH3:16][O:15][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:12]=1[O:13][CH3:14])[C:6]([NH:19][CH2:17][CH2:18][C:3]1[CH:12]=[CH:11][CH:10]=[C:5]([CH3:6])[CH:4]=1)=[O:8]
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1
Reactant: CCN
Solvent: ClCCl
Product: COc1cc(C(=O)NCCc2cccc(C)c2)cc(OC)c1OC

Procedure:
A solution of methyl 3,4,5-trimethoxybenzoate (31.3 g, 0.138 mol) and 2-)3-methylphenyl)ethylamine (18.6 g. 0.138 mol) was heated at 180° for 6 h. The dark reaction mixture was taken up in methylene chloride and washed with dilute HCl. The solvent was evaporated and the residue was chromatographed on 150 g of neutral alumina. Elution with methyl chloride/hexane (3:1) removed some by-products and elution with methylene chloride gave nearly pure amide F1 which was recrystallized from i-PrOH to give pure F1 (5.2 g, 11%), mp 105°-108°.
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][N:2]1[CH2:20][CH2:21][O:22][CH2:23][C:24](O)=[O:25].[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>O.O1CCCC1>[CH:27]1([NH:33][C:24](=[O:25])[CH2:23][O:22][CH2:21][CH2:20][N:2]2[CH2:3][CH2:4][N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][C:8]4[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=4[CH:6]3[CH2:1]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCCCC1
Reactant: O=C(O)COCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(COCCN1CCN2c3ccccc3Cc3ccccc3C2C1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 914.9 %

Procedure:
358 g of 2-(1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepin-2-yl)ethoxyacetic acid (prepared as described in Example 2), 0.1 g of cyclohexylamine and 0.11 g of triethylamine were added to 10 ml of tetrahydrofuran, and 0.17 g of diethyl cyanophosphonate was added dropwise to the mixture, whilst ice-cooling. The mixture was then stirred at room temperature for 5 hours, after which it was mixed with water and then extracted with methylene chloride. The extract was concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through silica gel, using 10 % by volume ethanol in ethyl acetate as the eluent, to afford 0. 4 g (yield 91%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26])[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2.[F:29][C:30]([F:37])([F:36])[CH2:31][S:32](Cl)(=[O:34])=[O:33]>>[F:29][C:30]([F:37])([F:36])[CH2:31][S:32]([NH:26][CH2:25][C:24]([C:15]1[NH:16][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[N:14]=1)([CH3:28])[CH3:27])(=[O:34])=[O:33]
Reactant: COc1ccc2cc(-c3nc(C(C)(C)CN)[nH]c3-c3ccncc3)ccc2c1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Product: COc1ccc2cc(-c3nc(C(C)(C)CNS(=O)(=O)CC(F)(F)F)[nH]c3-c3ccncc3)ccc2c1
Yield: 43 %

Procedure:
The title compound (12 mg, 43%) was prepared starting from the product of Example 2 and 2,2,2-trifluoroethanesulfonyl chloride using the method described in Example 4; MS(ES) m/e 519 [M+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:25]([NH2:27])=[O:26])[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.CN.C(O)(=O)C.[C:36]([BH3-])#[N:37].[Na+]>CO.CS(C)=O>[O:28]=[S:2]1(=[O:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:25]([NH2:27])=[O:26])[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:37][CH3:36])[CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: NC(=O)c1cc(-c2cccc(C=O)c2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-5-(3-formylphenyl)-1H-indole-7-carboxamide (0.160 g, 0.404 mmol) was taken up in MeOH (1.802 mL)/DMSO (1.802 mL). Methyl amine HCl (0.136 g, 2.018 mmol) was added followed by acetic acid (0.462 mL, 8.07 mmol). The reaction mixture was allowed to stir at room temperature for 1 hour. Sodium cyanoborohydride (0.051 g, 0.807 mmol) was added and the reaction mixture was allowed to stir for 45 minutes and LCMS then shows conversion to desired product. The reaction mixture was purified through a 500 mg SCX cartridge eluting with MeOH followed by ammonia in methanol. The fractions are concentrated under a stream of nitrogen. The residue was dissolved in DMSO (˜3 mL) and purified via RP-HPLC using an XBridge Prep C18 column with water/acetonitrile (0.1% NH4OH buffer). Obtained 0.023 g (13.85%) of the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)C.[C:12]1([C:23]2[C:24]([C:29](OCC)=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:13]([C:18](OCC)=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1>O>[C:23]1([C:12]2[C:13]([CH2:18][OH:19])=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:24]([CH2:29][OH:30])=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ccccc1-c1ccccc1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCc1ccccc1-c1ccccc1CO
Yield: 75 %

Procedure:
To 3 g LiAlH4 was added 100 ml anhydrous ethyl ether. While cooling with ice-bath and stirring intensely, 0.05 mol diethyl 2,2′-biphenyldicarboxylate was slowly added dropwise. The reaction mixture was heated refluxing for 5 hours, then cooled. Excess LiAlH4 was decomposed with water. The mixture was filtered, and the filtrate was extracted with ethyl ether. The extract was dried over anhydrous sodium sulfate. The solvent was removed. Column chromatography gave 2,2′-biphenyldimethanol as a white solid, the yield was 75%, and m.p. was 98-103° C. IR spectrum had a strong absorption peak at 3400 cm−1, and had no absorption peak at about 1700 cm−1. This demonstrated that the reduction reaction was carried out completely.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:4](=[O:18])[N:3]=1.[H-].[Na+].[C:21](=O)([O:29]C1C=CC=CC=1)[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.CCOC(C)=O>[C:23]1([O:22][C:21](=[O:29])[NH:1][C:2]2[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:10])=[O:11])[C:4](=[O:18])[N:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F)Oc1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 24.3 %

Procedure:
To a suspension of 4-amino-1-benzenesulfonyl-5-fluoro-1H-pyrimidin-2-one (0.20 g, 0.74 mmol) in anhydrous THF (3 mL) was added NaH (0.044 g of 60 wt % suspension in mineral oil, 1.11 mmol) at 0° C. After gas evolution had subsided, the mixture was transferred via cannula to an ice-cold mixture of diphenyl carbonate (1.5 g, 7.4 mmol) in anhydrous THF (5 mL) and stirred for 6 h. The reaction was diluted with EtOAc (25 mL) and the resulting solution was washed with satd aq NH4Cl (15 mL) and brine (15 mL). The organic phase was dried over Na2SO4, filtered, and the solvent evaporated. The residue was purified by precipitation from MeOH and Et2O to give (1-benzenesulfonyl-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)carbamic acid phenyl ester as a light brown solid (0.070 g, 24%): mp 182-185° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.95 (m, 2H), 7.87 (d, J=7.0 Hz, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.61 (t, J=7.7 Hz, 2H), 7.33 (t, J=7.9 Hz, 2H), 7.15 (d, J=7.3 Hz, 1H), 7.06 (d, J=7.6 Hz, 2H); ESIMS m/z 390 ([M+H]+), 388 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH2:35][C:36]#[N:37])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([N:27]([CH2:34][CH2:35][C:36]#[N:37])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:25][CH:26]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: N#CCCN(c1ccc(I)cc1)c1ncccn1
Product: COC(=O)C(C/C=C/c1ccc(N(CCC#N)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 78.9 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (73 mg) was reacted with 3-(N-(4-iodophenyl)-N-(pyrimidin-2-yl)amino)propanenitrile (94 mg) to obtain (E)-5-[4-((2-cyano-ethyl)-pyrimidin-2-yl-amino)-phenyl]-2-(2,6-dichlorobenzamido)-pent-4-enoic acid methyl ester (100 mg). Column chromatography (silica gel, eluent: cyclohexane/chloroform=2/1→1/2→1/5) was used for purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1>CCOCC.C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)[N:3]=1)[Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](OCc1cccc(Br)n1)(c1ccccc1)c1ccccc1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCc1cccc(-c2ccc(F)cc2)n1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 2-bromo-6-(tert-butyldiphenylsiloxy)methylpyridine (1 g; WO 94/00444), 4-fluorophenylmagnesium bromide (3.5 mL of a 2M solution in Et2O) and tetrakis (triphenylphosphine) palladium (200 mg) in THF (20 mL) was refluxed for 4 h. To the mixture was added NH4OAc buffer and the mixture was extracted with EtOAc. The organics were dried (MgSO4), concentrated and chromatographed (silica gel; hexane/EtOAc (30:1)) to provide the title compound as an oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl-:5].[CH2:6]([NH+:8]([CH2:15][CH3:16])[CH2:9][CH2:10][NH2+:11][CH2:12][CH2:13]O)[CH3:7].[Cl-]>ClCCl>[Cl-:3].[Cl:5][CH2:13][CH2:12][NH2+:11][CH2:10][CH2:9][NH+:8]([CH2:15][CH3:16])[CH2:6][CH3:7].[Cl-:3]
Reactant: CC[NH+](CC)CC[NH2+]CCO
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CC[NH+](CC)CC[NH2+]CCCl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of thionyl chloride (SOCl2) (16.9 g, 0.14 mol) in dichloromethane (20 ml) was added dropwise to a vigorously stirred suspension of N1,N1-diethyl-N2-(2-hydroxyethyl)ethane-1,2-diaminium chloride (21 g, 0.11 mol) in dichloromethane (120 ml) which was cooled at 0° C. The ice bath was removed and the reaction mixture was allowed to stir at room temperature for 1 hour. The mixture was then allowed to reflux for 1 hour. After cooling, the suspension was filtered and the product was washed with dichloromethane (40 ml) to give a colorless solid. (20 g, 78%). 1H NMR (methanol-d4): δ 4.03 (t, 3JHH=6.1, 2H, CH2Cl), 3.68 (br s, 4 H, CH2NH), 3.61 (t, 3JHH=5.7, 2H, Et2NCH2), 3.38 (q, 3JHH=7.3, 4H, CH3CH2), 1.43 (t, 3JHH=7.3, 6H, CH3).
Reaction SMILES: O.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)[N:12]=[C:11]([CH:20]([CH3:22])[CH3:21])[C:10]=2/[CH:23]=[CH:24]/[CH2:25][OH:26])=[CH:5][CH:4]=1>C1(C)C=CC=CC=1.[Mn]>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)[N:12]=[C:11]([CH:20]([CH3:22])[CH3:21])[C:10]=2/[CH:23]=[CH:24]/[CH:25]=[O:26])=[CH:5][CH:4]=1
Reactant: CC(C)c1nn(-c2cnccn2)c(-c2ccc(F)cc2)c1/C=C/CO
Agent: [Mn]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1nn(-c2cnccn2)c(-c2ccc(F)cc2)c1/C=C/C=O
Reaction time: 4 h
Yield: 91.9 %

Procedure:
Manganese IV dioxide (13.3 g, 153 mmol) was suspended in toluene (300 ml) and refluxed overnight with the azeotropic removal of H2O. The unsaturated alcohol (5.17 g, 15.3 mmol, Step D) was added and reflux was continued for four hours. The reaction was cooled and filtered through a bed of silica. Filtrate was evaporated to give 4.73 g (92%) of product as a yellow solid.