Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C(=O)C.[F:7][C:8]1[C:16]([F:17])=[C:15](C(O)=O)[C:14]([F:21])=[C:13]([F:22])[C:9]=1[C:10]([OH:12])=[O:11]>O>[F:7][C:8]1[C:16]([F:17])=[CH:15][C:14]([F:21])=[C:13]([F:22])[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1c(F)c(F)c(C(=O)O)c(F)c1F
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(O)c1c(F)c(F)cc(F)c1F
Temperature: 20 °C
Yield: 98 %

Procedure:
N,N-Dimethylacetamide (14.0 parts) and 2,3,5,6-tetrafluoroterephthalic acid (2.91 parts) was heated at 70° C. for 4 hours before cooling to 20° C. adding water (7 parts) and cooling to 5° C. The precipitated solid was collected by filtration and washed with cold water and dried, the aqueous filtrates were evaporated under vacuum and the resultant solids combined to give 2,3,5,6-tetrafluorobenzoic acid (98%). 1,2,4,5-tetrafluorobenzene (2%) was also formed.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([C:9]1C=CC(C)=CC=1)[CH2:7][OH:8].BrCCCCC(C)(C)C(OCC)=O.[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([CH3:9])[CH2:7][OH:8]
Reactant: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: CCOC(=O)C(C)(C)CCCCBr
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CO)CCCCBr
Yield: 99 %

Procedure:
According to the procedure described for the synthesis of 206e (Ackerley, N. et al. J. Med. Chem. 1995, 38, 1608-1628; Manley, P. W. et al. J. Med. Chem. 1987, 30, 1812-1818), 205c (500.0 g, 2.0 mol) was reacted with LiBH4 (65.0 g, 3.0 mol) and methanol (95.0 g, 3.0 mol) in CH2Cl2 (6.0 L) to afford 206c (417.0 g, 99%) as an oil. 1H NMR (CDCl3): δ 3.38 (t, 2H, J=7.4), 3.50-3.40 (br. s, 1H, OH), 3.22 (d, 2H, J=5.6), 1.85 (qv, 2H, J=7.4), 1.50-1.35 (m, 2H), 1.30-1.20 (m, 2H), 0.85 (s, 6H). 13C NMR (CDCl3) δ 71.4, 37.5, 34.9, 33.9, 33.4, 23.7, 22.4.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:18][OH:19])[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@@H:10]2[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].C>>[CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@H:10]([OH:17])[C@H:18]2[OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Product: OC[C@H]1O[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 5 °C

Procedure:
Incubation of Brevibacterium lactofermentum ATCC 13869 was effected in the same manner as in Example 1, except that sucrose was used as the carbon source. One liter of the culture obtained was sterilized, then treated with an anion exchange resin AMBERLITE IR-4B and a cation exchange resin AMBERLITE IR-120 and decolored with active charcoal. Next, the decolored liquid was concentrated to about 25 ml, and 75 ml of ethanol was added thereto and left to cool to 5° C. to obtain 8.5 g of trehalose crystals having a purity of 99%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 89.4 %

Procedure:
A mixture of 6.4 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 3.0 g of 2-(dimethylamino)ethyl chloride hydrochloride, 5.8 g of potassium carbonate and 150 ml of acetone is treated in the same manner as described in Example 1. The crude product thus obtained as recrystallized from a mixture of ethyl acetate and n-hexane. 6.93 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are thereby obtained as colorless needles.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[N+](=[CH2:15])=[N-]>CCOCC>[CH3:15][O:11][C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2)=[O:12]
Reactant: O=C(O)c1cccc2[nH]ccc12
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1cccc2[nH]ccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
To a 0° C. solution of indole-4-carboxylic acid (1.00 g, 6.21 mmol) in ether (60 mL) was added diazomethane (0.3M solution in ether, 24.8 mL, 7.45 mmol) and the reaction mixture was stirred for 0.5 hours at 0° C. An additional 20 mL of diazomethane solution was then added and stirring was continued for 1 hour at 0° C. The reaction mixture was quenched with formic acid (1.0 mL) and concentrated in vacuo to give 4-methoxycarbonylindole (1.1 g) as an off white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cc1ccncc1)c1ccc(Cl)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1ccncc1)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A toluene (5 ml) solution of the 4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained in Example 119, 1-benzylpiperidin-4-ol (103 mg, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heated under reflux for 3 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was added with 1-benzylpiperidin-4-ol (103 mg, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol), followed by heating under reflux for 22 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column. The fraction obtained from the methanol:methylene chloride (=1:10) eluate was concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid), whereby the title compound (40 mg, 35%) was obtained as an amorphous substance.
Reaction SMILES: CO[C:3]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=[O:8].B(Br)(Br)Br>>[OH:14][C:11]1[CH:10]=[C:4]2[C:3](=[CH:13][CH:12]=1)[O:8][C:7](=[O:9])[CH:6]=[CH:5]2
Reactant: COc1ccc(OC)c(C=CC(=O)O)c1
Agent: BrB(Br)Br
Product: O=c1ccc2cc(O)ccc2o1

Procedure:
In scheme F, 2,5-dimethoxycinnamic acid 15 is treated with boron tribromide (BBr3) to form 6-hydroxycoumarin 16. 6-Hydroxycoumarin 16 can be protected as the bis-methoxymethyl ether (MOM) 17a using N,N-diisopropylethylamine (iPr2NEt) and MOMCl or as the benzyl ether (Bn) 17b using cesium carbonate (CsCO3) and benzyl bromide (BnBr).
Reaction SMILES: C1COCC1.[F:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([F:15])[CH:8]=1.C([Li])CCC.[F:21][C:22]([F:27])([F:26])[C:23]([CH3:25])=[O:24]>CCCCCC>[F:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([F:15])[C:8]=1[C:23]([OH:24])([CH3:25])[C:22]([F:27])([F:26])[F:21]
Reactant: CC(=O)C(F)(F)F
Reactant: COc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(F)c(C(C)(O)C(F)(F)F)c(F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a THF (100 ml) solution of 1,3-difluoro-5-methoxybenzene (7 g, 48.6 mmol) was added dropwise 1.6 M hexane solution of n-butyllithium (30 ml, 48.6 mmol) at −78° C. over 30 minutes and the mixture was stirred for 2 hours at −78 ° C. Then 1,1,1-Trifluoroacetone (6.5 g, 58.3 mmol) was added at −78° C. and the mixture was stirred for 2 hours at −78° C. After stirring at room temperature for an additional 1 hour, the reaction was quenched with water. The whole was extracted with EtOAc and the organic layer was dried over sodium sulfate, filterd, and concentrated in vacuo. Purification by silica gel column chromatography eluting with hexane/EtOAc (10:1) gave the title compound (9.7 g, 78% yield) as a colorless oil.
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(O)(=O)C>[Br:1][CH2:11][C:4](=[O:3])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(C)=O
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)CBr
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.8 %

Procedure:
A solution of bromine (436 g, 2.73 mol) in acetic acid (750 mL) was added to a solution of ethyl 3-oxobutanoate (355 g, 2.73 mol) in acetic acid (1000 mL). The mixture was stirred at room temperature for 72 hours and was concentrated under reduced pressure at 45° C. to remove the acetic acid. The residue was partitioned between methylene chloride (400 mL) and water (250 mL). The organic layer was washed with saturated sodium bicarbonate (2×300 mL), water (300 mL), brine (125 mL) and was dried over anhydrous magnesium sulfate. The solution was filtered and concentrated to give ethyl 4-bromo-3-oxobutanoate as a yellow oil (421 g).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:30][C:29]=1[O:40][CH3:41]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:30][C:29]=4[O:40][CH3:41])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCCC(=O)Cc1ccc(OCCCBr)c(OC)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCC(=O)Cc1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(OC)c1
Yield: 68.7 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (3 g), 1-[4-(3-bromopropoxy)-3-methoxyphenyl]pentanone (3.7 g, 11.3 mmol) acetonitrile (140 ml) was heated at reflux for 4 hours. At the end of the reaction, the mixture was cooled and filtered. The filtrate was concentrated to an oil. Purification was performed by flash chromatography over a silica gel column (SiO2, 55 g; eluted with 1% methanol in dichloromethane, 600 ml; 3% methanol: 97% dichloromethane, 400 ml). The fractions containing pure product were pooled and concentrated to a solid (4.3 g, 91%). Recrystallization from ethanol (10 ml) gave a powdery solid of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-pentanone (3.22 g), m.p.=79°-80° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]1=[O:17])(=O)C.C[O-].[Na+].[Na]>CO>[F:23][C:21]1[C:19](=[O:20])[NH:18][C:16](=[O:17])[N:15]([CH:22]=1)[C@@H:6]1[O:7][C@H:8]([CH3:14])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(F)c(=O)[nH]c1=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: C[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 0 °C
Yield: 106.1 %

Procedure:
A solution of 860 g of 1-(5-deoxy-2,3-di-O-acetyl-β-D-ribofuranosyl)-5-fluorouracil in 16 liters of methanol was added to sodium methoxide freshly prepared from 42 g of sodium and 2000 ml of methanol. The methyl acetate resulting during the reaction was removed by repeated concentration of the mixture. The mixture was neutralised by the addition of 1000 ml of a strongly acidic cation exchange resin (H+ -form), freshly washed with methanol. After removing the ion exchange resin, the methanolic solution was concentrated under reduced pressure and the product, which separated in crystalline form, was washed with a mixture, cooled to 0° C., of 1000 ml of methanol and 1000 ml of ethyl acetate. By working-up the mother liquors there was obtained a total of 680 g (97%) of pure 5'-deoxy-5-fluorouridine; m.p. 192°-193° C.; [β]D25 =+139° (c=0.9 in methanol).
Reaction SMILES: [F:1]/[C:2](=[CH:8]\[CH3:9])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:10][CH2:9]/[CH:8]=[C:2](\[F:1])/[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: C/C=C(\F)C(=O)OCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C(F)=C/CBr
Yield: 79.3 %

Procedure:
Ethyl 2-fluorocrotonate (6.0 g) (prepared according to E. D. Bergmann and I. Shahak, J. Chem. Soc., 4033, 1961) N-bromosuccinimide (8.1 g) and benzoyl peroxide (0.15 g) was dissolved in carbon tetrachloride (120 ml) and heated at reflux for 3-5 hours. The mixture was cooled, filtered and the filtrate evaporated to dryness under reduced pressure. Chromatography on silica eluting with 10% diethyl ether:hexane gave ethyl 4-bromo-2-fluorocrotonate as a yellow oil (7.6 g). NMR 1H: 1.5(3H,t), 4.1(2H,dd), 4.4(2H,q), 6.4(1H,dt).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.BrC1C=CC(N)=CC=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>[N+]([O-])(O)=O>[CH3:21][C:20]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])=[O:22]
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: Nc1ccc(Br)cc1
Solvent: O=[N+]([O-])O
Product: CC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Preparation of 4-bromo-2-nitroaniline-4-bromoaniline (51.6 grams) and acetic anhydride (210 ml) were mixed under strong agitation. The temperature is raised to 65° C. in 10 minutes and slowly decreased to room temperature in one hour. An ice bath is used to maintain the temperature between 15°-20° C. and nitric acid (density 1.42, 30 ml) was added drop by drop in one hour. A yellow 4-bromo-2-nitroacetanilide was isolated by pouring the acetic anhydride solution into ice water followed by filtration. Hydrolysis of the acid acetanilide in aqueous hydrochloric acid (100 ml of concentrated HCL and 500 ml of water) at reflux temperatures for three hours yielded a 57% yield of 4-bromo-2-nitroaniline having the melting point of 109° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)=[O:6].CC1C=CC=CC=1C(N)=O.NC1C=CC(C)=C(C=1)C(NC1C=NC(N)=NC=1)=O.[F:47][C:48]([F:59])([F:58])[C:49]1[CH:50]=[C:51]([CH:55]=[CH:56][CH:57]=1)[C:52](Cl)=[O:53].CCN(CC)CC>C(Cl)Cl.N1C=CC=CC=1>[NH2:14][C:11]1[N:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([NH:1][C:52]([C:51]3[CH:55]=[CH:56][CH:57]=[C:49]([C:48]([F:47])([F:58])[F:59])[CH:50]=3)=[O:53])[C:3]=2[CH3:18])=[CH:13][N:12]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1c(N)cccc1C(=O)Nc1cnc(N)nc1
Agent: Cc1ccc(N)cc1C(=O)Nc1cnc(N)nc1
Agent: Cc1ccccc1C(N)=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(NC(=O)c2cccc(C(F)(F)F)c2)cccc1C(=O)Nc1cnc(N)nc1

Procedure:
3-amino-N-(2-aminopyrimidin-5-yl)-2-methylbenzamide 42 (113 mg, 0.464 mmol) [prepared according to the procedure described for methylbenzamide-5-amino-N-(2-aminopyrimidin-5-yl)-2-methylbenzamide in Example 1] was taken up in CH2Cl2 (4 mL) and pyridine (3 mL) and 3-(trifluoromethyl)benzoyl chloride (0.31 mL, 2.09 mmol) was added followed by NEt3 (0.13 mL, 0.928 mmol). Complete consumption of the amine starting material was indicated by LCMS. The crude reaction mixture was concentrated and the product purified using automated medium pressure chromatography (Isco—40 g column; eluting with a linear gradient from 97% CH2Cl2 (A line) to 100% 90/10/1 CH2Cl2/MeOH/NH3 (B line) on silica gel) to afford N-(2-amino-5-pyrimidinyl)-2-methyl-3-(((3-(trifluoromethyl)phenyl)carbonyl)amino)benzamide 43 as an off-white solid. MS m/z found 416 [MH+]; calc. for C20H16F3N5O2=415.13; and 2-methyl-3-(((3-(trifluoromethyl)phenyl)carbonyl)amino)-N-(2-(((3-(trifluoromethyl)phenyl)carbonyl)amino)-5-pyrimidinyl)benzamide 44 as an off-white solid. MS m/z found 588 [MH+]; calc. for C28H19F6N5O3=587.14.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][OH:10]>CCO>[OH:10][N:9]=[C:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccccc1
Solvent: CCO
Product: NC(=NO)c1ccccc1
Yield: 99.9 %

Procedure:
Benzonitrile (0.99 cm3, 1 g, 9.7 mmol) and hydroxylamine (50% in water, 0.89 cm3, 0.96 g, 14.55 mmol, 1.5 eq) were stirred under reflux in EtOH (10 cm3) for 48 hours. The solvent was evaporated under reduced pressure and water (10 cm3) was added to the residue. The mixture was extracetd with dichloromethane (100 cm3) and the organic extract was evaporated under reduced pressure. The residue was purified by column chromatography to give the product N′-hydroxybenzimidamide (1.32 g, 100%) as a white crystalline solid, mp 79-81° C. (lit 79-80° C. This procedure is suitable for all starting materials bearing a benzene ring.
Reaction SMILES: C1(=O)[N:5]([CH:6]2[CH2:11][S:10][C@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([CH2:18][C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[C:7]2=[O:28])C(=O)C2=CC=CC=C12.C(Cl)(Cl)Cl.CNN>CCOCC>[NH2:5][CH:6]1[CH2:11][S:10][C@H:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:8]([CH2:18][C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])=[O:20])[C:7]1=[O:28]
Reactant: C[Si](C)(C)CCOC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CS[C@@H]1c1ccccc1
Agent: CNN
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: C[Si](C)(C)CCOC(=O)CN1C(=O)C(N)CS[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the trimethylsilyl ester product from part (b) (1.17 g., 2.36 mmole) in 4 ml. of dry chloroform is treated with N-methylhydrazine (217 mg., 4.72 mmole). The stoppered reaction is stirred at room temperature overnight, then diluted with ether and filtered to remove N-methyl-phthalhydrazide. Removal of organic solvents in vacuo yields (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1I.[CH:15]([Sn](CCCC)(CCCC)CCCC)=[CH2:16]>ClC(Cl)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[CH:15]=[CH2:16]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1I
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(Cl)Cl
Product: C=Cc1c(C(=O)OC)nc(Cl)c(F)c1N
Temperature: 70 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoro-3-iodopicolinate (7.05 g, 21.33 mmol, prepared as described in Epp et al., WO 2013003740 A1) and vinyltri-n-butyltin (7.52 mL, 25.6 mmol) were suspended in dichloroethane (71.1 mL) and the mixture was degassed with Argon for 10 min. bis(triphenylphosphine)palladium(II) chloride (1.497 g, 2.133 mmol) was then added and the reaction mixture was stirred at 70° C. overnight (clear orange solution). The reaction was monitored by gas chromatography-mass spectrometry (GCMS). After 20 h, the reaction mixture was concentrated, adsorbed onto Celite, and purified by column chromatography (SiO2, hexanes/ethyl acetate gradient) to afford the title compound as a light brown solid (3.23 g, 65.7%) as a light brown solid: mp 99-100° C.; 1 H NMR (400 MHz, CDCl3) δ 6.87 (dd, J=18.1, 11.6 Hz, 1H), 5.72 (dd, J=11.5, 1.3 Hz, 1H), 5.52 (dd, J=18.2, 1.3 Hz, 1H), 4.79 (s, 2H), 3.91 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −138.79 (s); EIMS m/z 230.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[C:12](#[N:15])[CH:13]=[CH2:14]>O>[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH2:13][C:12]#[N:15])=[CH:7][CH:6]=1
Reactant: Oc1ccc(F)cc1
Reactant: C=CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: N#CCCOc1ccc(F)cc1
Reaction time: 0.17 h

Procedure:
5.4 g of sodium methylate were added portionwise at 60° C. to 112.1 g of 4-fluoro-phenol. After 10 minutes, the mixture was treated with 500 ml of acrylonitrile, boiled in an oil-bath for 48 hours, thereafter poured into 3 l of water and extracted with chloroform. After drying the organic phase with sodium sulfate, it was concentrated completely in vacuo. There was obtained 3-(4-fluoro-phenoxy)propionitrile as a viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7](=O)[CH2:8][CH3:9])[O:4][N:3]=1.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>>[Br:1][C:2]1[CH:6]=[C:5](/[C:7](=[N:17]/[S:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])/[CH2:8][CH3:9])[O:4][N:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CCC(=O)c1cc(Br)no1
Product: CC/C(=N\S(=O)C(C)(C)C)c1cc(Br)no1
Reaction time: 24 h

Procedure:
To a solution of 1-(3-bromo-isoxazol-5-yl)-propan-1-one (452 mg, 2.22 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (342 mg, 2.82 mmol) in CH2Cl2 titanium (IV) isopropoxide (1.4 mL, 4.9 mmol) and the mixture was warmed at 45° C. After 24 hours, the reaction was monitored by LC-MS, and the solvent was concentrated in vacuo and the remaining residue was diluted with EtOAc (32 mL) and saturated aqueous NaCl (8 mL) was added. The heterogeneous mixture was filtered through a pad of diatomaceous earth. The EtOAc layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in heptane to afford 2-methyl-propane-2-sulfinic acid [1-(3-bromo-isoxazol-5-yl)-prop-(E)-ylidene]-amide. MS m/z 307 (M), 309 (M+2).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:13])[NH:9][CH2:10][CH2:11][OH:12])([CH3:6])([CH3:5])[CH3:4].Cl[CH2:15][C:16]([CH2:18]Cl)=[CH2:17]>CN1CCCC1=O.O>[C:3]([O:7][C:8]([N:9]1[CH2:18][C:16](=[CH2:15])[CH2:17][O:12][CH2:11][CH2:10]1)=[O:13])([CH3:6])([CH3:4])[CH3:5]
Reactant: C=C(CCl)CCl
Reactant: CC(C)(C)OC(=O)NCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C=C1COCCN(C(=O)OC(C)(C)C)C1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (992.6 mg, 60% in mineral oil, 24.8 mmol) was added portionwise to a solution of (2-hydroxy-ethyl)-carbamic acid tert-butyl ester (2 g, 12.4 mmol) in 1-methyl-2-pyrrolidinone (20 ml) at −2° C., in order to maintain the temperature below 5° C. The mixture was then stirred for 30 minutes, cooled to −5° C., and a solution of 3-chloro-2-chloromethyl-1-propene (1.44 ml, 12.4 mmol) in 1-methyl-2-pyrrolidinone (10 ml) added dropwise in order to maintain the temperature below 3° C. Once addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for a further 18 hours. The reaction mixture was diluted with water and extracted with ether (2×50 ml). The combined organic extracts were dried over magnesium sulphate and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using ethyl acetate:pentane (10:90) to give the title compound as a clear oil, 713 mg.