Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[O:4][N:3]=1.C1COCC1.CO.[OH-].[Na+]>O>[CH3:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[O:4][N:3]=1
Reactant: CCOC(=O)c1c(C)noc1-c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1noc(-c2ccncc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
To a solution of ethyl 3-methyl-5-(pyridin-4-yl)-1,2-oxazole-4-carboxylate (0.95 g) in a mixed solvent of THF (20 mL)/methanol (10 mL) was added 1N aqueous sodium hydroxide solution (5.0 mL), and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added water, and the mixture was washed with ethyl acetate. The obtained aqueous layer was acidified with 1N hydrochloric acid, sodium chloride was added thereto until the mixture became saturated, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.48 g).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](CC)([O-])=O.[N+](C)([O-])=O>[F:8][C:9]1[CH:15]=[CH:14][C:12]2[NH:13][C:6](=[O:7])[NH:5][S:2](=[O:4])(=[O:3])[C:11]=2[CH:10]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: CC[N+](=O)[O-]
Product: O=C1Nc2ccc(F)cc2S(=O)(=O)N1
Temperature: -80 °C
Reaction time: 0.17 h

Procedure:
After dissolving chlorosulfonyl isocyanate (3.29 mL, 37.8 mmol) in nitroethane (45 mL), the mixture was cooled to −80° C. A solution of 4-fluoroaniline (3.50 g, 31.5 mmol) in nitromethane (5 mL) was then added dropwise thereto over a period of 10 minutes. The reaction mixture was raised to 0° C., and aluminum chloride (5.33 g, 40.0 mmol) was added. After heating to reflux for 30 minutes, the reaction mixture was cooled to room temperature and poured into ice water (120 mL). The precipitated crystals were filtered out and dried to obtain 7-fluoro-2H,4H-benzo[e]1,2,4-thiadiazine-1,1,3-trione.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])C.[H][H]>[Cr]([O-])([O-])=O.[Cu+2]>[CH2:4]([OH:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)OCC
Reactant: [H][H]
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO

Procedure:
The acid chloride of 1-triacontanoic acid is converted to the ester by adding methanol or ethanol and stirring for 1/2 to 1 hour. The alcohol was evaporated on a rotary evaporator leaving ethyl-1-triacontanoate. The ester is then reacted in a pressure vessel under about 250 atmospheres of hydrogen in the presence of a powdered copper chromite catalyst for about 12 hours at 250° C. to produce 1-triacontanol. One part of catalyst is present for every 5 to 10 parts of ester.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]=C(Br)C2C=C(C3C=CC(F)=CC=3)SC=2C=1O)=[O:7])CCC.C(OC(C1C(O)=C2C=C(C3C=CC(F)=CC=3)SC2=C(Br)N=1)=O)CCC.C(O[C:56]([C:58]1[N:63]=[C:62]([CH3:64])[C:61]2[CH:65]=[C:66]([C:68]3[CH:73]=[CH:72][C:71]([F:74])=[CH:70][CH:69]=3)[S:67][C:60]=2[C:59]=1[OH:75])=[O:57])CCC.C(OC(C1C(O)=C2C=C(C3C=CC(F)=CC=3)SC2=C(C)N=1)=O)CCC>>[F:74][C:71]1[CH:70]=[CH:69][C:68]([C:66]2[S:67][C:60]3[C:59]([OH:75])=[C:58]([C:56]([NH:13][CH2:8][C:6]([OH:7])=[O:5])=[O:57])[N:63]=[C:62]([CH3:64])[C:61]=3[CH:65]=2)=[CH:73][CH:72]=1
Reactant: CCCCOC(=O)c1nc(C)c2cc(-c3ccc(F)cc3)sc2c1O
Reactant: CCCCOC(=O)c1nc(Br)c2cc(-c3ccc(F)cc3)sc2c1O
Agent: CCCCOC(=O)c1nc(Br)c2sc(-c3ccc(F)cc3)cc2c1O
Agent: CCCCOC(=O)c1nc(C)c2sc(-c3ccc(F)cc3)cc2c1O
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccc(F)cc3)cc12

Procedure:
The title compound was prepared from 4-bromo-2-(4-fluoro-phenyl)-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester and 7-bromo-2-(4-fluoro-phenyl)-4-hydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester, example 34-c, under conditions analogous to experimental example 32-b. MS for 2-(4-fluoro-phenyl)-7-hydroxy-4-methyl-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester: (+) m/z 360.0.0 (M+1). MS for 2-(4-fluoro-phenyl)-4-hydroxy-7-methyl-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester: (+) m/z 360.0.0 (M+1).
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:30])[CH2:27][C:26]2[C:21](=[CH:22][C:23]([CH3:29])=[C:24]([CH3:28])[CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:30][C:11]([C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][C:23]([CH3:29])=[C:24]([CH3:28])[CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(N)Cc2cc(C)c(C)cc2C1
Reactant: O=C(O)c1cccc2c1CCCC2
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: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2cc(C)c(C)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (400 mg, 2.27 mmol), 2-amino-5,6-dimethyl-indan-2-carboxylic acid ethyl ester (636 mg, 2.72 mmol), HATU (1.30 g, 3.41 mmol) in anhydrous DMF (15 mL) is added DIPEA (563 μL, 3.41 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (78) as white solid (817 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)=[O:11]>CO>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)(=[O:11])[CH3:9]
Reactant: Clc1ccc(I)cc1
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Solvent: CO
Product: CC(=O)c1ccc(-c2ccc(Cl)cc2)c([N+](=O)[O-])c1

Procedure:
4-chloroiodobenzene and 4-bromo-3-nitroacetophenone were reacted in an analogous manner to that described in Example 1 (a) to give the novel intermediate 4-acetyl-4'-chloro-2-nitrobiphenyl, m.p. 103° - 105°C. (from methanol). This compound was reduced with stannous chloride and concentrated hydrochloric acid in an analogous manner to that described in Example 1 (b) to give the novel intermediate 4-acetyl-2-amino-4'-chlorobiphenyl, m.p. 139° - 140°C. (from methanol). This compound was converted to the novel intermediate 4-acetyl-4'-chloro-2-hydroxybiphenyl and thence to the novel intermediate 4-acetyl-4'-chloro-2-methoxybiphenyl, b.p. 167° - 170°C./0.4 mm., by diazotization and methylation methods analogous to those described in Example 2.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:44]=[C:43]([O:45][CH3:46])[C:38]2[O:39][CH2:40][CH2:41][O:42][C:37]=2[C:36]=1[F:47])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:47][C:36]1[C:37]2[O:42][CH2:41][CH2:40][O:39][C:38]=2[C:43]([O:45][CH3:46])=[CH:44][C:35]=1[CH:21]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:27][CH:28]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)OCCO2
Reactant: NNc1ncccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c(F)c2c1OCCO2
Temperature: 85 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
After adding 21 mg of 2-hydrazinopyrimidine and 50 ul of triethylamine to a solution of 105 mg of [2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 200 mg of sodium cyanotrihydroborate to the reaction mixture it was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (58 mg) as a light brown solid.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]1[CH2:7][O:6][C@@H:5](OC(C)C)[O:4]1.[P:12]([O:21]C(C)C)([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15].P(Cl)(Cl)Cl>[Cl-].[Zn+2].[Cl-]>[Br:1][CH2:2][C@@H:3]1[CH2:7][O:6][C@@H:5]([P:12]([O:17][CH:18]([CH3:20])[CH3:19])([O:13][CH:14]([CH3:16])[CH3:15])=[O:21])[O:4]1
Reactant: CC(C)O[C@@H]1OC[C@@H](CBr)O1
Reactant: CC(C)OP(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClP(Cl)Cl
Product: CC(C)OP(=O)(OC(C)C)[C@@H]1OC[C@@H](CBr)O1
Temperature: 0 °C
Reaction time: 10 h
Yield: 72 %

Procedure:
To the mixture of cis and trans 4-(bromomethyl)-2-isopropoxy-1,3-dioxolane (example 2) (6.13 g, 9:1 of isopropoxy:methoxy) was added triisopropyl phosphite (4.43 mL, 18.0 mmol, 0.66 eq.), phosphorus trichloride (0.784 mL, 8.99 mmol, 0.33 eq.) and zinc chloride (few milligrams) at 0° C. The mixture was stirred at 0° C. for 2 hr and at room temperature for 10 hr. The crude mixture of cis and trans isomers in a 2:5 ratio was purified by flash chromatography on silica gel using dichloromethane:ethyl acetate 4:1 as eluant to give the cis isomer (0.242 g), a mixture of cis and trans isomers (3.13 g) and the trans isomer (3.15 g) for a total yield of 72%. Several chromatographic purifications were performed to obtain the cis and trans isomers in pure form.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=[O:19])=[CH:10][CH:9]=1>C1COCC1>[CH3:7][N:6]1[C:2]([CH:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]=[CH:9][CH:10]=2)[OH:19])=[CH:3][N:4]=[CH:5]1
Reactant: O=Cc1ccnc2ccccc12
Reactant: Cn1cncc1Br
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1ccnc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Analogous to the general method described in J. Org. Chem. 2004, 69, 8115 and Chem. Pharm. Bull 1997, 1145. To a 2-necked flask containing 5-bromo-1-methyl-1H-imidazole (2.05 g, 12.7 mmol) was added THF (50 mL) and the solution was cooled to 0° C. To this clear homogeneous solution was added isopropyl magnesium chloride-LiCl complex (1.3 M, 10.5 mL, 13.6 mmol) which initially resulted in a white suspension, but became grayish once the addition of the Grignard reagent was complete. The reaction was stirred in an ice bath for 30 min, then a THF solution (20 mL) of quinoline-4-carbaldehyde (1.00 g, 6.36 mmol) was introduced and the reaction mixture became a greenish-grey color, and was subsequently allowed to warm to room temp. After 2 hours, the reaction mixture became brown in color and still remained heterogeneous. The reaction was quenched after 2 hours with saturated NH4Cl solution and the aqueous portion was extracted with EtOAc (4×75 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give an amber oil which solidified to a white solid upon standing. The crude material was triturated with DCM and then MeOH leaving behind the title compound as a white solid. The mother liquors were concentrated and chromatographed on silica gel (30% EtOAc-DCM increasing gradient to 10% MeOH-DCM) to provide more title compound as an off-white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[Cl-:25].[CH2:23]([O:22][C:20]([C:18]1[N:19]=[C:14]([CH:11]2[CH2:12][CH2:13][NH2+:8][CH2:9][CH2:10]2)[CH:15]=[CH:16][CH:17]=1)=[O:21])[CH3:24]
Reactant: Cl
Reactant: CCOC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(C2CC[NH2+]CC2)n1
Product: [Cl-]
Temperature: 0 °C

Procedure:
To a solution of ethyl 6-[1-(tert-butoxycarbonyl)piperidin-4-yl]pyridine-2-carboxylate (2.0 g) was added dropwise, at 0° C., a 4 molar solution of hydrochloric acid in 1,4-dioxane (45 ml). The reaction mixture was stirred at 0° C. and then gradually warmed to room temperature. After stirring overnight, the solvent and excess hydrogen chloride were removed. This gave 4-[6-(ethoxycarbonyl)pyridin-2-yl]piperidinium chloride (1.75 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C@H:6]([CH3:8])[S:5](=[O:10])(=[O:9])[C:4]2[S:11][CH:12]=[CH:13][C:3]1=2.S1C2C=CCSC=2C=C1>>[OH:1][C:2]1[CH2:7][C@H:6]([CH3:8])[S:5](=[O:10])(=[O:9])[CH:4]2[S:11][CH:12]=[CH:13][C:3]=12
Reactant: C[C@H]1CC(=O)c2ccsc2S1(=O)=O
Agent: C1=Cc2sccc2SC1
Product: C[C@H]1CC(O)=C2C=CSC2S1(=O)=O

Procedure:
A process for preparing trans-(4S, 6S)-5,6-dihydro-4-hydroxy-6-methyl-thieno[2,3-b]thiopyran-7,7-dioxide having the formula (IIb): ##STR11## in a trans/cis ratio of at least 50/50, which comprises subjecting 5,6-dihydro-4-oxo-(S)-6-methyl-thieno[2,3-b]thiopyran-7,7-dioxide having the formula (I): ##STR12## to the action of a microorganism to reduce the thienothiopyran derivative having the formula (I), to obtain the trans-(4S, 6S)-isomer of 5,6-dihydro-4-hydroxy-(S)-6-methyl-thieno-[2,3-b]thiopyran-7,7-dioxide having the formula (II): ##STR13## in a trans-(4S, 6S)/cis-(4R, 6S) ratio of at least 50/50, wherein said microorganism is a member selected from the group consisting of Ashbya gossypii IFO 0560, Candida cantarellii IFO 1261, Candida kefyr IFO 0706, Candida magnoliae IFO 0705, Candida maris IFO 10003, Candida parapsilosis IFO 0585, Candida saitoana IFO 0768, Candida tropicalis IFO 0589, Candida tropicalis IFO 1404, Candida versatilis IFO 1228, Cryptococcus albidus IFO 0378, Cryptococcus terreus IFO 0727, Pichia capsulata IFO 0721, Hansenula glucozyma IFO 1472, Pichia holstii IFO 0980, Pichia minuta IFO 1473, Kluyveromyces marxianus IFO 0288, Metschnikowia bicuspidata IFO 1408, Metschnikowia pulcherrima IFO 0561, Metschnikowia reukaufii IFO 0749, Pichia carsonii IFO 0946, Pichia toletana IFO 0950, Rhodosporidium dacryodium IFO 1930, Rhodosporidium sphaerocarpum IFO 1438, Rhodosporidium toruloides IFO 0413, Rhodotorula minuta IFO 0928, Rhodotorula minuta IFO 0715, Saccharomyces cerevisiae IFO 0258, Saccharomycopsis malanga IFO 1710, Schwanniomyces occidentalis IFO 1840, Stephanoascus ciferrii IFO 1854, Trigonopsis variabilis IFO 0671 and Trichosporon cataneum IFO 1198.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:8](=[O:23])[CH:7]=1.C1C(=O)N([Cl:36])C(=O)C1>ClC(Cl)C(O)=O.ClC(Cl)C>[Cl:36][C:7]1[C:8](=[O:23])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Agent: O=C(O)C(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Cl)c1=O
Yield: 51.6 %

Procedure:
3-[4-[(2,4-Difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (from above) (7.5 g, 19.4 mmol) and NCS (2.6 g, 19.4 mmol) were taken up in 65° C. dichloroethane (100 ml). A catalytic amount of dichloroacetic acid (2 drops) was added. After two hours the solvent was removed in vacuo and the residue was taken up in diethyl ether. The precipitate was collected on a filter pad and then taken up in 50% ethyl acetate/hexanes to remove residual succinimide. The precipitate was collected on a filter pad and then dried in vacuo to produce a white powder (4.2 g, 52%). 1H NMR (300 MHz, CD3OD) δ 8.10 (dd, J=7.85) 1.81 Hz, 1H), 7.83 (d, J=8.26, 1.81 Hz, 1H), 7.40 (app q, J=8.26 Hz, 1H), 7.58 (d, J=7.85 Hz, 1H), 7.13-7.06 (m, 2H), 6.74 (s, 1H), 5.40 (s, 2H), 2.14 (s, 3H), 2.04 (s, 3H); ES-MS m/z 420 (M+H). ES-HRMS m/z 420.0786 (M+H calcd for C21H17ClF2NO4 requires 420.0809).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18](O)[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:24][C:25]1C=C(C=CC=1)C#N.Cl[C:34]1N=C(Cl)C(F)=C[N:35]=1>>[C:25]([C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:34]#[N:35])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1)#[N:24]
Reactant: N#Cc1cccc(N)c1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: N#Cc1cccc(Nc2ncc(F)c(Nc3cccc(C#N)c3)n2)c1
Yield: 76 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 3-aminobenzonitrile (177 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gave N2,N4-bis(3-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine (75 mg, 76%). 1H NMR (acetone-d6): δ 7.33 (dt, J=1.8, 7.8 Hz, 1H), 7.46-7.52 (m, 2H), 7.59 (t, J=7.8 Hz, 1H), 7.90 (ddd, J=0.9, 2.1 and 8.4 Hz, 1H), 8.09 (ddd, J=1.2, 2.4 and 8.4 Hz, 1H), 8.17 (d, J=3.3 Hz, 1H), 8.31 (m, 1H), 8.35 (t, J=2.1 Hz, 1H), 8.98 (br, 1H, NH), 9.02 (br, 1H, NH); 19F NMR (282 MHz, acetone-d6): δ −165.80; LCMS: 24.64 min.; purity: 98.02%; MS (m/e): 331.01 (MH+).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:16](=[O:18])[NH2:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C.[C:19]([O:23][C:24]([NH:26][C@H:27]([C:38]([OH:40])=O)[C@@H:28]([CH3:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([NH:26][C@H:27]([C:38]([NH:8][C@@H:9]([C:16](=[O:18])[NH2:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:40])[C@@H:28]([CH3:37])[O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:25])([CH3:20])([CH3:21])[CH3:22]
Reactant: COC(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: COC(=O)CC[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1)C(N)=O
Yield: 64.7 %

Procedure:
Methyl t-butyloxycarbonyl-D-isoglutaminate (0.65 g, 2.5 mmol) and t-butyloxycarbonyl-O-benzyl-L-threonine (0.77 g, 2.5 mmol) were reacted by the similar procedure to that described in Example 44 (I) to obtain methyl t-butyloxycarbonyl-O-benzyl-L-threonyl-D-isoglutaminate (0.73 g). m.p. 131°-132° C. [α]D22 +7.0° (C 0.5, ethanol). Rf3 =0.39, Rf5 =0.46.
Reaction SMILES: [N+:1]([CH2:4][C@@]1(CC(OC(C)(C)C)=O)C[C@H]2[C@@H]1C=CC2)([O-:3])=[O:2].[CH3:20][C:21]1[CH2:22][C@H:23]2[C@@H:26]([C:27]=1[CH3:28])[C:25](=[CH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]2>>[CH3:20][C:21]1[CH2:22][C@@H:23]2[C@H:26]([C:27]=1[CH3:28])[C@@:25]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([CH2:4][N+:1]([O-:3])=[O:2])[CH2:24]2
Reactant: CC1=C(C)[C@H]2C(=CC(=O)OC(C)(C)C)C[C@H]2C1
Reactant: CC(C)(C)OC(=O)C[C@]1(C[N+](=O)[O-])C[C@@H]2CC=C[C@@H]21
Product: CC1=C(C)[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]

Procedure:
The compound of interest (4.5 g, 85%) was obtained as an oil substance in the same way as in paragraph (1-c) using tert-butyl(±)-(1S,5R)-[3,4-dimethylbicyclo[3.2.0]hept-3-en-6-ylidene]acetate (4.2 g, 18 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]O)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)ccc21
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from the product of Example 2 (140 mg), collidine (0.061 mL), and DMAP (8.1 mg) in 6.7 mL anhydrous DMF is cooled to 0° C. Methanesulfonyl chloride (0.12 mL) is added dropwise. The reaction is stirred at room temperature for approx. 2-3 hrs. Morpholine (0.34 mL) is added. The product is precipitated by addition of H2O. The crude product is adsorbed onto silica and chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 70.1 mg (42%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@@H:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[N+:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21].[OH2:32].[OH2:33].O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.C1(C)C=CC=CC=1.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>[C:8]([OH:17])(=[O:33])[C:7]([OH:32])=[O:6].[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][CH2:9][C@H:8]([OH:17])[CH2:7][O:6][C:5]2[CH:18]=[CH:19][C:2]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:20]([O-:22])=[O:21])[CH:28]=3)=[CH:3][CH:4]=2)[CH:12]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O
Reactant: O[C@@H](CCc1cccnc1)COc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(O)C(=O)O
Product: O=[N+]([O-])c1cccc(-c2ccc(OC[C@@H](O)CCc3cccnc3)cc2)c1

Procedure:
Prepared according to the method described in Example 33a) from (2S)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.25 g), 3-nitrobenzeneboronic acid (0.194 g), sodium carbonate decahydrate (0.444 g) and tetrakis(triphenylphosphine)palladium(0) (0.022 g) in ethanol (1 ml), water (1 ml) and toluene (5 ml). Conversion to the oxalate salt upon treatment with excess saturated ethereal oxalic gave the title compound as a hygroscopic glass (0.21 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:16])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Br:17][C:18]([F:25])([F:24])[C:19](OCC)=[O:20]>CN(C=O)C>[Br:17][C:18]([F:25])([F:24])[C:19]([NH:1][CH2:2][C:3]1([OH:16])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:7][CH2:8]1)=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Reactant: CCOC(=O)C(F)(F)Br
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(O)(CNC(=O)C(F)(F)Br)CC1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
A solution of tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (1.702 g) in DMF (20 mL) at 20° C. was treated with ethyl 2-bromo-2,2-difluoroacetate (1.5 g) and the mixture stirred for 90 minutes at 20° C. under nitrogen. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 2.5 g.