Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[H-].[Na+].Cl[C:13]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[C:16]([Cl:35])[C:17]([O:33][CH3:34])=[CH:18][CH:19]=2)[N:14]=1.CCOC(C)=O>CN(C=O)C>[Cl:35][C:16]1[C:17]([O:33][CH3:34])=[CH:18][CH:19]=[C:20]2[C:15]=1[N:14]=[C:13]([N:5]1[CH:6]=[CH:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]1)[CH:22]=[C:21]2[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: COc1ccc(COc2cc(Cl)nc3c(Cl)c(OC)ccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a stirred solution of compound 233a (821 mg, 1.1 eq.) in anhydrous DMF (20 mL) at 0° C. was added NaH (241 mg, 1.1 eq.) portionwise. After the reaction mixture was stirred for 1 hr at room temperature, compound 221d (2 g, 1 eq.) was added and the mixture was stirred at 90° C. for 16 hrs. After the reaction mixture was cooled to room temperature, EtOAc was added. The organic phase was washed with HCl (2.5 N), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (petroleum ether/DCM, 50/50) to give compound 234a as a white solid in 51% yield. MS (ESI, EI−) m/z=461.9 (MH−).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:10])=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C[O:12][C:13]1C=CC=C(N)[CH:14]=1>>[NH2:6][C:5]1[C:4]([CH3:10])=[C:3]([O:2][CH3:1])[CH:9]=[CH:8][C:7]=1[C:13](=[O:12])[CH3:14]
Reactant: COc1cccc(N)c1
Reactant: COc1cccc(N)c1C
Product: COc1ccc(C(C)=O)c(N)c1C
Yield: 23 %

Procedure:
1-(2-Amino-3-methyl-4-methoxyphenyl)ethanone 201b was synthesized from 3-methoxy-2-methylaniline 215b as a yellow solid in 23% yield, according to the procedure as described for compound 215a. MS (ESI, EI+): m/z=180 (MH+).
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[CH:10](OC)(OC)[O:11][CH3:12].ClC(Cl)C>ClCCCl>[OH:2][C:1]1[C:3]2[O:4][CH:10]([O:11][CH3:12])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccc(O)c1O
Reactant: COC(OC)OC
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: COC1Oc2cccc(O)c2O1

Procedure:
A mixture of pyrogallol (25 parts), trimethyl orthoformate (32 parts) and 1,2-dichloroethane (250 parts) was heated with continuous distillation of the solvent for 4 hours. The volume of solvent was kept constant by simultaneous addition of dichloroethane. The mixture was then washed three times with water and dried over sodium sulphate. Removal of the solvent under reduced pressure and distillation of the residue gave 4-hydroxy-2-methoxy-1,3-benzodioxole, boiling point 104°-105° C/1 mmHg.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[CH3:9][O:10][C:11]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:12]=1[CH2:13][N:14]1[C@H:17]([CH2:18][CH:19]=O)[C@H:16]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]1=[O:32]>O.CCO>[CH3:9][O:10][C:11]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:12]=1[CH2:13][N:14]1[C:15](=[O:32])[C@@H:16]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:17]1[CH2:18]/[CH:19]=[N:2]/[OH:3]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CC=O)c(OC)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2C/C=N/O)c(OC)c1
Reaction time: 20 h

Procedure:
To a solution of hydroxylamine hydrochloride (160 mg, 2.25 mmol) and sodium bicarbonate (2.4 mL, 2.23 mmol) in water (6 mL) was added a solution of benzyl ((3S,4R)-1-(2,4-dimethoxybenzyl)-2-oxo-4-(2-oxoethyl)azetidin-3-yl)carbamate (886 mg, 2.15 mmol) in EtOH (200 μL) followed by an EtOH (200 μL) wash. After stirring for 20 h, the reaction mixture was partially concentrated in vacuo and partitioned between DCM and brine. The aqueous layer was extracted with DCM (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was used as such in the following step. LCMS: Rt=0.76 min, m/z=428.1 (M+1). Method 2m_acidic.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:23]=[CH:22][C:12]([CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1>CO.Cl.[Pd]>[NH2:21][CH2:20][C:16]1[CH:15]=[C:14]([CH2:13][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:3]=[C:2]([NH2:1])[N:7]=3)=[CH:23][CH:22]=2)[CH:19]=[CH:18][N:17]=1
Reactant: N#Cc1cc(Cc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1cc(Cc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.9 %

Procedure:
10% Degussa Pd on carbon (15 mg, 0.14 mmol) was flushed with nitrogen then diluted in methanol (1 mL). 4-[4-(2-amino-6-phenyl-pyrimidin-4-ylamino)-benzyl]-pyridine-2-carbonitrile (Example 35, 90 mg, 0.24 mmol) in methanol (2 mL) and concentrated HCl (0.03 mL) were subsequently added, and the mixture was flushed again with nitrogen prior to placing a hydrogen balloon on the flask. The mixture was stirred at rt for 3 h then filtered through Celite® and concentrated. The residue was purified by prep HPLC to give N4-[4-(2-aminomethyl-pyridin-4-ylmethyl)-phenyl]-6-phenyl-pyrimidine-2,4-diamine (10 mg, 11%). 1H NMR (CD3OD) δ 8.50 (d, J=5.3 Hz, 1H), 7.76 (m, 4H), 7.63 (m, 3H), 7.28 (m, 4H), 6.53 (s, 1H), 4.22 (s, 2H), 4.05 (s, 2H); MS ES: 383 (M+H)+, calcd 383, RT=1.84 min.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[OH:10][CH2:11][C:12]1[C:13]([CH3:19])=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][OH:10])[C:13]=1[CH3:19])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1c(O)cccc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(CO)cccc1OCC(=O)OC(C)(C)C
Yield: 94.2 %

Procedure:
Tert-butyl bromoacetate (75 g, 385 mmol) was added to a solution/suspension of 3-hydroxymethyl-2-methylphenol (46.6 g, 337 mmol) and finely powdered potassium carbonate (60 g) in acetone (500 mL). The mixture was heated at reflux for about 40 hours or until the reaction was complete. The solids were filtered, and the liquid residue was evaporated. Purification of the residue by silica gel chromatography, eluting with acetone/hexane, gave (3-hydroxymethyl-2-methylphenoxy)acetic acid tert-butyl ester as a pale yellow oil (80.1 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH3:12])[C:7](=O)[CH2:6][CH2:5]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:25]([NH2:29])(=[O:28])[CH:26]=[CH2:27]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3([CH3:12])[C:7](=[CH:6][CH2:5][C:4]=2[CH:3]=1)[NH:29][C:25](=[O:28])[CH2:26][CH2:27]3
Reactant: CC1C(=O)CCc2cc(F)ccc21
Reactant: C=CC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC12CCC(=O)NC1=CCc1cc(F)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.4 %

Procedure:
To 6-fluoro-1-methyl-2-tetralone (7.06 g; 39.6 mmol) in a round bottomed flask was added p-toluenesulfonic acid (1.23 g; 6.5 mmol) and the mixture was stirred at room temperature under nitrogen for 15 minutes. Acrylamide (5.62 g; 79.2 mmol) was added and the reaction mixture was heated to 88°-90° C. under nitrogen for three days. The mixture was diluted with ethyl acetate and water and stirred at room temperature for 1 hour. The resulting layers were separated. The organic layer was washed three times with water, dried over MgSO4 and concentrated to a viscous oil. The crude product was crystallized from ethyl acetate to afford 1.59 g (17% yield) of the subtitle compound. Melting point 202° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[NH:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[C:6]=2[N:22]=1.[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:7]1[CH2:8][CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([N:26]4[CH2:25][CH2:24][O:23][CH2:28][CH2:27]4)[CH:34]=3)=[N:22][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCCNc3ncc(Br)nc32)c1Cl
Reactant: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C
Product: Fc1ccc(F)c(CN2CCCNc3ncc(-c4cccc(N5CCOCC5)c4)nc32)c1Cl

Procedure:
9-(2-chloro-3,6-difluorobenzyl)-2-[3-(morpholin-4-yl)phenyl]-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b][1,4]diazepine was prepared from 2-bromo-9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b][1,4]diazepine and 3-morpholinophenylboronic acid pinacol ester using standard Suzuki conditions as described in Example 1 or 2.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:8]([NH:10][C@@H:11]([C:26](O)=[O:27])[CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:35][C:36]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][NH2:46])=[CH:41][CH:40]=1)=[O:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:35][C:36]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][NH:46][C:26](=[O:27])[C@@H:11]([CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[NH:10][C:8](=[O:9])[CH:7]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:41][CH:40]=1)=[O:37]
Reactant: O=C(NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)O)OCc1ccccc1
Reactant: NCc1ccc(CC(N)=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: NC(=O)Cc1ccc(CNC(=O)[C@@H](CCCNC(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 89 %

Procedure:
Prepared analogously to Example 6d) from (R)-N2 -diphenylacetyl-N5 -(phenylmethoxycarbonyl)-ornithine, 4-(aminocarbonylmethyl)-benzenemethanamine and TBTU in a yield of 89% of theory. Colourless crystals, Mp. 203-205° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=3[F:24])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:25][C@@H:26]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[NH:27]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:27]4[C@H:26]([CH3:25])[CH2:30][CH2:29][S:28]4(=[O:32])=[O:31])=[CH:19][C:18]=3[F:24])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 54.3 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](2-fluoro-4-iodophenyl)methanone (439 mg) described in Preparation Example 155 and (R)-3-methylisothiazolidine 1,1-dioxide (135 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (242 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.ClCCCl.C(=O)([O-])[O-].[K+].[K+].[C:38](Cl)(=[O:43])[O:39][CH2:40][CH:41]=[CH2:42]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([NH:16][C:38](=[O:43])[O:39][CH2:40][CH:41]=[CH2:42])([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:19]([F:27])[CH:18]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: C=CCOC(=O)Cl
Reactant: N[C@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: C=CCOC(=O)N[C@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(R)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine was dissolved in DCE (400 uL, 0.1 M in DCE, 40 umol) and potassium carbonate added (100 mg, 723 umol, 18 eq), followed by allyl carbonochloridate (400 uL, 0.2 M in DCE, 80 umol, 2.0 eq). The reaction mixture was agitated at room temperature for 18 h and then filtered and rinsed with DCE (2×250 uL). The combined filtrate was evaporated and the residue was redissolved in 1 mL of MeOH and purified by reverse phase preparative HPLC using MeOH:water:TFA system. (R)-allyl 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethylcarbamate was obtained as a colorless oil (13.2 umol, 33% yield). LCMS: M+calc=478.11; found=479.35.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8](CC1C=CC(C(OC)=O)=CC=1)[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])[CH3:3].Br[CH2:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34]>>[CH3:4][C:2]([O:5][C:6]([N:8]([CH2:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:1])[CH3:3]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: COC(=O)c1ccc(CN(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Product: COC(=O)c1cccc(CN(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1

Procedure:
Compound prepared in an analogous manner to Intermediate #54, replacing Methyl 4-(Bromomethyl)Benzoate with Methyl 3-(Bromomethyl)Benzoate
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:23]O.[CH2:25]([SH:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:23][S:33][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1c(CO)oc2cccc(OCCCNCc3cccnc3)c12
Reactant: SCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(CSCCc2ccccc2)oc2cccc(OCCCNCc3cccnc3)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97 %

Procedure:
To a solution of the compound in Example 11 (20 mg, 0.06 mmol) and phenethyl mercaptan (30 mg) in anhydrous CH2Cl2 (0.9 ml) was added trifluoroacetic acid (TFA, 0.2 ml). The mixture was stirred at room temperature for 2.5 hours. The solvent was removed under reduced pressure. The residue was purified over preparative TLC (CH2Cl2/MeOH=100/1) to give the desired compound (26 mg, 95%) as a colorless oil. FAB-MS: m/z 446 (MH+); 1H-NMR (CDCl3): δ 2.10 (2H, m), 2.32 (3H, s), 2.79-2.97 (6H, m), 3.54 (2H, s), 3.85 (2H, s), 3.90 (2H, s), 6.63 (1H, d, J=7.6 Hz), 7.09-7.30 (3H, m), 7.71 (1H, d, J=7.8 Hz), 8.55 (1H, d, J=2.0 Hz), 8.62 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[O:5][CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C@H:13]([CH3:49])[CH2:14][O:15][C:16]2[CH:48]=[CH:47][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:22]3=[O:46])=[CH:18][CH:17]=2)[CH2:8]1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[O:5][CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C@H:13]([CH3:49])[CH2:14][O:15][C:16]2[CH:48]=[CH:47][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:46])=[CH:18][CH:17]=2)[CH2:8]1
Reactant: C[C@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](COc1ccc(CC2SC(=O)NC2=O)cc1)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Yield: 80.9 %

Procedure:
A procedure similar to that described in Example 1 was repeated, except that 0.96 g of 5-[4-{2(R)-[5(S)-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]propoxy}benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 29), 4 ml of methylene chloride and 4 ml of trifluoroacetic acid were used, to give 0.52 g of the title compound having a melting point of 48° C. to 53° C. (softening) and having [α]D =+54.0° (methanol, c=1.000).
Reaction SMILES: [CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[CH2:22]([NH:29][C:30](=[O:33])[NH:31][NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)C.C(=O)(O)[O-].[Na+]>O>[CH2:22]([NH:29][C:30](=[O:33])[NH:31]/[N:32]=[C:10]1/[C:8](=[O:9])[N:7]([CH2:6][CH2:5][N:4]([CH:18]([CH3:20])[CH3:19])[CH:1]([CH3:3])[CH3:2])[C:17]2[C:12]/1=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NNC(=O)NCc1ccccc1
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)N(CCN1C(=O)/C(=N/NC(=O)NCc2ccccc2)c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 11 h
Yield: 69.8 %

Procedure:
A suspension of 137 mg of 1-(2-diisopropylaminoethyl)isatin and 120 mg of 4-benzylsemicarbazide hydrochloride in 2 ml of a mixture of ethanol and water (2:1) was stirred for 11 hours at room temperature, and an aqueous sodium bicarbonate solution was added to the reaction mixture. The precipitates were collected by filtration, washed with water and recrystallized from aqueous ethanol to obtain 147 mg of (E)-1-(2-diisopropylaminoethyl)isatin 3-(4-benzylsemicarbazone). Chemical properties of the product were identical with those of the product obtained by Example 5.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:39](=[O:73])/[C:40](/[C:48]2[N:49]=[C:50]([NH:53][C:54]([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)[C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[S:51][CH:52]=2)=[N:41]\[O:42]C(OC)(C)C)[C:19]3=[O:74])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(OCC)(=O)C>CC(C)=O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:39](=[O:73])/[C:40](/[C:48]2[N:49]=[C:50]([NH:53][C:54]([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)([C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=4)[C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)[S:51][CH:52]=2)=[N:41]\[OH:42])[C:19]3=[O:74])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nn4c(=O)cc(C)nc4s3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cc1cc(=O)n2nc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)[C@@H](NC(=O)/C(=N\O)c5csc(NC(c6ccccc6)(c6ccccc6)c6ccccc6)n5)[C@H]4SC3)sc2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 75.8 %

Procedure:
To a solution of the product obtained in Step 3 (1.5 g) in acetone (12 ml) was added 1N hydrochloric acid (2.6 ml), and the resulting solution was stirred at room temperature for 3.5 hours. Ethyl acetate was added to the solution, and the organic layer was washed with water, 5% sodium bicarbonate solution and brine in that order, and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, giving 1.06 g of the objective compound as milky white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.C([Li])CCC.O1CCCC1.[C:19](=[O:21])=[O:20]>O1CCCC1>[F:1][C:2]1[C:7]([C:19]([OH:21])=[O:20])=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1
Reactant: O=C=O
Reactant: Fc1cccc(F)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)nc1F
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Fifty (50) g of 2,6-difluoropyridine was dissolved in 200 ml of tetrahydrofuran, and into the solution 326 ml of 1.6M n-butyl lithium-tetrahydrofuran solution was added dropwise at -70° C., followed by an hour's stirring at the same temperature. To the reaction mixture 29 g of dry ice blocks were added little by little, followed by 30 minutes' stirring at the same temperature. Raising the temperature to about 5° C., 500 ml of ice water was added. The reaction mixture was washed twice with ethyl acetate, and the aqueous layer was adjusted to pH 3 with conc. hydrochloric acid. The aqueous layer was then extracted with chloroform. The extract was washed with saturated saline water, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The crystalline precipitate was collected by filtration, and recrystallized from diethyl ether-n-hexane to provide 63 g of 2,6-difluoro-3-pyridinecarboxylic acid (m.p. 170-171° C.).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[CH2:5][C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([I:24])[CH:18]=2)=[N:8][N:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[N:11][C:10]=12)[CH3:2].[C:28]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4](=[O:25])[CH2:5][C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:28])=[C:19]([I:24])[CH:18]=2)=[N:8][N:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[N:11][C:10]=12)[CH3:27]
Reactant: CCN(CC)C(=O)Cc1c(-c2ccc(O)c(I)c2)nn2c(C)cc(C)nc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Cc1c(-c2ccc(OC)c(I)c2)nn2c(C)cc(C)nc12
Reaction time: 8 h
Yield: 952.4 %

Procedure:
To a solution of 4 (30 mg, 0.063 mmol) in DMF (5 mL) was added K2CO3 (300 mg, 2.2 mmol) and MeI (100 μL×2M, 0.2 mmol). The reaction was stirred overnight and the solvent was removed under vacuum and the residue was purified by silica gel column chromatography (EtOAc as eluent) to give 1 (29 mg, 0.60 mmol, 95%). 1H NMR (CD3OD, 400 MHz) δ 1.15 (t, J=7.2 Hz, 3H), 1.29 (t, J=7.2 Hz, 3H), 2.57 (s, 3H), 2.77 (s, 3H), 3.43 (q, J=7.2 Hz, 2H), 3.58 (q, J=7.2 Hz, 2H), 3.92 (s, 3H), 3.97 (s, 2H), 6.80 (s, 1H), 7.06 (d, J=8 Hz, 1H), 7.74 (d, J=8 Hz, 1H), 8.09 (s, 1H). ESI MS m/z: [M+H]+ C21H26IN4O2: calculated 493.1, found 493.1.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:12](OCC)=[O:13].[Na]>CCCCCC.C(O)C>[CH:12]([CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:10]#[N:11])=[O:13]
Reactant: N#CCc1ccccc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCCCCC
Product: N#CC(C=O)c1ccccc1

Procedure:
A 20.0 g. amount of sodium hydride (50% in oil) is added portionwise with stirring to a solution of 20.0 g. of phenylacetonitrile and 40.0 ml. of ethyl formate in 200 ml. of sodium dried benzene. The mixture is heated on a steam bath to start the reaction and after the vigorous reaction has subsided, the mixture is heated on the steam bath for 2 hours with stirring. Ethanol is then added dropwise to decompose the excess sodium hydride. The mixture is then swamped with n-hexane and the precipitate is collected and washed with n-hexane. The precipitate is suspended in water then an excess of dilute hydrochloric acid is added and the product is extracted with ether. The ether extracts are dried and evaporated. The residue is crystallized from acetone-n-hexane to give 12.0 g. of the product of the Example m.p. 161°-163° C. Reference: D. J. Brown and T. C. Lee, J. Chem. Soc. (C), 214 (1970).