Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[NH:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[K+].Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CS(C)=O>[CH2:1]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]2)[N:8]([CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: ClCCN1CCCC1
Reactant: CC(C)Cc1c[nH]c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)Cc1cn(CCN2CCCC2)c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 106.9 %

Procedure:
Combine tert-butyl 4-(4-isobutyl-1H-imidazol-2-yl)piperidine-1-carboxylate (1.50 g, 4.88 mmol) and potassium hydroxide (1.65 g, 6.0 eq) (freshly powdered) in dimethyl sulfoxide (30 mL). Heat the reaction mixture to 45° C. under nitrogen. After 5 minutes, add 1-(2-chloroethyl)pyrrolidine hydrochloride (1.08 g, 1.3 eq). Stop heating after 2 hours. Add water and extract with ethyl acetate. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo to give the title compound as a yellow oil (2.11 g, 100%). MS (ES) m/z=405 [M]+.
Reaction SMILES: C([C:5]1[C:6]([OH:20])=[C:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:8]=[C:9]([CH3:11])[CH:10]=1)(C)(C)C.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[OH:20][C:6]1[CH:5]=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19]
Reactant: Cc1cc(Cc2ccccc2O)c(O)c(C(C)(C)C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cc1ccc(O)c(Cc2ccccc2O)c1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
(3-t-Butyl-2-hydroxy-5-methylphenyl)-(2-hydroxyphenyl)methane (4.34 g, 16 mmol) was combined with 3.2 g (24 mmol) of aluminum chloride and 100 ml of benzene and the mixture heated at reflux with stirring for 24 hours. It was then allowed to cool and was poured onto an ice-water mixture. The organic phase was collected and extracted with water and then 1N potassium hydroxide. The alkaline extract was acidified and then extracted with ether. The ether extract was dried with magnesium sulfate and the volatiles removed by evaporation under reduced pressure to obtain 1.66 g (48 percent of theory) of the title compound as an oil. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C@:16]3([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=O)[NH:17]3)[CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C@:16]3([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=[S:38])[NH:17]3)[CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3cc(Cl)cc(Cl)c3)ccc2F)C1(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3cc(Cl)cc(Cl)c3)ccc2F)C1(F)F
Yield: 97.3 %

Procedure:
The reaction of (R)-5-(3′,5′-dichloro-4-fluoro-biphenyl-3-yl)-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (250 mg, 578 μmol) with Lawesson's reagent (187 mg, 463 μmol) in 1,4-dioxane (19 ml) yielded the (R)-5-(3′,5′-dichloro-4-fluoro-biphenyl-3-yl)-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (202 mg, 78% yield) as a white foam. MS (ISN): m/z=446.0 [M−H]− and 447.9 [M+2-H]−.
Reaction SMILES: [C:1]1([CH2:7][SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[C:11]([OH:16])(=[O:15])[C:12]([CH3:14])=[CH2:13]>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1>[CH2:7]([S:8][CH2:13][CH:12]([CH3:14])[C:11]([OH:16])=[O:15])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(C)C(=O)O
Reactant: SCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: CC(CSCc1ccccc1)C(=O)O
Temperature: 82 °C

Procedure:
To a 25 mL three-necked reaction flask, 3.55 mL (0.03 mole) of α-toluenethiol, 0.58 g (1.5×10-3 mole) of benzyl triphenyl phosphonium chloride and 15 mL (0.03 mole) of 2N NaOH solution were added. The resulting solution was heated to 82° C. with agitation for one hour. Thereafter, 2.3 mL (0.027 mole) of methacrylic acid was added dropwise over a 30 minute period to the preheated mixture, and the reaction mixture was heated to 125° C. and maintained under reflux for 18 hours.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)cc(C)c1C#N
Reaction time: 10 h
Yield: 99 %

Procedure:
2-chloro-4,6-dimethyl-nicotinonitrile (2.5 g, 15.01 mmol) was dissolved in anhydrous methanol(70 mL), added with sodium methoxide (4.27 g, 75.03 mmol) at 0° C. and stirred for about 10 hours at nitrogen atmosphere. The above mixture was concentrated under reduced pressure and then neutrailized with a saturated solution of ammonium chloride and then extracted twice with 150 mL of methylenechloride. The resulting organic layer was dried using anhydrous sodium sulfate, filtered and concentrated. A silica gel column chromatography (20% EtOAc/Hexanes) was performed on the resulting residue and 2.41 g (99%) of 2-methoxy-4,6-dimethyl-nicotinonitrile was obtained in white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(#N)N(C)C>[Br:23][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2ccc(C(=O)c3ccccc3)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc(-c2ccc(C(=O)c3ccccc3)cc2)cc1
Yield: 85.4 %

Procedure:
19 g of 4'-ethyl-4-benzoyl-biphenyl, 12.4 g of N-bromosuccinimide and 0.12 g of azaisobutyronitrile in 400 mL of carbon tetrachloride were heated to boiling under reflux for 1.5 hours. After filtering off the precipitated material the solution was evaporated and the residue was recrystallized from cyclohexane. There were obtained 20.7 g (85%) of 4'-(1-bromo-ethyl)-4-benzoylbiphenyl as a colorless solid with a m.p. of 132°-134° C.
Reaction SMILES: [OH:1][CH:2]([C:8]1[C:17]([CH3:18])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH3:18][C:17]1[C:8]([C:2](=[O:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:9]([O:19][S:20]([C:23]([F:24])([F:25])[F:26])(=[O:22])=[O:21])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CCOC(=O)C(O)c1c(C)cc2ccccc2c1OS(=O)(=O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(C)cc2ccccc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
A solution of ethyl 2-hydroxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate (5.5 g, crude) in DCM (160 mL) was treated with Dess-Martin periodinane (7.18 g, 16.9 mmol) at 23° C. After 1 h, the reaction was added slowly over 5 min to 10% Na2S2O3 (100 mL). After 30 min, the reaction was extracted with DCM (3×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was treated with benzene, filtered, and wet-loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product in semipure form (3.9 g). 1H NMR (400 MHz, CDCl3): δ 8.11-8.08 (m, 1H), 7.86-7.83 (m, 1H), 7.76 (s, 1H), 7.66-7.60 (m, 2H), 4.41 (q, J=7.4 Hz, 2H), 2.50 (s, 3H), 1.40 (t, J=7.4 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ−73.3 (s).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].Cl.[C:12]([O:16][C:17](=[O:22])[C:18]([NH2:21])([CH3:20])[CH3:19])([CH3:15])([CH3:14])[CH3:13].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[C:12]([O:16][C:17](=[O:22])[C:18]([CH3:20])([NH:21][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH3:19])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(C)(C)Nc1ccccc1[N+](=O)[O-]
Temperature: 85 °C
Yield: 49.6 %

Procedure:
To a mixture of 1-fluoro-2-nitrobenzene (485 μL, 4.6 mmol) and 2-amino-2-methyl-propionic acid tert-butyl ester hydrochloride (1.0 g, 5.1 mmol) in DMF (5 mL) was added Et3N (1.3 mL, 9.3 mmol). The mixture was heated at 85° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 10% EtOAc in Hexane as the eluent to afford the desired 2-methyl-2-(2-nitro-phenylamino)-propionic acid tert-butyl ester (640 mg, 50%).
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[Cl:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][C:41]=1[C:49]([F:52])([F:51])[F:50]>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:43]2[CH:44]=[CH:45][C:40]([Cl:39])=[C:41]([C:49]([F:52])([F:51])[F:50])[CH:42]=2)[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(Cl)c(C(F)(F)F)c2)c1

Procedure:
5-(tert-Butyl)-4′-chloro-2-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 4-chloro-3-(trifluoromethyl)phenylboronic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([C:10](OCC)=[O:11])=[CH:9][C:2]=12.[BH4-].[Na+]>C1COCC1.CO.[NH4+].[Cl-]>[N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([CH2:10][OH:11])=[CH:9][C:2]=12
Reactant: CCOC(=O)c1cc2nccnc2s1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc2nccnc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a solution of ethyl thieno[3,2-b]pyrazine-6-carboxylate 86 (600 mg, 2.88 mmol) in THF (3 mL) and methanol (3 mL) was added sodium borohydride (1.09 g, 28.8 mmol). The reaction was stirred at rt for 30 min. Poured in NH4Cl solution and extracted with EtOAc. Organic layer was washed with brine, dried and evaporated to give the crude thieno[3,2-b]pyrazin-6-ylmethanol 87 (438 mg, 91%) which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C@@H:7]([NH:10][S@](C(C)(C)C)=O)[CH2:8][CH3:9].[ClH:17].O>CO.O1CCOCC1>[ClH:17].[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C@@H:7]([NH2:10])[CH2:8][CH3:9]
Reactant: CC[C@H](N[S@@](=O)C(C)(C)C)c1ncccn1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC[C@H](N)c1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of (S)-2-methyl-propane-2-sulfinic acid ((S)-1-pyrimidin-2-yl-propyl)-amide (Comp. No. 14a) (1.4 g, 5.8 mmol) in methanol was added 4 M hydrogen chloride in dioxane (4.35 ml) and the mixture was stirred for 1 h at 25° C. Water (100 ml) was added and the aqueous phase was washed with methyl tert-butyl ether. The aqueous layer was freeze-dried to give 0.919 g (75%) of (S)-1-pyrimidin-2-yl-propylamine hydrochloride. LC/MS (method 5): Rt=0.69 min; m/z=138.15 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:24]=2[NH:23][CH:22]=[C:21]3[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:34]I.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:24]=2[N:23]([CH3:34])[CH:22]=[C:21]3[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:26])=[O:27])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c(S(=O)(=O)c4ccccc4)c[nH]c23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(S(=O)(=O)c2ccccc2)c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
Sodium hydride (0.12 g of 60% dispersion in mineral oil, 3 mmol) was added to a solution of 4-(3-benzenesulfonyl-1H-indol-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (1 g, 2.3 mmol) in 20 mL of DMF with ice cooling. After stirring 15 min at room temperature the mixture was treated with methyl iodide (0.17 mL, 3 mmol). Water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried (sodium sulfate) and evaporated. Silica gel chromatography (20% ethyl acetate-hexane) afforded 0.9 g of 4-(3-benzenesulfonyl-1-methyl-1H-indol-7-yl)-piperazine-1-carboxylic acid tert-butyl ester as a foam, mass spec. M+ 455.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]Cl.O>CN(C)C=O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Reactant: CN(C)CCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(=O)c1cnc2c(OCCN(C)C)cccc2c1Nc1ccccc1C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) and potassium t-butoxide (5.0 g, 40 mmol) were stirred in dry dimethylformamide at 80° and 2-dimethylaminoethyl chloride hydrochloride (2.9 g, 20 mmol) added. The mixture was stirred for 2 hours, poured into water and extracted with ether. The extracts were dried and evaporated. Chromatography (silica gel, 3-5% methanolic ammonia in dichloromethane) and recrystallisation from ether gave 3-butyryl-4-(2-methylphenylamino)-8-(2-dimethylaminoethoxy)quinoline (1.0 g, 34%), m.p. 88°-90°.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:13][C:14]1[S:15][CH:16]=[C:17]([CH2:19][C:20]([OH:22])=O)[N:18]=1.[NH2:23][C@@H:24]1[C:31](=[O:32])[N:30]2[C@@H:25]1[S:26][CH2:27][C:28](/[CH:36]=[C:37]1/[C:38](=[O:46])[N:39]([CH2:42][CH:43]3[CH2:45][CH2:44]3)[CH2:40][CH2:41]/1)=[C:29]2[C:33]([OH:35])=[O:34]>CN(C)C=O>[NH2:13][C:14]1[S:15][CH:16]=[C:17]([CH2:19][C:20]([NH:23][C@@H:24]2[C:31](=[O:32])[N:30]3[C@@H:25]2[S:26][CH2:27][C:28](/[CH:36]=[C:37]2/[C:38](=[O:46])[N:39]([CH2:42][CH:43]4[CH2:45][CH2:44]4)[CH2:40][CH2:41]/2)=[C:29]3[C:33]([OH:35])=[O:34])=[O:22])[N:18]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12
Reactant: Nc1nc(CC(=O)O)cs1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Nc1nc(CC(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(/C=C4\CCN(CC5CC5)C4=O)CS[C@H]23)cs1

Procedure:
With 167.0 mg (1.03 mmol) 1,1′-carbonyldiimidazole, 163.0 mg (1.03 mmol) (2-aminothiazole-4-yl)-acetic acid and 300.0 mg (0.86 mmol) (E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 6 ml N,N-dimethylformamide. The resulting solid was purified by reversed phase chromatography (RP-18 LiChroPrep gel, water:acetonitrile=9:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: [C:1]([C:3](=[C:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)SC)[C:4]([O:6]C)=O)#[N:2].Cl.[CH:20]1([CH2:25][C:26]([NH2:28])=[NH:27])[CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:20]1([CH2:25][C:26]2[NH:28][C:4](=[O:6])[C:3]([C:1]#[N:2])=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[N:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N=C(N)CC1CCCC1
Reactant: COC(=O)C(C#N)=C(Nc1cccc(F)c1)SC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(Nc2cccc(F)c2)nc(CC2CCCC2)[nH]c1=O

Procedure:
0.1 g (0.37 mmol) of methyl 2-cyano-3-[(3-fluorophenyl)amino]-3-(methylsulfanyl)-2-propenoate and 0.06 g (0.41 mmol) of 2-cyclopentylethanamidine hydrochloride are dissolved in 1 ml of DMF and heated with 0.11 g (0.82 mmol) of potassium carbonate at 90° C. overnight. After filtration, the solvent is removed in vacuo and the residue is purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 μm; eluent A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B) purified. 70 mg (59% of theory) of the product are obtained as a colorless solid.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[F:25][C:26]1[CH:27]=[C:28]([NH:32][NH2:33])[CH:29]=[CH:30][CH:31]=1>>[F:25][C:26]1[CH:27]=[C:28]([N:32]2[C:2]3[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=3)[C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:33]2)[CH:29]=[CH:30][CH:31]=1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: NNc1cccc(F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1ccc(-c2nn(-c3cccc(F)c3)c3cc(O)ccc23)c(O)c1
Yield: 3.2 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.400 g, 1.60 mmol), sodium acetate (0.267 g, 3.3 mmol) and 3-fluorophenylhydrazine hydrochloride (0.400 g, 2.5 mmol) to give 0.017 g of product as a pink solid.
Reaction SMILES: CC(OC(N1[C@H](CP(C2C=CC=CC=2)C2C=CC=CC=2)C[C@H](P(C2C=CC=CC=2)C2C=CC=CC=2)C1)=O)(C)C.[CH:40](=[C:47]([CH2:51][C:52]([N:54]1[CH2:62][C@H:61]2[C@H:56]([CH2:57][CH2:58][CH2:59][CH2:60]2)[CH2:55]1)=[O:53])[C:48]([OH:50])=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH:44]1[CH:43]=[CH:42][C:41]([CH2:40][C@H:47]([C:48]([OH:50])=[O:49])[CH2:51][C:52]([N:54]2[CH2:55][C@H:56]3[C@H:61]([CH2:60][CH2:59][CH2:58][CH2:57]3)[CH2:62]2)=[O:53])=[CH:46][CH:45]=1
Reactant: O=C(O)C(=Cc1ccccc1)CC(=O)N1C[C@H]2CCCC[C@H]2C1
Agent: CC(C)(C)OC(=O)N1C[C@@H](P(c2ccccc2)c2ccccc2)C[C@H]1CP(c1ccccc1)c1ccccc1
Product: O=C(O)[C@H](CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1

Procedure:
The preparation was carried out in the same manner as in Example 1, except that 2.92 mg of BPPM was used instead of 3.02 mg of PCPPM of Example 1. After the reaction, the residual ratio of 2-benzylidene-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid was 10.85%, and the optical purity of mitiglinide thus obtained was 96.1% e.e.
Reaction SMILES: [Si]([O:18][C:19]1[CH:60]=[CH:59][C:22]([O:23][CH2:24][C@@H:25]([OH:58])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[C:40]4=[N:41][CH:42]=[CH:43][CH:44]=[C:39]4[N:38]=[C:37]3[C:45]3[CH:50]=[CH:49][C:48]([N:51]4[CH:55]=[CH:54][C:53]([CH3:56])=[N:52]4)=[CH:47][C:46]=3[Cl:57])=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[Cl:57][C:46]1[CH:47]=[C:48]([N:51]2[CH:55]=[CH:54][C:53]([CH3:56])=[N:52]2)[CH:49]=[CH:50][C:45]=1[C:37]1[N:36]([C:33]2[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][CH2:26][CH:25]([OH:58])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:60][CH:59]=3)=[CH:31][CH:32]=2)[C:40]2=[N:41][CH:42]=[CH:43][CH:44]=[C:39]2[N:38]=1
Reactant: Cc1ccn(-c2ccc(-c3nc4cccnc4n3-c3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)c(Cl)c2)n1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccn(-c2ccc(-c3nc4cccnc4n3-c3ccc(CCNCC(O)COc4ccc(O)cc4)cc3)c(Cl)c2)n1
Yield: 62 %

Procedure:
(2S)-1-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-3-[(4-{2-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)phenyl]-3H-imidazo[4,5-b]pyridin-3-yl}phenethyl)amino]-2-propanol (0.18 g, 0.216 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.08 g, 0.134 mmol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:13][C:14]([F:32])([F:31])[C:15]1[N:20]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.N>ClCCl>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:30][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:14]([F:32])([F:13])[F:31])[N:20]=2)=[CH:27][CH:26]=1
Reactant: Fc1cccc2c(Cl)ccnc12
Reactant: NCCc1ccc(Oc2cccc(C(F)(F)F)n2)cc1
Agent: N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1cccc2c(NCCc3ccc(Oc4cccc(C(F)(F)F)n4)cc3)ccnc12
Yield: 58.5 %

Procedure:
A mixture of 4-chloro-8-fluoroquinoline (1.81 g, 0.01 mol), and 2-(4-(6-trifluoromethyl-2-pyridinyloxy)-phenyl)ethylamine (2.82 g, 0.01 mol), triethylamine (1.1 g, 0.011 mol) was heated at 180°-190° C. for two hours and allowed to cool to a glass. Dichloromethane (50 mL) and concentrated ammonia solution (50 mL) were added, and the mixture was stirred until the glass dissolved. The organic phase was washed with 0.5M sodium hydroxide solution and water, and was dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure and recrystallization from ethyl acetate:hexane gave 2.5 g of product. MP 157° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1ccc(Nc2cc(Cl)ncn2)cc1
Yield: 76 %

Procedure:
A mixture of 4,6-dichloropyrimidine (3.0 g), 4-aminophenol (2.2 g) and triethylamine (6 ml) in ethanol.(50 ml) was refluxed for 2 hours. The product so obtained was recrystallised from a mixture of ethyl acetate and hexane to give 6-chloro-4-(4'-hydroxyanilino)pyrimidine in 76% yield, m.p. 241-244° C.;