Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CON(C)[C:8](=[O:18])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[O:18]=[C:8]([CH2:1][CH3:2])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16]
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=O)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
Ethyl magnesium bromide (1M solution in tetrahydrofuran, 13.7 ml, 13.7 mmol)) was added to a stirred solution of tert-butyl 2-[methoxy(methyl)amino]-2-oxoethylcarbamate (Synth. Commun. 1988, 18, 2273) (1 g, 4.58 mmol) in tetrahydrofuran (25 ml) at 0° C. then stirred at 0° C. for 15 minutes. The solution was allowed to warm to room temperature and was stirred for 45 minutes. Ethyl acetate (5 ml) was added, followed by saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution and brine. The organic phase was then dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a solvent gradient of hexane:ethyl acetate (85:15 to 70:30), to afford the title compound as a colorless oil, 730 mg, 84% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH2:13][CH2:12]1>C(OCC)C.C1(C)C=CC=CC=1>[CH3:10][N:11]1[CH2:12][CH2:13][CH:14]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:16]1
Reactant: COC(=O)C1=CCCN(C)C1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)C1CN(C)CCC1c1ccc(F)cc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A 2 molar solution of 4-fluorophenylmagnesium bromide in diethyl ether (5 ml, 2 molar equivalents) was stirred at −5 to −10° C. under nitrogen, and a solution of arecoline (0.78 g) in toluene (5.0 ml) added over 15 minutes at −5° C. The clear solution was stirred at −5° C. for 1 hour, then quenched by the addition of a mixture of water (25 ml) and concentrated hydrochloric acid (3 ml). Analysis of the aqueous phase by HPLC showed that yield of cis/trans 1-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine was about 905 mg (72 %).
Reaction SMILES: [CH3:1][C:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4]([CH3:10])([CH3:9])[CH:3]2[NH2:11].[Cl:12][CH2:13][C:14](Cl)=[O:15]>C(Cl)Cl.C(N(CC)CC)C>[Cl:12][CH2:13][C:14]([NH:11][CH:3]1[C:4]([CH3:10])([CH3:9])[CH:5]2[CH2:8][C:2]1([CH3:1])[CH2:7][CH2:6]2)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: CC12CCC(C1)C(C)(C)C2N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC12CCC(C1)C(C)(C)C2NC(=O)CCl
Reaction time: 12 h

Procedure:
To a solution of 1,3,3-trimethylbicyclo[2.2.1]hept-2-ylamine (5 g, 26.3 mmol) in methylene chloride (20 ml) and triethylamine (4 ml) was added chloroacetyl chloride (2.1 ml, 26.4 mmol) dropwise. The resulting solution was stirred for 12 hours, then the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic layer washed with brine, and dried over magnesium sulfate. The ethyl acetate solution was absorbed onto silica gel, which was eluted with 10% ethyl acetate/hexane, to yield 2-chloro-N-(1,3,3-trimethylbicyclo[2,2,1]hept-2-yl)acetamide as a white solid.
Reaction SMILES: [CH3:1][Si:2]([C:5]1([Sn](C)(C)C)[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:4])[CH3:3].Cl[B:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][Si:2]([C:5]1([B:15]([C:5]2([Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:9]=[CH:8][CH:7]=[CH:6]2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)C1([Sn](C)(C)C)C=CC=C1
Reactant: ClB(Cl)c1ccccc1
Product: C[Si](C)(C)C1(B(c2ccccc2)C2([Si](C)(C)C)C=CC=C2)C=CC=C1
Temperature: 40 °C

Procedure:
To 2.230 g (7.41 mmol) of (trimethylsilylcyclopentadienyl)-trimethyltin is added 0.59 g (0.48 ml, 3.7 mmol) of dichloro-(phenyl)borane dropwise at room temperature. An intense yellow color immediately appears. The mixture is heated at 40° C. for 2 h whereupon the yellow color intensifies. This is followed by fractional distillation wherein the chlorotrimethylstannane formed can first be separated off. In the distillation, a heavy decomposition occurs from about 120° C. bath temperature to give a dark-red oil.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C[O:19]CC1>CC#N>[C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:19]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C1CCOC1
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
O,O-Dibenzoyl tartaric acid monohydrate (18.8 g, 50 mmole) was dissolved in 250 ml CH3CN and the solvent was removed in vacuo. This process was repeated. The resulting oil was dissolved in 250 ml THF and dicyclohexylcarbodiimide (DCC) (10.6 g, 50 mmole) dissolved in 50 ml THF was added. A precipitate started forming in a few minutes. After stirring for 18 hr at 20° C. the reaction mixture was filtered, and the precipitate washed with a little THF. The precipitate was then dried in high vacuum to give 10.8 g (100%, 50 mmole) dicyclohexylurea (DCHU). To the combined filtrate was added 2-(N-methyl)aminoethanol (4.0 ml, 50 mmole) and the reaction mixture was stirred for 1 hr at 20° C. Then, DCC (10.6 g, 50 mmole) in 50 ml THF was added; a small precipitate was formed. After about 1 hr, 2-(N-methyl)aminoethanol (4.0 ml, 50 mmole) was added and the reaction mixture stirred for 18 hours at 20° C.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:18]=[CH:17][C:11]2[NH:12][C@@H:13]([CH3:16])[CH2:14][O:15][C:10]=2[C:9]=1[F:19].C(O[CH:23]=[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])C>CN(C=O)C>[F:7][C:8]1[CH:18]=[CH:17][C:11]2[N:12]([CH:23]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C@@H:13]([CH3:16])[CH2:14][O:15][C:10]=2[C:9]=1[F:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: C[C@H]1COc2c(ccc(F)c2F)N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN1c2ccc(F)c(F)c2OC[C@@H]1C)C(=O)OCC
Yield: 79.7 %

Procedure:
To DMF (2.5 ml) was added potassium tertiary-butoxide (75 mg) under ice-cooling. After dropping a solution of the compound (100 mg) obtained in Example 78 and diethyl ethoxymethylenemalonate (233 mg) in DMF (0.5 ml), the resultant mixture was stirred for 2 hours. After treating in a conventional manner, the obtained residue was subjected to silica gel column chromatography to thereby give 153 mg (88%) of the title compound as an oily product. The physical constants of the obtained compounds was identical with those described in Japanese Patent No. 2,769,174.
Reaction SMILES: [O:1]([CH2:8][C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCO[AlH2-]OCCOC.[Na+].C[Si]([C:27]#[N:28])(C)C>C1(C)C=CC=CC=1>[NH2:10][CH:9]([CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:27]#[N:28]
Reactant: C[Si](C)(C)C#N
Reactant: N#CCOc1ccccc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC(N)COc1ccccc1
Temperature: 0 °C
Yield: 20 %

Procedure:
10 millimoles (1.33 g) of phenoxyacetonitrile are dissolved in 10 ml of anhydrous toluene at 0° C., under an argon atmosphere. A solution of vitride (NaH2Al[O-CH2 -CH2OCH3 ]2) at 70% in toluene (1,4 ml viz 0.5 eq) in 3 ml of anhydrous toluene is added, dropwise, at this temperature. The stirring is maintained for 1 hour at 0° C., then 2 ml (1.5 eq) of trimethylsilyl cyanide are added. The reaction mixture is maintained at room temperature for 3 hours, while stirring, then hydrolyzed by usual way. After purification by acid base extraction, there are obtained 0.300 g of -2-amino-3-phenoxy propionitrile with a yield of 20%.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH2:6]([CH:8]1[CH:12]([C:13]2[N:17]3[C:18]4[CH:24]=[CH:23][N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:19]=4[N:20]=[CH:21][C:16]3=[N:15][N:14]=2)[CH2:11][C:10](=[O:33])[CH2:9]1)[CH3:7]>C(Cl)Cl>[CH3:4][S:1]([O:33][CH:10]1[CH2:11][CH:12]([C:13]2[N:17]3[C:18]4[CH:24]=[CH:23][N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:19]=4[N:20]=[CH:21][C:16]3=[N:15][N:14]=2)[CH:8]([CH2:6][CH3:7])[CH2:9]1)(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1CC(=O)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Solvent: ClCCl
Product: CCC1CC(OS(C)(=O)=O)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
Mesyl chloride (0.067 mL, 0.866 mmol) was added dropwise to a solution of 3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone (0.316 g, 0.787 mmol, Example #35 Step H) and TEA (0.219 mL, 1.57 mmol) in DCM (8 mL), and the reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography (0 to 60% EtOAc in DCM) to yield 3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl methanesulfonate (0.29 g, 77%) as a white amorphous solid: LC/MS (Table 1, Method a) Rt=2.53 min; MS m/z 480 (M+H)+.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[N:16]1([C:2]2[CH:15]=[CH:14][C:5]([C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccccc1)c1ccc(N2CCNCC2)cc1
Temperature: 100 °C
Yield: 99.5 %

Procedure:
To a 500 mL one-neck flask was added 4-fluorobenzophenone (35 g), piperazine (13 g), potassium carbonate (22 g) and dimethyl sulfoxide (100 mL). The reaction mixture was heated to 100° C. for 20 hours. The mixture was cooled to room temperature and poured into water (400 mL). The mixture was extracted with chloroform (200 mL) and the recovered bottom layer was dried over sodium sulfate. The solvent was removed and the product was dried in vacuum oven at 60° C. for 6 hours to afford 40 g of waxy 4-piperazinobenzophenone. The product was used as is in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:15]([OH:17])=O.[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15]([N:32]2[CH2:33][CH2:34][N:29]([CH2:28][C:25]3[CH:24]=[CH:23][N:22]=[CH:27][CH:26]=3)[CH2:30][CH2:31]2)=[O:17])[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: Cc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Reactant: c1cc(CN2CCNCC2)ccn1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCN(Cc3ccncc3)CC2)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.094 g (0.29 mmol) of 3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methyl-benzoic acid was dissolved in 2 ml of DMF and treated with 0.146 ml (1.16 mmol) of N-NEM and 51 mg (0.29 mmol) of 1-Pyridin-4-ylmethyl-piperazine and 0.098 g (0.3 mmol) of TOTU. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in DCM and the solution was washed three times with saturated aqueous sodium bicarbonate. The organic phase was dried with sodium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with DCM, and DCM/MeOH (20/1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[N:13]1([CH2:18][CH2:19][NH2:20])[CH2:17][CH2:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([NH:20][CH2:19][CH2:18][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[NH2:8]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: NCCN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(NCCN2CCCC2)ccc1N
Temperature: 80 °C
Yield: 1.5 %

Procedure:
To a stirred solution of 4-fluoro-2-methoxy-1-nitro-benzene (Fluorochem; 2.57 g; 15 mmol) in DMA was 2-pyrrolidin-1-ylethanamine (Aldrich; 1.88 g, 16.5 mmol) followed by DIPEA (2.97 mL, 18 mmol). The mixture was heated at 80° C. for 20 hours, then cooled to room temp. The mixture was concentrated in vacuo, dissolved in DCM and purified by SCX (50 g SCX 2 column). The product was eluted from the column with 7N ammonia in methanol, concentrated in vacuo to give the title compound (53 mg) which was dissolved in Methanol as a 0.05 mmol solution and reduced using an H-cube hydrogenator. 10% Pd/C catalyst, 1 bar hydrogen (full hydrogen setting), 3 mL/min flow-rate at 50° C. The resultant solution was concentrated in vacuo, and the resultant material purified by column chromatography, eluting with 0-10% ammonia/methanol in DCM, to give the title compound as a solid.
Reaction SMILES: [CH2:1]([N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:8](=O)[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[C:18]([NH:26][NH2:27])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)/[C:8](=[N:27]/[NH:26][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(=O)c2ccc(OC)cc21
Reactant: NNC(=O)c1ccccc1
Product: CCCCN1C(=O)/C(=N\NC(=O)c2ccccc2)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-butyl-6-methoxy-isatin and benzhydrazide according to the synthetic method E. NMR (CDCl3): δ 0.98 (t, 3H), 1.38 to 1.45 (m, 4H), 1.67-1.73 (m, 2H), 3.73 (t, 2H), 3.87 (s, 3H), 6.44 (d, 1H), 6.64 (dd, 1H), 7.51 (t, 2H), 7.59 (t, 1H), 7.80 (d, 1H), 8.00 (d, 1H), 13.97 (br s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.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>[Cl:8][C:7]1[C:2]([C:14]2[CH:15]=[CH:16][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: O=Cc1ccc(B(O)O)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: CCO
Solvent: O
Product: O=Cc1ccc(-c2ncccc2Cl)cc1
Yield: 83 %

Procedure:
{circle around (2)} 100 g (0.676 mol) of 2,3-dichloropyridine was dissolved in 500 mL of ethanol, and 101.4 g (0.676 mol) of (4-formylphenyl)boronic acid and 78 g (0.0676 mol) of Pd(PPh3)4 were sequentially added. A solution of 86 g (0.811 mol) of sodium carbonate in 500 mL of distilled water was placed in the reactor, and the mixture was heated to reflux for 4˜6 hours so as to allow it to react. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove ethanol, and extracted with ethyl acetate. The extract was treated with magnesium sulfate, filtered and concentrated under reduced pressure, yielding 4-(3-chloropyridin-2-yl)benzaldehyde as represented below in a 83% yield.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].Cl.[CH3:16][C@@H:17]([NH2:22])[C:18]([F:21])([F:20])[F:19].C(O)(=O)C>CO>[CH3:16][C@@H:17]([NH:22][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=1)[C:18]([F:21])([F:20])[F:19]
Reactant: C[C@@H](N)C(F)(F)F
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](NCc1ccc(C#N)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
Add sodium cyanoborohydride (3.36 g, 53.5 mmol) to a solution of 4-cyanobenzaldehyde (1.75 g, 13.35 mmol) and (R)-1-methyl-2,2,2-trifluoro-ethylamine hydrochloride (2 g, 13.37 mmol) in methanol (17 mL) containing acetic acid (1.53 mL, 26.75 mmol). Stir the mixture at room temperature overnight. Partition the mixture between 1N aqueous NaOH/DCM (1:1, 500 mL) and extract the aqueous layer twice with DCM. Dry the combined organic extracts over MgSO4, concentrate in vacuo and purify by chromatography on silica gel (120 g) eluting with hexane/EtOAc (19:1, 9:1, 85:15 and 4:1) to obtain the desired intermediate (0.83 g, 27%). MS (ES+) m/z: 229 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[S:14][N:13]=[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:11]=2)[C:6]([CH3:24])=[CH:5][C:3]=1[NH2:4].CO.O([CH:29](OC)[N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[S:14][N:13]=[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:11]=2)[C:6]([CH3:24])=[CH:5][C:3]=1/[N:4]=[CH:29]\[N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: Cc1cc(N)c(Cl)cc1Oc1nc(CCc2ccc(Cl)cc2)ns1
Reactant: COC(OC)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(/N=C\N2CCCCC2)c(Cl)cc1Oc1nc(CCc2ccc(Cl)cc2)ns1
Yield: 34.6 %

Procedure:
0.30 g (0.79 mmol) of 2-chloro-4-({3-[2-(4-chlorophenyl)ethyl]-1,2,4-thiadiazol-5-yl}oxy)-5-methylaniline is dissolved in 3 ml of toluene and 0.75 ml of methanol and treated with 0.37 g (2.37 mmol) of 1-(dimethoxylmethyl)piperidine. The reaction mixture is refluxed for 18 h, subsequently cooled, freed from the solvent under vacuum and purified by column chromatography. 0.13 g of product is obtained (84.2% purity, 29.3% yield, log P (pH 2.3)=2.64).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].N12CCCN=C1C[CH2:17][CH2:16][CH2:15][CH2:14]2.BrC(CC)C>CN(C=O)C>[CH:15]([O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7])([CH2:16][CH3:17])[CH3:14]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCC(C)Br
Solvent: CN(C)C=O
Product: CCC(C)ON1C(=O)c2ccccc2C1=O
Temperature: 55 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
N-hydroxylphthalimide (18.4 mmol, 3.0 g) was dissolved in anhydrous DMF (20 mL) under nitrogen. To the stirring solution, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (27.6 mmol, 4.13 mL) was injected followed by 2-bromobutane (22.1 mmol, 2.41 mL) and the reaction was warmed to 55° C. After stirring for 18 hour, the reaction was cooled to room temperature and concentrated to a red oil. The reaction was partitioned between ethyl acetate and 1N HCl. The organic layer was washed with saturated aqueous sodium bicarbonate solution, distilled water, brine and dried over magnesium sulfate. The solvent was removed under vacuum providing 3.57 g (89%) of a yellow solid. Rf: 0.8 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ7.80 (2H,m), 7.73 (2H,m), 4.31 (1H,m), 1.81 (1H,m), 1.64 (1H,m), 1.32 (3H,d), 1.03 (3H,t).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5](O)=[O:6].C(N1C=CN=C1)([N:22]1C=CN=C1)=O.C([O-])(=O)C.[NH4+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([NH2:22])=[O:6]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 59.1 %

Procedure:
To a solution of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (145.0 mg, 0.33 mmol) in N,N-dimethylformamide (1.50 ml), 1,1′-carbonylbis(1H-imidazole) (60 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature for 7 hours to obtain a homogeneous solution. Ammonium acetate (65 mg, 0.83 mmol) was added, and stirred for 2 h. Water (10 ml) was added, and the precipitated solid was filtered, washed with hot methanol to obtain 2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-isonicotinamide as an yellow solid (85 mg, 58%) LC/MS: [9.59 min; 436, 438]
Reaction SMILES: CN(N=O)C(N[C@H:6]1[CH:11]([OH:12])[O:10][C@H:9]([CH2:13][OH:14])[C@@H:8]([OH:15])[C@@H:7]1[OH:16])=O.CC[O:21]CC>O>[OH:14][CH2:13][C@@H:9]([C@H:8]([C@@H:7]([C@@H:6]([CH2:11][OH:12])[OH:21])[OH:16])[OH:15])[OH:10]
Reactant: CCOCC
Reactant: CN(N=O)C(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 18 h

Procedure:
Spraque-Dawley rats (male, 5-7-week-old, 5 animals per group) were fasted for 18 hours, and received injection of 70 mg/kg of streptozocin (Cal Biochem Co.) into the caudal vein under anesthesia with ether, so that diabetic rats were obtained. From immediately after the injection of streptozocin these rats were given orally the test compound of 50 mg/kg or 30 mg/kg in the form of 5% gum arabic suspension twice a day (at 10 a.m. and 5 p.m.) for 2 days. During this period the rats were allowed to take CE-2 diet (Clea Japan, Inc.) and water ad libitum. In the morning on the 3rd day (9 a.m.) the rats were killed (decapitation and venesection), and immediately the sciatic nerves were isolated, from which sorbitol was extracted according to the method of M. J. Peterson et al. described in Metabolism, 28, 456 (1979) and the sorbitol level was determined by the enzymatic method of P.S. Clements et al. in Science, 166, 1007 (1969). The results are expressed in percentage (%) taking the value of the untreated control group as 100, and shown in table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH3:33])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH:26]5[CH2:29][NH:30][CH2:31][CH:25]45)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].CCN(CC)CC.[C:41](Cl)(=[O:43])[CH3:42]>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH3:33])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH:26]5[CH2:29][N:30]([C:41](=[O:43])[CH3:42])[CH2:31][CH:25]45)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2CNCC21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2CN(C(C)=O)CC21
Reaction time: 2 h
Yield: 36.7 %

Procedure:
To a mixture of N-(3-chloro-4-fluorophenyl)-6-(3-(hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)propoxy)-7-methoxyquinazolin-4-amine (0.10 g) and Et3N (0.072 g) at 0° C. was added acetyl chloride (0.019 g) dropwise and the reaction was continued to stir for 2 h at same temperature. Then the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent of the filtrate was removed by reduce vacuum pressure, and the residue was recrystallized from DCM/PE to give the title compound (0.04 g, 40.00%), HPLC: 96.24%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 514.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.50-1.53 (m, 2H), 1.83-1.87 (m, 2H), 2.25-2.29 (m, 3H), 2.30 (s, 3H), 2.44 (t, J=4.2 Hz, 2H), 2.90-2.93 (m, 1H), 3.50-3.61 (m, 4H), 4.03 (s, 3H), 4.08 (t, J=4.8 Hz, 2H), 7.16 (s, 1H), 7.26 (s, 1H), 7.45 (s, 1H), 7.57-7.60 (m, 1H), 7.91-7.95 (m, 1H), 8.64 (s, 1H) ppm.