Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14](O)[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)(O)[C:28]#[N:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:28]#[N:29])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(O)C#N
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(C(F)(F)F)cc2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(C#N)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.2 %

Procedure:
To a solution of 4-[hydroxy-(4-trifluoromethyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (990 mg, 2.75 mmol), acetone cyanohydrin (913 mg, 10.73 mmol) and Ph3P (2.5 g, 9.63 mmol) in THF (25 mL) was added DIAD (2.2 g, 10.94 mmol) in THF (10 mL) over 5 hours at 0° C. and the resulting mixture was stirred for another 72 hours at room temperature. Standard work-up and purification afforded 4-[cyano-(4-trifluoromethyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (539 mg, 53%) as a white foam.
Reaction SMILES: [C:1]([O:9][CH:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28]C(N)=S>CN(C)C=O>[C:2]1([C:1]2[O:9][C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[N:28]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: CN(C)c1ccc(C(=O)C(OC(=O)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2nc(-c3ccccc3)oc2-c2ccccc2)cc1
Temperature: 160 °C

Procedure:
0.5 g of 2-[4-(dimethylamino)phenyl]-2-oxo-1-phenylethyl benzoate is dissolved in 10 ml of dimethylformamide in a reactor. 0.212 g of thiourea (2 eq.) is subsequently added and the reaction mixture is left to react at reflux (160° C.) for 6 hours.
Reaction SMILES: [CH3:1]N(C)CCN(C)C.BrCBr.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([CH2:25][O:26][C:27](=O)[C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>[Ti](Cl)(Cl)(Cl)Cl.[Zn].O1CCCC1>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][C:22]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)([CH2:25][O:26][C:27]([C:28]2[CH:29]=[C:30]([C:38]([F:40])([F:41])[F:39])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=2)=[CH2:1])[CH2:23][CH2:24]1)=[O:18])([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Reactant: CN(C)CCN(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCBr
Product: C=C(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Titanium tetrachloride (1.06 g) was added to cooled (0° C.) stirred tetrahydrofuran under a dry nitrogen atmosphere. After the exotherm had subsided the solution was allowed to warm to room temperature and tetramethylethylene diamine (1.69 g) added followed 15 minutes later by freshly activated zinc dust (819 mg). The resulting mixture was stirred for 30 minutes at room temperature at which point dibromomethane (0.21 ml) and the compound of step (b) above (716 mg) were added. The reaction was allowed to proceed for 18 hours at room temperature. After this time the reaction was quenched with saturated K2CO3 (7 ml) and diluted with diethyl ether. The resulting black suspension was filtered through a plug of grade III neutral alumina, eluting with 1 % triethylamine/diethyl ether. The filtrate was dried over MgSO4, filtered and the solvent removed under reduced pressure. The residual oil was purified by chromatography on silica gel (10% ethyl acetate/n-hexane) to afford the title compound. 1H NMR (360 MHz, CDCl3) δ 1.2 (9H, s), 1.95 (2H, m), 2.38 (2H, m), 3.05 (2H, m), 3.8 (2H, s), 3.95 (2H, m), 4.21 (1H, d, J=1.0 Hz), 4.63 (1H, d, J=1.0 Hz), 7.1-7.3 (5H, m), 7.7 (1H, s), 7.76 (2H, s).
Reaction SMILES: ClC1C(Cl)=CC(N[C:13](=O)[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:18][CH:17]=2)=CC=1C(O)=O.[NH2:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[NH2:46])[C:39]([O:41][CH3:42])=[O:40].C(N(CC)CC)C>ClCCl>[C:28]1([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:13]3[NH:35][C:36]4[CH:37]=[C:38]([C:39]([O:41][CH3:42])=[O:40])[CH:43]=[CH:44][C:45]=4[N:46]=3)=[CH:17][CH:18]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: O=C(CCc1ccc(OCCCCCc2ccccc2)cc1)Nc1cc(Cl)c(Cl)c(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(CCc3ccc(OCCCCCc4ccccc4)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the compound prepared in Reference Example 3 which prepared by the same procedure as described in Example 3 using the compound prepared in Reference Example 2 (150 mg) in dichloromethane (5 mL) was added methyl 3,4-diaminobenzoate (160 mg) and triethylamine (0.34 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. To a solution of the obtained residue in toluene (10 mL) was added p-toluenesulfonate (50 mg). The reaction mixture was refluxed overnight. Saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was washed with diisopropyl ether to give the compound of the present invention (99 mg) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:5]([N+:17]([O-])=O)=[CH:4][CH:3]=1>[Ni].CO.ClCCl>[NH2:17][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: N#Cc1cccc(Nc2nc(Cl)ccc2[N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cccc(Nc2nc(Cl)ccc2N)c1

Procedure:
In step 1-2, Raney nickel was added to a suspension of 3-(6-chloro-3-nitropyridin-2-ylamino)benzonitrile in methanol/dichloromethane (1:1) and the resulting suspension was set up in Parr shaker under a hydrogen atmosphere (40 psi) for 18 hours. The remaining catalyst was removed through a Celite pad, and the reaction mixture was concentrated to afford the crude product 3-(3-amino-6-chloropyridin-2-ylamino)benzonitrile (1-2) which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([NH2:15])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[CH2:7]2>CO.[Pd]>[F:25][C:23]([F:24])([F:26])[C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:6]2[CH2:5][CH2:4][C:3]3[C:8](=[C:9]([NH2:15])[C:10]([NH2:12])=[CH:11][CH:2]=3)[CH2:7]2)=[CH:22][CH:21]=1
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CN(Cc1ccc(C(F)(F)F)cc1)CC2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1N)CN(Cc1ccc(C(F)(F)F)cc1)CC2
Reaction time: 2.3 h
Yield: 117.8 %

Procedure:
A solution of the product from Example 15 (0.6 g, 1.4 mmol) in methanol (100 mL) was shaken over 20% Pd/C under hydrogen and pressure for 2.3 hours. The catalyst was filtered off and concentrated under vacuum to give the title compound (0.53 g, 95% yield) as a dark red-brown solid, mp=130-135° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][C:9]=2[CH3:16])=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[N:18][OH:19])=[CH:10][C:9]=2[CH3:16])=[CH:4][CH:3]=1
Reactant: Cc1cc(C=O)ccc1-c1ccc(O)cc1
Reactant: NO
Agent: Cl
Product: Cc1cc(C=NO)ccc1-c1ccc(O)cc1

Procedure:
The title compound was prepared by reacting 4′-hydroxy-2-methyl-1,1′-biphenyl-4-carbaldehyde (350 mg, 1.65 mmol) with hydroxylamine hydrochloride (230 mg, 3.30 mmol) according to Method C to yield 360 mg (96%) of white solid: mp 169-171° C.;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][NH2:19])=[N:15][CH:16]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:19][CH2:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C:10]([F:21])([F:9])[F:20])=[CH:16][N:15]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: NCCc1ccc(C(F)(F)F)cn1
Product: FC(F)(F)c1ccc(CCNc2ccc(Br)cc2)nc1

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (4-bromo-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 347.0 [M+H]+) was prepared from 1-bromo-4-iodo-benzene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:37][S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from the coupling of 1a and benzene sulfonamide by the method described in Procedure 1, Method A. Yield (76%); 1H NMR (CDCl3) δ 8.41 (br. s, 1H), 8.08 (d, J=8.4 Hz, 2H), 7.65-7.07 (m, 16H), 6.86 (d, J=8.4 Hz, 2H), 6.23 (d, J=15.7 Hz, 1H), 2.46 (q, J=7.3 Hz, 2H), 0.92 (t, J=7.3 Hz, 3H); ESI m/z: 492 (M−H−, 100%).
Reaction SMILES: N[C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[C:27]([O:32]C)(=[O:31])[C@@H:28]([CH3:30])[OH:29].N(OCCC(C)C)=O.[Li+].[OH-]>O.CO>[O:23]=[C:14]1[N:13]([CH2:24][CH2:25][CH3:26])[C:12]2[N:11]=[C:10]([C:5]34[CH2:6][CH2:7][C:2]([O:29][C@H:28]([CH3:30])[C:27]([OH:32])=[O:31])([CH2:9][CH2:8]3)[CH2:3][CH2:4]4)[NH:18][C:17]=2[C:16](=[O:19])[N:15]1[CH2:20][CH2:21][CH3:22]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(N)(CC3)CC4)nc2n(CCC)c1=O
Reactant: COC(=O)[C@@H](C)O
Agent: CC(C)CCON=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCn1c(=O)c2[nH]c(C34CCC(O[C@H](C)C(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 60 °C
Yield: 20 %

Procedure:
8-(4-Amino-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 20) (0.100 g. 0.279 mmol) was combined with 1.5 ml of (R)-methyl lactate and 0.075 ml of isoamyl nitrite. The mixture was heated to 60° C. for 2 h and cooled to rt. The reaction mixture was conc'd in vacuo and the residue was stirred with 8 ml of a 50% MeOH solution and 0.050 g LiOH overnight. The reaction mixture was conc'd in vacuo, taken up in 8 ml of water, the pH of the solution was adjusted to 10 and the mixture extracted twice with 6-ml portions of CH2Cl2. The water layer was acidified with conc'd HCl and the resultant precipitate collected by suction filtration to give 0.024 g (20% yield). (MH+=433.08)
Reaction SMILES: C([O:3][C:4](=[CH:9][C:10]1[N:14]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:13]=[N:12][CH:11]=1)[C:5]([F:8])([F:7])[F:6])C.S(=O)(=O)(O)O>CCOCC.O>[S:15]([N:14]1[C:10]([CH2:9][C:4]([C:5]([F:8])([F:6])[F:7])=[O:3])=[CH:11][N:12]=[CH:13]1)([C:18]1[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=1)(=[O:16])=[O:17]
Reactant: CCOC(=Cc1cncn1S(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2cncc2CC(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 20 mmole of 5-acetoxymethyl-1-tosylimidazole and 22 mmole of triphenylphosphine in 100 ml of benzene is heated at reflux temperature for 4 days. The solid which separates on cooling is filtered, washed with benzene, dried under reduced pressure then added slowly to a solution of 20 mmole of sodium amide in 100 ml of liquid ammonia (prepared by adding 0.46 g of sodium to liquid ammonia in the presence of a catalytic amount of ferric nitrate). After stirring for 10 minutes the ammonia is evaporated under a stream of nitrogen. To the residue is added 100 ml of anhydrous benzene and the heterogeneous mixture is heated at reflux for 10 minutes. The solid residue is filtered, and to the filtrate containing salt-free 1-tosyl-5-imidazolylmethylidene triphenylphosphorane is added 5.10-2M of ethyl trifluoroacetate. The reaction mixture is heated at reflux temperature under nitrogen for 12 hours. Concentration of the solvent leaves a residue which is distilled under high vacuum to afford 2-ethoxy-1,1,1-trifluoro-3-(1-tosyl-5-imidazolyl)prop-2-ene. A solution of 3 g of 2-ethoxy-1,1,1-trifluoro-3-(1-tosyl-5-imidazolyl)prop-2-ene in 50 ml of ether is treated with a solution of 1 M of sulfuric acid in 50 ml of water. The reaction mixture is stirred for 1/2 hour at 25° C. The ether phase is separated, washed with brine, dried over magnesium sulfate and concentrated to give trifluoromethyl 1-tosylimidazol-5-ylmethyl ketone.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][O:11][C:10]=1[CH:14]=O)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19]>CCCCCC>[C:1]([C:9]1[CH:13]=[CH:12][O:11][C:10]=1/[CH:14]=[CH:17]/[C:18]([OH:20])=[O:19])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1ccoc1C=O
Reactant: O=C(O)CC(=O)O
Solvent: CCCCCC
Product: CCCCCCC#Cc1ccoc1/C=C/C(=O)O
Yield: 87.7 %

Procedure:
Reaction of 3-(1-octynyl)furan-2-carboxaldehyde (1.02 g, 5 mmole from example 14) with malonic acid (1.04 g, 10 mmole) as described in Example 2 gave 1.08 g (88%) of the title compound, mp (Hexane) 81°-81.5° C., νmax (mull) 2600(broad), 1690, 1670(sh), 1620, 1410, 1320, 1270, 970, 890, 770 cm-1 ; δ(CDCl3) 0.91(3H, t, J=6.9 Hz), 1.34(2H, m), 1.46(2H, m), 1.62(2H, m), 2.45(2H, t, J=7.0 Hz), 6.40(1H, d, J=15.9 Hz), 6.46(1H, d, J=1.8 Hz), 7.41(1H, d, J=1.8 Hz), 7.66(1H, d, J=15.9 Hz), 11.60(1H, broad).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[F:16][C:17]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>>[NH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][C:14]=1[C:19]([C:18]1[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:17]=1[F:16])=[O:20]
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1
Product: Nc1ccc(Cl)cc1C(=O)c1cccc(F)c1F
Yield: 14 %

Procedure:
In a manner similar to that described above for compound 1aa, 4-Chloro-N-Boc-aniline and 2,3-difluoro-benzoyl chloride were converted to 1v (14% yield) MS m/z=268 (M+H).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OC1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]([NH:19][C:20]([NH2:22])=[O:21])[CH2:11]C1>O>[C:5]([O:4][CH:1]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]([NH:19][C:20]([NH2:22])=[O:21])[CH2:11][CH2:2]1)(=[O:7])[CH3:6]
Reactant: NC(=O)NC1CCC(O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OC1CCC(NC(N)=O)c2ccccc21
Reaction time: 1 h

Procedure:
To 10 ml of acetic anhydride 2.0 g of 1,2,3,4-tetrahydro-4-hydroxy-1-naphthylurea (cis/trans) is added and the mixture stirred for 1 hour. The mixture is poured into water and the title compound collected by filtration. Evaporation of the mother liquor in vacuo affords additional title compound.
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][S:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12.[BH4-].[Na+]>C(O)C>[OH:22][CH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1)=[O:17]
Reactant: O=C1c2ccccc2C(=O)N1CCCCSc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(NCCCCSc1ccncc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.2 %

Procedure:
To a solution of 6.25 g of (20.0 mmol) of 4-(4-phthalimidobutylthio)pyridine in 300 ml of ethanol, 7.57 g (200 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 14 hours. The solvent was distilled off and saturated saline was added to the residue. The mixture was extracted with chloroform and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10) to give 4.63 g of the desired compound (73.1% yield, colorless crystals), mp. 87°-88° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[O:25]=[C:26](Cl)OC(Cl)(Cl)Cl>O1CCOCC1>[CH2:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:7]=[C:3]3[C:4]([O:6][C:26](=[O:25])[NH:1][C:2]3=[CH:10][CH:9]=2)=[O:5])[CH2:12][CH2:13]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c2ccc(N3CCN(Cc4ccccc4)CC3)cc2c(=O)o1

Procedure:
To the mixture of 15 g of 2-amino-5-(4-benzylpiperazin-1-yl)benzoic acid in 90 mL of dioxane, under stirring and external cold water cooling 12.7 mL of diphosgene is added dropwise. The mixture is heated under reflux conditions for 4 hours. From the cold reaction mixture the solid material is filtered off, washed with 120 mL of ether. The product is stirred for 5 minutes in the mixture of 100 mL of methanol and 10 mL of triethylamine, it is filtered off and washed with 50 mL of methanol. After drying 17 g of the title product is obtained, m.p.: 235° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][F:28]>O>[F:28][CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1
Reactant: FCCCBr
Reactant: Oc1ccc(-c2cn3cc(I)cnc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: FCCCOc1ccc(-c2cn3cc(I)cnc3n2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 59.4 %

Procedure:
339 mg (corresponding to 1.0 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyrimidine that was sufficiently dried to remove moisture was dissolved in 20 mL of N,N-dimethylformamide, and 414 mg (corresponding to 3.0 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 138 μL (corresponding to 1.5 mmol) of 1-bromo-3-fluoropropane, and then stirred at room temperature for 22 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was recrystallized from N,N-dimethylformamide to obtain 236 mg (corresponding to 0.594 mmol) of 2-[4′-(3″-fluoropropoxy)phenyl]-6-iodoimidazo[1,2-a]pyrimidine (FIG. 1-8, Step 3).
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH3:27])[N:21]=1.C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[CH2:26]([C:22]1[N:21]=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:25]=[CH:24][CH:23]=1)[CH3:27]
Reactant: CCc1cccc(N)n1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCc1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)n1
Temperature: 68 °C
Reaction time: 0.25 h
Yield: 32.9 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (6 g) is added, at a temperature between 68° and 75° C., to a solution of 2-amino-6-ethylpyridine (2.45 g) and triethylamine (4.05 g) in dioxane (150 cc) which is heated to a temperature in the vicinity of 68° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and 15 minutes and then stirred at a temperature of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (300 cc). The solution obtained is washed twice with distilled water (300 cc in total), twice with an aqueous 2N sodium hydroxide solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolorizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude product (6.5 g) is thereby obtained, which is dissolved in boiling acetonitrile (75 cc). Decolorizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 16 hours. The crystals formed are separated by filtration, washed twice with acetonitrile cooled to a temperature in the vicinity of 4° C. (10 cc in total) and 3 times with diethyl ether (90 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(6-ethyl-2-pyridyl)- 3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (2.3 g) in the form of cream-coloured crystals, m.p. 150° C., is thereby obtained.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13]([CH:15]1[CH2:19][C:18](=[O:20])[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH2:16]1)=[O:14].I[CH:30]1[CH2:33][CH2:32][CH2:31]1.[NH4+].[Cl-]>C1COCC1>[CH3:11][O:12][C:13]([C:15]1([CH:30]2[CH2:33][CH2:32][CH2:31]2)[CH2:19][C:18](=[O:20])[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH2:16]1)=[O:14]
Reactant: IC1CCC1
Reactant: COC(=O)C1CC(=O)N(c2c(C)cccc2C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C2CCC2)CC(=O)N(c2c(C)cccc2C)C1
Temperature: -50 °C
Reaction time: 0.08 h

Procedure:
LHMDS (1 M solution in THF, 2.4 mL, 2.4 mmol) was added slowly to a cooled (−50° C.) solution of 1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (494 mg, 2 mmol) in THF (5 mL). Stirred at −50° C. for 5 min then warmed to 0° C. and stirred for 5 min. After cooling back to −50° C., iodocyclobutane (736 mg, 4 mmol) was added and the resulting reaction mixture was warmed to room temperature and stirred for 2 h. Saturated aqueous NH4Cl solution (10 mL) was added, extracted with EtOAc (3×25 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried (Na2SO4) and evaporated to give crude product 3-cyclobutyl-1-(2,6-dimethyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester which was taken on directly to the next step. MS: (ES) m/z 302.3 (M+H+).