Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[O:20][CH:4]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[C:3]([OH:29])=[O:2]
Reactant: COC(=O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CCOCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of (2,4-difluoro-phenoxy)-[4-(tetrahydro-pyran-4-sulfonyl)-phenyl]-acetic acid methyl ester (0.35 g, 0.82 mmol) in THF (3 ml), was added lithium hydroxide monohydrate (0.035 g, 2.05 mmol) in 1 ml water and stirred overnight at room temperature. Solvent was removed under reduced pressure, residue obtained was taken into water (5 ml), extracted with diethyl ether (10 ml×2). Aqueous layer was acidified with 1 N HCl solution, and extracted with ethyl acetate (10 ml×3), washed with water and brine (20 ml, each) dried over anhydrous sodium sulfate, filtered and solvent was concentrated to provide (2,4-difluoro-phenoxy)-[4-(tetrahydro-pyran-4-sulfonyl)-phenyl]-acetic acid (0.28 gm).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH:15]([CH3:17])[CH3:16])[CH:13]=O)=[N:7][C:6]=12.[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH:15]([CH3:17])[CH3:16])[CH2:13][NH:22][CH2:21][CH2:20][O:19][CH3:18])=[N:7][C:6]=12
Reactant: COCCN
Reactant: CC(C)[C@@H](C=O)Nc1ccn2ncc(Br)c2n1
Product: COCCNC[C@@H](Nc1ccn2ncc(Br)c2n1)C(C)C

Procedure:
(S)—N2-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-N1-(2-methoxyethyl)-3-methylbutane-1,2-diamine was prepared by the procedure described in Example 15, Step 4, from (S)-2-(3-bromopyrazolo[1,5-a]pyrimidin-5-ylamino)-3-methylbutanal and 2-methoxyethanamine. LCMS (APCI+) m/z 356, 358 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:34][C:35](=[O:46])[CH2:36][C:37]1[CH:38]=[N:39][C:40]([O:44][CH3:45])=[C:41](Br)[CH:42]=1)C>>[C:9]([N:8]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[CH:15][C:14]=1[C:41]1[CH:42]=[C:37]([CH2:36][C:35]([OH:46])=[O:34])[CH:38]=[N:39][C:40]=1[O:44][CH3:45])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:11])[CH3:10]
Reactant: CCOC(=O)Cc1cnc(OC)c(Br)c1
Reactant: CC(=O)N(Cc1ccccc1)Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Product: COc1ncc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1ccccc1)C(C)=O

Procedure:
Prepared according to the procedure described in Example 17, Step 4 and Step 5, using the following starting materials: N-benzyl-N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-acetamide and (5-bromo-6-methoxy-pyridin-3-yl)-acetic acid ethyl ester.
Reaction SMILES: [OH:1][CH:2]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][N:4]([CH2:14][CH:15]([OH:24])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[OH-].[K+]>C(O)CC>[CH2:33]([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][N:4]([CH2:14][CH:15]([OH:24])[CH2:16][O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:3][CH:2]([OH:1])[CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:12][CH:11]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(CCN(CC(O)COc2ccccc2)CC(O)COc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Product: OC(COc1ccccc1)CN(CCc1ccc(OCc2ccccc2)cc1)CC(O)COc1ccccc1
Temperature: 0 °C

Procedure:
A solution of 1.0 g of p-[2-[bis[(RS)-2-hydroxy-3-phenoxypropyl]amino]ethyl]phenol, 0.27 ml of benzyl bromide and 257 mg of potassium hydroxide in 30 ml of n-propanol was heated to 120° for 18 hours. The reaction mixture was poured on to ice-water and extracted with ethyl acetate. The crude product obtained after evaporation of the solvent was chromatographed on silica gel. The fractions which were uniform according to thin-layer chromatography were recrystallized from acetone-hexane and yielded pure 1,1'-[[p-(benzyloxy)phenethyl]imino]bis-[(RS)-3-phenoxy-2-propanol], m.p. 106°-110°, ε219 =30020.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:20][C:21](C)([O-])[CH3:22].[K+].O>CN(C)C=O>[CH2:22]([S:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH:21]=[CH2:20]
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1S
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCSc1cc(-c2ccc(C(F)(F)F)cc2)ccc1C#N
Yield: 43.5 %

Procedure:
1.0 g (3.6 mmol) of 2-mercapto-4-(4-trifluoromethylphenyl)benzonitrile, 0.45 g (4.0 mmol) of potassium tert-butoxide and 0.5 g (4.1 mmol) of 3-propenyl bromide were stirred in 20 ml of N,N-dimethylformamide at room temperature for 1 hour. The resulting reaction mixture was poured into 20 ml of water and extracted with 50 ml of ethyl acetate twice. The ethyl acetate layer was washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 0.5 g of 2-(2-propenylthio)-4-(4-trifluoromethylphenyl)benzonitrile (yield 43.0%) as yellow crystals (m.p. 89-90° C.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[N:36]=[C:37]([C@@H:40]6[CH2:44][CH2:43][CH2:42][N:41]6[C:45](=[O:55])[C@@H:46]([NH:50][C:51]([O:53][CH3:54])=[O:52])[CH:47]([CH3:49])[CH3:48])[NH:38][CH:39]=5)=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>>[CH3:54][O:53][C:51](=[O:52])[NH:50][C@H:46]([C:45]([N:41]1[CH2:42][CH2:43][CH2:44][C@H:40]1[C:37]1[NH:38][CH:39]=[C:35]([C:32]2[CH:31]=[CH:30][C:29]([C:26]3[CH:27]=[CH:28][C:23]([C:21](=[O:22])[NH:20][C:17]4[CH:16]=[CH:15][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:19][CH:18]=4)=[CH:24][CH:25]=3)=[CH:34][CH:33]=2)[N:36]=1)=[O:55])[CH:47]([CH3:49])[CH3:48]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cc3)cc2)c[nH]1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc(N5CCNCC5)cc4)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [4-{4-[(4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-biphenyl-4-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (42.4 mg, 0.0565 mmol) in dichloromethane (0.67 mL, 10 mmol) was added trifluoroacetic acid (0.3 mL, 0.004 mmol). The reaction mixture was stirred for 1 h at room temperature, concentrated, dissolved in methanol (1 mL), passed through a Stratospheres™ PL-CO3 resin, and the filtrate was concentrated to provide the title compound. (m/z): [M+H]+ calcd for C37H43N7O4 650.34 found 650.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([NH2:40])[CH2:35]1)(=[O:33])=[O:32]>>[NH2:40][CH:36]1[CH2:37][CH2:38][CH2:39][N:34]([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:33])=[O:32])[CH2:35]1
Reactant: NC1CCCN(S(=O)(=O)c2ccccc2Br)C1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCCC(N)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and racemic-1-((2-bromophenyl)sulfonyl)piperidin-3-amine. MS (ESI): mass calcd. for C26H30FN5O4S, 427.15; m/z found, 428.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 8.33 (s, 1H), 8.11-8.07 (m, 1H), 8.03 (m, 1H), 7.76-7.70 (m, 1H), 7.67-7.62 (m, 1H), 7.46-7.42 (m, 1H), 7.36-7.29 (m, 2H), 3.40-3.41 (m, 1H), 3.13-3.02 (m, 2H), 2.66-2.60 (m, 2H), 2.01-1.92 (m, 1H), 1.78-1.67 (m, 1H), 1.55-1.42 (m, 2H).
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[K+].[CH3:10][N:11]=[C:12]=[O:13]>O1CCCC1.C(Cl)(Cl)Cl>[CH3:10][NH:11][C:12]([N:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[NH2:7])=[O:13]
Reactant: CN=C=O
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CNC(=O)N(N)C(C)(C)C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 6.23 g t-butylhydrazine hydrochloride (0.050 moles) in 50 mL tetrahydrofuran was degassed, then stirred under nitrogen as, first, one equivalent of powdered potassium hydroxide and then, dropwise, 2.85 g methyl isocyanate in 25 mL tetrahydrofuran were added. The solution was stirred overnight. The mixture was filtered to remove the residual solid impurity which was washed several times with tetrahydrofuran. The combined filtrates were evaporated to yield a white product which was taken up in chloroform and dried. Removal of the solvent yielded 5.80 g (79.9%) white crystalline N-methyl-1-t-butylhydrazinecarboxamide (m.p. 127°-9° C.). This structure was confirmed by NMR analysis.
Reaction SMILES: [CH2:1]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:17]([O:21][C:22]([N:24]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:25][C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:17]([O:21][C:22]([N:24]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:25][C:26]([N:14]1[CH2:13][CH2:12][N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:16][CH2:15]1)=[O:27])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCCCCCCCCCN1CCNCC1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCCCN1CCN(C(=O)CN(C(=O)OC(C)(C)C)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.9 %

Procedure:
A 2.3 g (8.64 mmoles) quantity of N,N,-dicyclohexylcarbodiimide was added to 20 ml of a solution of 2.0 g (7.35 mmoles) of N-decylpiperazine, 1.9 g (7.56 mmoles) of N-t-butoxycarbonylphenylglycine, 1.3 g (15.5 mmoles) of sodium hydrogen carbonate and 122 mg (1.0 mmole) of 4-dimethylaminopyridine in anhydrous methylene chloride. The mixture was stirred at room temperature for 12 hours. The precipitated crystals were collected by filtration and washed with methylene chloride. Mother liquor and the washings were concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=15:1), giving 2.8 g (yield: 83%) of 1-(N-t-butoxycarbonylphenylglycyl)-4-decylpiperazine.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:7]1=[O:28])C.O.[OH-].[Li+].Cl>O.CO>[C:24]([O:23][C:21]([N:16]([CH2:17][CH:18]1[CH2:19][CH2:20]1)[CH2:15][CH2:14][CH2:13][NH:12][C:8]1[C:7](=[O:28])[N:6]([CH2:5][C:4]([OH:29])=[O:3])[CH:11]=[CH:10][N:9]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)Cn1ccnc(NCCCN(CC2CC2)C(=O)OC(C)(C)C)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCCNc1nccn(CC(=O)O)c1=O)CC1CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of {3-[3-(tert-butoxycarbonyl-cyclopropylmethyl-amino)-propylamino]-2-oxo-2H-pyrazin-1-yl}-acetic acid ethyl ester (250 mg, 0.61 mmol) and lithium hydroxide monohydrate (33 mg, 0.79 mmol) in water (0.72 ml) and methanol (3.6 ml) was stirred at room temperature for 2 h. hydrochloric acid solution (1N, 0.79 ml) was added and the reaction mixture was stirred at room temperature for 10 min. Concentration from methanol gave {3-[3-(tert-butoxycarbonyl-cyclopropylmethyl-amino)-propylamino]-2-oxo-2H-pyrazin-1-yl}-acetic acid; 1H NMR (CD3OD, 400 MHz) δ 6.78 (d, 1H, J=4.8 Hz), 6.69 (d, 1H, J=4.9 Hz), 4.61 (s, 2H), 3.32 (m, 4H), 3.12 (d, 2H, J=6.8 Hz), 1.89 (m, 2H), 1.45 (s, 9H), 1.00 (m, 1H), 0.48 (m, 2H), 0.22 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19]Cl)=[CH:7]2.[N-:21]=[N+]=[N-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19][NH2:21])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1cc2cccc(Cl)c2nc1Oc1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: NCc1cc2cccc(Cl)c2nc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 8-chloro-3-(chloromethyl)-2-phenoxyquinoline (1 eq) in DMSO (0.25 M) was added NaN3 (3 eq) at rt and the mixture was stirred for 4 h at rt. The mixture was diluted with water, extracted with EtOAc (2 times) and the combined organic layers were washed with water (2 times), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH and treated with 10% Pd—C (5 wt %) and the mixture was then stirred under H2 balloon over night. The mixture was filtered through a Celite™ pad followed by removal of solvents to give (8-chloro-2-phenoxyquinolin-3-yl)methanamine.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].CS(O[CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=O)=O.O>CS(C)=O>[CH2:18]([O:17][CH2:16][CH2:15][CH2:14][O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: OCCCCO
Reactant: CCCCCCCCCCCCCCCCCCOCCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCCCOCCCOCCCCO
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.2 g) is heated at 70° C. for 10 minutes in dimethyl sulfoxide (50 ml), to which is added 1,4-butanediol (4.5 g). The mixture is heated for one further hour. To this reaction mixture is added dropwise a solution of 3-(octadecyloxy)propyl methanesulfonate obtained in Reference Example 1 (4.06 g) in dimethyl sulfoxide (15 ml), and the mixture is stirred at 70° C. for one hour. The reaction mixture is poured into cold water, and the mixture is subjected to extraction with a mixture of hexane and ethyl acetate. The extract is washed with water and then dried, and the solvents are then distilled off under reduced pressure. The residue is subjected to purification by means of silica gel column chromatography to obtain the above-titled compound (2.2 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[F:9][C:10]([F:28])([F:27])[CH2:11][N:12]=[C:13]([NH2:26])[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH2:22][CH2:23][CH2:24][NH2:25])[N:16]=1.CCO>C(N(CC)CC)C>[F:28][C:10]([F:9])([F:27])[CH2:11][N:12]=[C:13]([NH2:26])[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH2:22][CH2:23][CH2:24][NH:25][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[N:16]=1
Reactant: O=C(Cl)c1ccco1
Reactant: NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NCC(F)(F)F)Nc1ccnc(SCCCNC(=O)c2ccco2)n1
Reaction time: 2 h
Yield: 74.6 %

Procedure:
2-Furoyl chloride (145 mg.) was added to a mixture of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropylthio)pyrimidine (308 mg.), EtOH (10 ml.) and triethylamine (0.5 ml.), the mixture left at room temperature for 2 hours and then evaporated to dryness. The residue was dissolved in N aqueous HCl and the solution washed with EtOAc. The aqueous phase was basified with 10N aqueous NaOH and then extracted with EtOAc, and the extract was dried amd evaporated to dryness. The residue was recrystallised from EtOAc to give N-[3-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimidin-2-yl-thio)propyl]-2-furamide (300 mg.), m.p. 127°-129°.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16](O)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([Cl:23])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)CCCC2O
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)CCCC2Cl
Yield: 86.3 %

Procedure:
6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ol (0.65 g, 2.26 mmol) was dissoved in 50 mL toluene, and 1 mL of thionyl chloride was added. The reaction was refluxed for one hour, and then cooled. Solvent was removed under reduced pressure to yield 6-benzenesulfonyl-1-chloro-1,2,3,4-tetrahydro-naphthalene (0.6 g, 86.3%) as a crude oil. MS: 308 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:9])[CH2:4][CH2:3]1.N1C=CC=CC=1.[O:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42](Cl)=[O:43].Cl>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[N:25]2[CH2:26][CH2:27][N:28]([C:42]([C:38]3[O:37][CH:41]=[CH:40][CH:39]=3)=[O:43])[CH2:29][CH2:30]2)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(Cl)c1ccco1
Reactant: CN1CCN(C(=O)c2c(N3CCNCC3)n(-c3ccccc3)c3ccccc23)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CN1CCN(C(=O)c2c(N3CCN(C(=O)c4ccco4)CC3)n(-c3ccccc3)c3ccccc23)CC1
Temperature: -20 °C
Reaction time: 4 h

Procedure:
To a mixture of 16.1 g (0.04 mol) of 1-phenyl-2-(1-piperazinyl)-indole 3-carboxylic acid 4-methyl piperazide (Example 7), 5 ml of pyridine and 40 ml of chloroform, that had been cooled to -20° C., a solution of 6.5 g (0.05 mol) of furan-2-yl carboxylic acid chloride in 80 ml of chloroform was added. The mixture was allowed to stand for 4 hours at room temperature, then 200 ml of chloroform were added and the mixture was washed four times with water. The solvent was eliminated in vacuo, the crystallized residue was digested with ether, suction-filtered and washed with ether. Yield: 19 g (95% of the theoretical yield), m.p. 180°-181° C.; the hydrochloride decomposed above 300° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23].[Li+].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.C1COCC1.C=O>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[C:21](=[CH2:27])[C:22]([O:24][CH3:25])=[O:23]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Agent: C=O
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=C(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Yield: 36 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]acetate (0.386 g; 1.1 mmol), LHMDS 1N in THF (1.21 mL; 1.21 mmol), para-formaldehyde (0.050 g; 1.65 mmol) in DMF (4 mL) for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-100%) in heptane furnished 0.154 g (36%) of the title compound as a light yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.Cl.[CH3:9][O:10][C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13]>>[CH3:9][O:10][C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][C:5](=[O:7])[CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: O=C(O)CC1CC1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)CC1CC1

Procedure:
Following General Procedure A above using cyclopropylacetic acid (Aldrich) and L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.15 in 25% ethyl acetate/hexanes) and purification was by flash column chromatography using 25% ethyl acetate/hexanes as the eluant.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1.Cl[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22].O>CN(C)C=O>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc2[nH]ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c([N+](=O)[O-])cc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 109.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.17 g, 6.61 mmol) was suspended in 30 mL dimethylformamide. The mixture was stirred for 15 min and was cooled at 0° C. with an ice bath. 6-Chloro-4-nitro-1H-indole (1 g, 5.09 mmol) dissolved in 5 mL dimethylformamide was added dropwise and the mixture was stirred 30 min. At the same temperature [2-(chloromethoxy)ethyl](trimethyl)silane (1.1 g, 6.61 mmol) dissolved in 5 mL dimethylformamide was added dropwise and stirred for 30 min at 0° C. The mixture was poured into water and extracted twice with ethyl acetate. The organic were dried over sodium sulphate and concentrated under reduced pressure to give 1.82 g (100% yield) of the title compound as a yellow oil. Purity 96%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([OH:35])=[O:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:38][OH:39].C([O-])(O)=O.[Na+]>>[OH:39]/[N:38]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][CH:10]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([OH:35])=[O:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:19])([F:20])[F:18]
Reactant: Cc1cc(C(=O)CC(c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccccc2C(F)(F)F)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccccc2C(F)(F)F)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-(2-trifluoromethyl-phenyl)-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a light yellow solid, MS (ESI+): m/z=505.173 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)=[O:31]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][C:15]=2[CH2:24][N:25]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)=[O:31])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)OCc1ccc(Cl)cc1
Reactant: CCNCc1ccc(C(F)(F)F)cc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc(C(F)(F)F)ccc2CN(CC)C(=O)OCc2ccc(Cl)cc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-5′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and 4-chlorobenzyl chloroformate.