Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[C:29](Cl)(=O)[C:30]([CH3:33])(C)[CH3:31].[CH2:36](N(CC)CC)[CH3:37].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OC(C)C)(=O)C.O>[CH2:36]([O:13][C:11](=[O:12])[C@H:10]([CH3:14])[CH2:9][C@H:8]([NH:15][C:16](=[O:18])[C:30]([CH3:33])([CH3:31])[CH3:29])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:2][CH:3]=1)[CH3:37].[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)C(=O)Cl
Agent: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CC(=O)OC(C)C
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
10 g (2S,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (3-a, R1=R2=1-1, R3=Et) in isopropyl acetate (50 ml) is added to a mixture of pivaloyl chloride (4.1 ml) in isopropyl acetate (50 ml). The mixture is then stirred for 40 min at room temperature. Triethylamine (10.3 ml) in isopropyl acetate (30 ml) is then added over a period of 1 h. The resulting mixture is stirred for 16 h. Citric acid (7.5 g) dissolved in water (30 ml) is added and the phases are separated. The organic phase is washed twice with water (30 ml) and concentrated in vacuo to give (2R,4S)-5-Biphenyl-4-yl-4-(2,2-dimethylpropionylamino)-2-methylpentanoic acid ethyl ester (3-a, R1=Piv, R2=H, R3=Et). 1H NMR (DMSO): 1.05 (9H), 1.09 (3H), 1.15 (3H), 1.54 (1H), 1.78 (1H), 2.48 (1H), 2.72 (2H), 3.97 (1H), 4.00 (2H), 7.15 (1H), 7.25 (2H), 7.34 (1H), 7.45 (2H), 7.55 (2H), 7.62 (2H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22].C([N-]C(C)C)(C)C.[Li+].[CH3:31][Si:32](Cl)([CH3:34])[CH3:33].FC(F)(F)S(OC)(=O)=O>O1CCCC1.CCOCC>[Br:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([Si:32]([CH3:34])([CH3:33])[CH3:31])[C:15]=1[F:22]
Reactant: C[Si](C)(C)Cl
Reactant: Fc1cc(F)c(Br)cc1F
Agent: CC(C)[N-]C(C)C
Agent: COS(=O)(=O)C(F)(F)F
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: C[Si](C)(C)c1c(F)c(F)cc(Br)c1F
Yield: 88 %

Procedure:
This preparation route is very expensive. The first and the second synthesis step each involve reaction with butyllithium and diisopropylamine in tetrahydrofuran at −78° C., and the third synthesis step involves reaction with butyllithium in ether, likewise at −78° C. In the first step, 1-bromo-2,4,5-trifluorobenzene is reacted first with lithium diisopropylamide and then with trimethylsilyl chloride, the resulting 1-bromo-2,4,5-trifluoro-3-(trimethylsilyl)benzene (88% yield) is once more reacted with lithium diisopropylamide and subsequently with methyl trifluoromethanesulfonate, the resulting 1-bromo-2,4,5-trifluoro-6-methyl-3-(trimethylsilyl)benzene (75% yield) is reacted with butyllithium and subsequently with CO2 in the form of dry ice, and the resulting 2,4,5-trifluoro-6-methyl-3-(trimethylsilyl)- benzoic acid (62% yield) is reacted with cesium fluoride in acetonitrile to give 6-methyl-2,4,5-trifluorobenzoic acid (89% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7](Cl)[C:8]=1Cl)[NH2:5].[Cl:11][C:12]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:13]=1[NH2:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:11][C:12]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:13]=1[NH2:14]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Agent: Nc1cc(Cl)c(Cl)cc1Cl
Product: Nc1cccc(Cl)c1

Procedure:
Example 9 is repeated, the 3,4,5-trichloroaniline being replaced by 2,4,5-trichloroaniline and 0.5 g of the same catalyst being introduced in place of 0.1 g. After a reaction time of 10 hours under the same conditions, 3-chloroaniline is obtained with a yield of 100% for a complete conversion of the 2,4,5-trichloroaniline and of the intermediates (2,5-, 2,3- and 3,4-dichloroanilines). The degree of hydrodechlorination of the solvent is 0.09%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29].C(O[Na])(C)(C)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:29][CH2:28][C:27]([O:31][CH3:32])=[O:30])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(C(F)(F)F)cc3)c2C1
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: COC(=O)CCn1nc(-c2ccc(C(F)(F)F)cc2)c2c1CCN(C(=O)OC(C)(C)C)C2
Temperature: 75 °C
Reaction time: 48 h
Yield: 15 %

Procedure:
3-(4-Trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.85 g, 5.04 mmol) and methyl acrylate (0.50 mL, 5.6 mmol) were combined in toluene (30 mL) and heated to 75° C. The resulting mixture was treated with t-BuONa (100 mg), and heating continued for 48 h. The mixture was allowed to cool and partitioned between EtOAc (300 mL) and NaHCO3 (75 mL). The aqueous layer was extracted with EtOAc (3×75 mL). The combined extracts were dried over Na2SO4 and concentrated. Column chromatography (silica, 30-60% EtOAc/hexanes) afforded 343 mg (15%) of the title compound. TLC (silica, 50% EtOAc/hexanes): Rf=0.4. MS (electrospray): m/z calculated for C22H27F3N3O4 [M++H] 454.20. found 454.1. 1H NMR (CDCl3, 400 MHz): 7.75 (br d, J=8.1 Hz, 2H), 7.64 (br s, 2H), 4.63 (br s, 2H), 4.30 (t, J=6.6 Hz, 2H), 3.75 (br s, 2H), 3.68 (s, 3H), 2.98 (t, J=6.6 Hz, 2H), 2.79 (br t, J=5.6 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[F:61][C:62]([F:73])([F:72])C1C=CC=CC=1N=C=S>>[CH3:33][CH:32]([CH3:34])[C@H:27]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][CH:25]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[C:62]([F:73])([F:72])[F:61])=[S:35])=[CH:16][CH:15]=3)[CH:18]=2)[C:22]1=[O:26])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Reactant: FC(F)(F)c1ccccc1N=C=S
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4C(F)(F)F)cc3)ccc2C1=O

Procedure:
The compound of example 270 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 2-trifluoromethyl phenyl isothiocyanate. The compound of example 270 was used directly without isolation, for the preparation of compound of example 271.
Reaction SMILES: COC(=O)[NH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([Br:23])[CH:21]=3)[NH:16][CH:15]=2)=[O:13])[C:6]=1[F:24].C(#N)C.C[Si](I)(C)C>C(OCC)(=O)C>[NH2:4][C:5]1[C:6]([F:24])=[C:7]([C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([Br:23])[CH:21]=3)[NH:16][CH:15]=2)=[O:13])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: COC(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.5 %

Procedure:
Into a reaction flask under nitrogen, [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-carbamic acid methyl ester (6, 15.00 g, 36.6 mmol) is combined with 300 mL of anhydrous acetonitrile and trimethylsilyl iodide (21.95 g, 109.7 mmol). The reaction is stirred at room temperature overnight, then diluted with 500 mL of ethyl acetate and washed with 2×500 mL of 10% aqueous sodium thiosulfate. The aqueous layers are combined and back extracted with 1×500 mL of ethyl acetate. The organic layers are combined and washed with 1×500 mL of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (7, 13.34 g).
Reaction SMILES: [I:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:15])[C:4]=2[CH:3]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.CC(OC(C)=O)=O.CC(O)=O.[Br:42]Br>S(=O)(=O)(O)O.C(O)(=O)C>[Br:42][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:4](=[CH:3][C:2]([I:1])=[CH:14][CH:13]=3)[C:5](=[O:15])[C:6]=2[CH:7]=1
Reactant: O=C1c2ccccc2-c2ccc(I)cc21
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: Ic1ccccc1
Product: O=C1c2cc(Br)ccc2-c2ccc(I)cc21
Reaction time: 2 h
Yield: 79.8 %

Procedure:
A suspension of 2-iodofluoren-9-one (1.046 g, 3.42 mmol; Maybridge) and iodobenzene diacetate (1.21.g, 3.76 mmol; Aldrich) in 1:1 Ac2O-HOAc (10 mL) was treated with bromine (180 μL, 3.48 mmol; Aldrich) followed by 3 drops concentrated sulfuric acid. The mixture solidified, so it was diluted with acetic acid until it could be stirred. After 2 h, the reaction was quenched with aq. Na2S2O3, neutralized with K2CO3, and filtered. The solid filter cake was washed with water, dried, and recrystallized from hot EtOH to afford the title compound (1.05 g, 2.73 mmol; 80% yield): 1H NMR (300 MHz, CDCl3) δ ppm 7.97 (dd, J=2, 1 Hz, 1H), 7.84 (dd, J=8, 2 Hz, 1H), 7.75-7.79 (m, 1H), 7.63 (dd, J=8, 2 Hz, 1H), 7.39 (d, J=7 Hz, 1H), 7.24-7.31 (m, 1H); MS (DCl/NH3): m/z 384 (M+1)+, 386 (M+3)+.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.Cl>C(O)C.[Pd]>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH:4][CH:12]([CH3:14])[C:11]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Nc1ccc(F)c(F)c1F
Reactant: CCOC(=O)C(C)=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)Nc1ccc(F)c(F)c1F
Temperature: 40 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
2,3,4-Trifluoroaniline (0.83 g) and ethyl pyruvate (1.15 g) were dissolved in ethanol (8 ml). After adding 5% Pd—C (0.11 g) and conc. hydrochloric acid (0.03 g), the mixture was stirred at 40° C. under a hydrogen gas pressure of 2.94 MPa for 3 hours. After filtering off Pd—C, the obtained filtrate was concentrated under reduced pressure. Thus the title compound (1.32 g) was obtained as slightly yellow oily substance. Various spectral data of this product was identical with those obtained in Example 7.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12])#[N:2].[C:13](=O)(O)O.NNC(N)=N>CO.O.Cl>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:13][CH2:5][CH2:6][C:7]2=[O:12])#[N:2]
Reactant: O=C(O)O
Reactant: N#Cc1cccc2c1CCC2=O
Agent: Cl
Agent: N=C(N)NN
Solvent: O
Solvent: CO
Product: N#Cc1cccc2c1CCCC2=O

Procedure:
4-Cyano-1-indanone-2'-amidinohydrazone hydrochloride Analogously to Example 1,314 mg (2 mmol) of 4-cyano-1-indanone are dissolved in 20 ml of methanol; a solution of 272 mg (2 mmol) of aminoguanidine hydrogen carbonate in 9 ml of water and 1 ml of 2N hydrochloric acid is added and the mixture is stirred at reflux for 4 days. After cooling, the reaction mixture is concentrated to dryness by evaporation and the residue is crystallised from water, yielding stamping compound (a), m.p. >230°: 1H--NMR (DMSO-d6 /D2O): δ=8.16 (d, 1H; 7.9 (d, 1H; 7.55 (t, 1H; 3.28 (m,2H); 2.9 (m,2H); IR(Nujol): 2190 cm-1 (CN).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[N:15][C:10]3[O:11][CH2:12][CH2:13][NH:14][C:9]=3[CH:8]=2)[CH:2]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Br:29])[C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22].C(N(CC)CC)C.O>ClCCl>[Br:17][C:18]1[CH:19]=[C:20]([C:21]([N:14]2[CH2:13][CH2:12][O:11][C:10]3[N:15]=[CH:16][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][C:9]2=3)=[O:22])[CH:24]=[C:25]([Br:29])[C:26]=1[O:27][CH3:28]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: c1cncc(-c2cnc3c(c2)NCCO3)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4cccnc4)cc32)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
In a 10 ml flask, 7-pyridin-3-yl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (30 mg, 0.140 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (50.5 mg, 0.154 mmol) were dissolved in dichloromethane (2 ml). Triethylamine (0.058 ml, 0.42 mmol) was added thereto and then stirred at room temperature for 1 hour. After completion of the reaction by adding water dropwise, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by preparative TLC eluting a solvent of ethyl acetate:methanol=20:1. Silica gels containing the product were eluted with dichloromethane and the solvent was evaporated to obtain (3,5-dibromo-4-methoxy-phenyl)-(7-pyridin-3-yl-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl)-methanone as white solid (35 mg, 49%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[C:14]([NH:16]C(=O)C)[CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl>O1CCOCC1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][N:11]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1ccnc(N2CCN(C(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N1CCN(c2cc(N)ccn2)CC1
Temperature: 100 °C
Yield: 56.7 %

Procedure:
A mixture of 2.1 g (8 mmol) N-[2-(4-isopropyl-piperazin-1-yl)-pyridin-4-yl]-acetamide and 10.5 ml 4N HCl in 25 ml dioxane was heated to 100° C. for 2 h. After evaporation of all volatiles the residue was treated with water and NaHCO3 aq. sat. and extracted with DCM. The combined organic layers were washed with NaCl aq. sat., dried with MgSO4 and evaporated. The residue was triturated with DCM and dried to yield 1 g (57%) of the title compounds as white solid. MS: (m/e): 221.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CCO>[NH2:8][C:6]1[N:5]2[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:9]=[C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cc(Br)cc(N)n1
Solvent: CCO
Product: CCOC(=O)c1cn2c(N)cc(Br)cc2n1

Procedure:
4-bromopyridine-2,6-diamine (3 g, 15.96 mmol) was dissolved in EtOH (300 mL). Ethyl bromopyruvate (2.34 mL, 16.8 mmol, 90% tech grade) was added. The mixture was heated at reflux for 5 h. The solvent was evaporated under reduced pressure to give a dark tan foam which was triturated with 200 mL of saturated NaHCO3 overnight. The solids were filtered, washed with 2×10 mL of saturated NaHCO3, then triturated with EtOAc (100 mL) twice, filtered and air dried to give the desired product as a tan powder weighing 3.15 g (70%).
Reaction SMILES: IC.[F:3][C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[CH:9]1.[C:32](=O)([O-])[O-].[Na+].[Na+]>C(O)C.O1CCCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][CH3:32])[CH:15]=2)[C:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[CH:9]1
Reactant: Nc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cc(F)cc(F)c3)c2c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CI
Product: CNc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cc(F)cc(F)c3)c2c1
Yield: 25 %

Procedure:
Iodomethane (0.568 ml, 9.12 mmol) was added to a solution of 1-(3,5-difluoro-benzyl)-3-(2-nitro-phenylsulfanyl)-1H-indol-6-ylamine (Example 15a; 2.5 g, 6.1 mmol) in a mixture of ethanol and tetrahydrofuran containing sodium carbonate (0.657 g, 6.08 mmol). The reaction mixture was heated under reflux overnight and concentrated. Water was added and the product was extracted into ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (heptane/ethyl acetate 8:2) afforded [1-(3,5-difluoro-benzyl)-3-(2-nitro-phenylsulfanyl)-1H-indol-6-yl]-methyl-amine (0.647 g) and [1-(3,5-difluoro-benzyl-3-(2-nitro-phenylsulfanyl)-1H-indol-6-yl]-dimethyl-amine (0.815 g). 1H-NMR (CDCl3) δ 8.26 (dd, 1H, J=8.2 and 1.2 Hz), 7.35 (d, 1H, J=8.6 Hz), 7.27 (ddd, 1H, J=8.2, 7.4 and 1.2 Hz), 7.25 (s, 1H), 7.17 (ddd, 1H, J=8.2, 7.4 and 1.2 Hz), 7.03 (dd, 1H, J=8.2 and 1.2 Hz), 6.78 (dd, 1H, J=8.6 and 2.3 Hz), 6.74 (tt, 1H, J=8.6 and 2.3 Hz), 6.68 (m, 2H), 6.48 (d, 1H, J=2.3 Hz), 5.29 (s, 2H), 2.95 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([OH:22])=[CH:13][CH:12]=3)=[O:5])[CH3:2].Cl[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([O:22][C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(O)cc3c2c1COC
Reactant: Clc1ncccn1
Product: CCOC(=O)c1ncc2[nH]c3ccc(Oc4ncccn4)cc3c2c1COC

Procedure:
Analogously to Example 8 from 6-hydroxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester and 2-chloropyrimidine, mp 128°-129° C.
Reaction SMILES: [CH2:1]([Cl:5])[C:2]([OH:4])=[O:3].[C:6]1([CH:12]=[CH:13][C:14]2[CH:15]=[C:16]([OH:24])[C:17]([CH:21]([CH3:23])[CH3:22])=[C:18](O)[CH:19]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[Cl:5][CH2:1][C:2]([O:4][C:18]1[CH:19]=[C:14]([CH:13]=[CH:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:15]=[C:16]([O:24][C:2](=[O:3])[CH2:1][Cl:5])[C:17]=1[CH:21]([CH3:23])[CH3:22])=[O:3]
Reactant: CC(C)c1c(O)cc(C=Cc2ccccc2)cc1O
Reactant: O=C(O)CCl
Product: CC(C)c1c(OC(=O)CCl)cc(C=Cc2ccccc2)cc1OC(=O)CCl
Yield: 72 %

Procedure:
This material was synthesized from anhydrous chloroacetic and 5-(2-Phenylethenyl)-2-i-propyl-1,3-benzenediol obtained in example 11 in 72% yield by the same procedure as described in example 12. 1HNMR (CDCl3, ppm): δ 1.30 (d, J=7.0 Hz, 6H), 3.08 (hept, J=7.0 Hz, 1H), 4.39 (s, 4H), 6.96 (d, J=17 Hz, 1H), 7.14 (d, J=17 Hz, 1H) 7.17 (s, 2H), 7.2-7.5 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=O)[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccccc1NC(=O)CNCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccccc1NCCNCc1ccccc1

Procedure:
In a manner similar to Preparation 2, react N-(2-methoxyphenyl)-2-[(phenylmethyl)amino]acetamide (0.31 g, 1.1 mmol) with lithium aluminum hydride (0.09 g, 2.4 mmol) to obtain the title compound.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[S:35])=[C:29]([CH3:36])[CH:28]=1)=[O:26]>>[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]2[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:35]2)=[C:29]([CH3:36])[CH:28]=1)=[O:26]
Reactant: COC(=O)c1ccc(N=C=S)c(C)c1
Reactant: CC(C)C[C@H](N)CO
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: COC(=O)c1ccc(N=C2N[C@@H](CC(C)C)CS2)c(C)c1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methyl butylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-(Methoxycarbonyl)-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [NH2:1]N.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][CH2:11][CH2:12]C1C=CC=C2C(NC(=O)C=12)=O>CO>[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][CH2:11][CH2:12][NH2:1]
Reactant: NN
Reactant: CN1CCNCC1CCCc1cccc2c1C(=O)NC2=O
Solvent: CO
Product: CN1CCNCC1CCCN

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 3-(N-methylpiperazinyl)propylphthalimide (229 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: F[B-](F)(F)F.[CH:6](=[N:13][N+:14]1[CH:18]=[CH:17][N:16](N=CC2C=CC=CC=2)[C:15]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C-]#N.[K+]>CO.O>[CH:6](=[N:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C(=Nn1cc[n+](N=Cc2ccccc2)c1N1CCOCC1)c1ccccc1
Agent: F[B-](F)(F)F
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: O
Product: C(=Nn1ccnc1N1CCOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4.47 g of 1,3-bis(benylideneamino)-2-morpholinoimidazolium tetrafluoroborate are suspended in 50 ml of methanol. A solution of 1.3 g of potassium cyanide in 20 ml of water is added dropwise within 15 minutes while cooling in an ice-bath, whereby a yellow solution results. The solution is stirred at room temperature for an additional 15 minutes, 150 ml of water are added and the mixture is extracted three times with 30 ml of methylene chloride each time. The combined methylene chloride extracts are dried over sodium sulfate, filtered and evaporated in a vacuum. The yellow oil which remains behind as the residue is treated with 70 ml of ice-cold water. Then the mixture is acidified (pH about 1) with 2N hydrochloric acid and subsequently extracted three times with diethyl ether. The colorless, acidic-aqueous phase is treated with 2N sodium hydroxide solution up to an alkaline reaction (pH about 8-9). The resulting pale yellow precipitate is removed by filtration and reprecipitated from methanol/water. There is obtained 1-benzylideneamino-2-morpholinoimidazole of m.p. 59°-61°.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14]2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:68]1[N:73]=[C:72]([CH3:74])[C:71]([F:75])=[CH:70][CH:69]=1>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[N:14]2[C:68]2[CH:69]=[CH:70][C:71]([F:75])=[C:72]([CH3:74])[N:73]=2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(Br)ccc1F
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCC(=O)N2)on1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc(N2C(=O)CC[C@H]2C(=O)Nc2cc(C(C)(C)C)no2)ccc1F
Temperature: 100 °C
Yield: 27.3 %

Procedure:
(S)-5-Oxo-pyrrolidine-2-carboxylic acid (3-tert-butyl-isoxazol-5-yl)-amide (300 mg, 1.19 mmol), tris(dibenzylideneacteone)dipalladium (0) (32.80 mg, 0.036 mmol), Xantphos ® (62.20 mg, 0.011 mmol), caesium carbonate (654.16 mg, 2.01 mmol) and 6-bromo-3-fluoro-2-methylpyridine (226.90, 1.20 mmol) are charged to a vessel, diluted with dioxane (anhydrous, 3 ml) and heated to 100° C. overnight. On completion, the reaction is diluted with ethyl acetate and partitioned between water. The organic phase is separated, dried over sodium sulphate and the solvents removed under vacuum. The crude residue is purified by flash column chromatography eluting with a gradient solution of heptane/ethyl acetate 0-50% to isolate 117 mg of title compound as a white solid, yield 27%. ESI m/z 361=MH+