Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[O:4]([C:11]1[CH:31]=[CH:30][C:14]2[CH:15]=[C:16]([CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[O:17][C:13]=2[CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.NN>O>[O:4]([C:11]1[CH:31]=[CH:30][C:14]2[CH:15]=[C:16]([CH2:18][NH2:19])[O:17][C:13]=2[CH:12]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc2ccc(Oc3ccccc3)cc2o1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cc2ccc(Oc3ccccc3)cc2o1
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To an ethanol (5 mL) solution of 2-(6-phenoxy-benzofuran-2-ylmethyl)-isoindole-1,3-dione (209 mg, 566 μmol) described in Production Example 49-1-3 was added hydrazine hydrate (549 μL, 11.3 mmol) at room temperature, which was stirred for 1 hour while heating under reflux. Water was added to the reaction solution at room temperature followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (92 mg, 68%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][CH2:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:24]([CH2:23][Cl:22])(=[O:26])=[O:25])=[CH:6][CH:7]=1
Reactant: Clc1ccc(NCc2cccnc2)cc1
Reactant: O=S(=O)(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=S(=O)(CCl)N(Cc1cccnc1)c1ccc(Cl)cc1

Procedure:
A 2.6 g. portion of 3-(4-chlorophenylaminomethyl)pyridine was dissolved in dichloromethane with stirring, and to the solution was added 2.1 g. of potassium carbonate and 2.25 g. of chloromethanesulfonyl chloride. The mixture was stirred at ambient temperature for several days, and was then worked up as described in Example 3 to obtain 0.6 g. of the desired product, m.p. 98°-100°.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([F:27])[CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].[N:33]1([CH2:38][CH2:39][NH2:40])[CH2:37][CH2:36][CH2:35][CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O>[C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:40][CH2:39][CH2:38][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:23])=[C:20]([F:27])[CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:31])([F:30])[F:32])#[N:2]
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)O)c(F)c3)C2=S)cc1C(F)(F)F
Reactant: NCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)NCCN4CCCC4)c(F)c3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoic acid (Compound 224, 100 mg, 0.21 mmol), 2-(pyrrolidin-1-yl)ethanamine (32 mg, 0.28 mmol), HATU (106 mg, 0.28 mmol), and DIEA (0.1 mL, 0.63 mmol) in DCM (3 mL) and DMF (1.5 mL) was stirred at room temperature for 18 h. Brine and EtOAc were added and the aqueous layer was extracted with EtOAc (4×), the organics were combined, dried over sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0 to 10% MeOH/DCM to afford impure desired product that was repurified by reverse phase HPLC (acetonitrile/water:TFA). The fractions containing the desired compound were combined, acetonitrile was removed in vacuo, and the remaining aqueous layer was treated with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with DCM (3×), the organics were combined, dried over sodium sulfate, and evaporated to dryness to afford 88 mg of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(2-(pyrrolidin-1-yl)ethyl)benzamide as an off-white solid. LCMS [M+1]+ 561.1.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]2[CH:33]=[CH:32][C:29]([CH2:30][NH:2][CH2:3][C:4]3[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=3)=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(C(=O)OC)cc3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure A using methyl 4-(aminomethyl)benzoate hydrochloride and 4-[(4-butylphenyl)ethynyl]benzaldehyde as a white solid (54%). 1H NMR (CDCl3, 300 MHz) δ 8.02 (d, J=8.3 Hz, 2H), 7.51 (d, J=7.9 Hz, 2H), 7.44 (m, 4H), 7.33 (d, J=7.9 Hz, 2H), 7.17 (d, J=7.9 Hz, 2H), 3.92 (s, 3H), 3.87 (s, 2H), 3.82 (s, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.94 (t, J=7.3 Hz, 3H). M+ (ESI): 412.4. HPLC, Rt: 4.28 min (Purity: 99.4%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]2[NH:18][C:17](=O)[CH2:16]2)[CH:11]=[CH:12][C:13]=1[Cl:14].[Cl-].[NH4+]>C(OCC)C>[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]2[CH2:16][CH2:17][NH:18]2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)N1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: Clc1ccc(C2CCN2)cc1Cl
Yield: 47.3 %

Procedure:
To lithium aluminium hydride (0.63 g, 16.5 mmol) in diethyl ether (12 ml) was added 4-(3,4-dichlorophenyl)azetidin-2-one (1 g, 4.6 mmol). The mixture was refluxed under argon for 4 h then cooled and 20% aqueous ammonium chloride solution (3 ml) added. Diethyl ether (30 ml) was added and the mixture filtered, and the insoluble material washed with more diethyl ether (20 ml). The combined filtrates were dried (Na2SO4) and evaporated under reduced pressure to give a yellow oil, (0.76 g). A portion of this material (0.55 g) was purified by column chromatography on silica gel eluting with 2-10% (9:1 MeOH/0.880 NH3) in dichloromethane gave the title compound, (0.44 g, 65%). δH (CDCl3) 2.0 (1H, bs), 2.3 (1H, m), 2.55 (1H, m), 3.34 (1h, m), 3.75 (1H, m), 4.9(1H, t), 7.2 (1H, dd), 7.4(1H, d), 7.5 (1H, d).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:16]=[C:15]3[C:10]([C:11](=[O:22])[C:12]([C:19]([OH:21])=[O:20])=[CH:13][N:14]3[CH:17]=[CH2:18])=[CH:9][C:8]=2[F:23])[CH2:3]1.[NH2:24][C@H:25]([C:30]([OH:32])=[O:31])[CH2:26][C:27]([OH:29])=[O:28]>O>[NH2:24][C@H:25]([C:30]([O-:32])=[O:31])[CH2:26][C:27]([O-:29])=[O:28].[NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:16]=[C:15]3[C:10]([C:11](=[O:22])[C:12]([C:19]([OH:21])=[O:20])=[CH:13][N:14]3[CH:17]=[CH2:18])=[CH:9][C:8]=2[F:23])[CH2:3]1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(N)C3)nc21
Solvent: O
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]

Procedure:
An equimolar mixture of the compound 1 and L-aspartic acid was treated in water in a similar manner to give L-aspartate (as a mono-hydrate) of the compound 1, m.p. 235°-240° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=1.[Mg+2].[Cl-].[Cl-].[CH2:16]=[O:17].Cl>C(#N)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:5]([OH:9])=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=1)[CH:16]=[O:17]
Reactant: Cc1cc(O)c(C(C)C)cc1Cl
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: Cc1c(Cl)cc(C(C)C)c(O)c1C=O
Yield: 100.7 %

Procedure:
To a solution of 4-chloro-2-isopropyl-5-methylphenol (5.00 g, 27.08 mmole) in anhydrous acetonitrile (150 mL) was added MgCl2 (3.87 g, 40.61 mmole), TEA (10.28 mL, 101.55 mmole) and paraformaldehyde (5.48 g, 182.79 mmole), and the resulting mixture was refluxed under a dry N2 atmosphere for 18 hrs. The mixture was then cooled, acidified with 2.4 N HCl and extracted with EtOAc (2×250 ml). The combined extracts were washed with brine (100 ml), dried over MgSO4, filtered and concentrated in vacuo to give dark orange oil which was subjected to flash chromatography (silica gel) and eluted with 25% hexane/ CH2Cl2 to yield 5.8 g (99% yield) of the product as a pale yellow oil. GCMS m/z 212.0 (M+). This ester was of suitable purity to use without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][O:5][C:6](=[O:20])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[NH:10][C:9]=1[CH3:19].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:33][C:34]1[CH:42]=[C:41]([Cl:43])[CH:40]=[C:39]([Cl:44])[C:35]=1[C:36](Cl)=[O:37].[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:22][Si:2]([CH3:21])([CH3:1])[CH2:3][CH2:4][O:5][C:6](=[O:20])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]([C:36](=[O:37])[C:35]2[C:39]([Cl:44])=[CH:40][C:41]([Cl:43])=[CH:42][C:34]=2[Cl:33])[C:9]=1[CH3:19]
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: COc1ccc2[nH]c(C)c(CC(=O)OCC[Si](C)(C)C)c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)c(CC(=O)OCC[Si](C)(C)C)c(C)n2C(=O)c1c(Cl)cc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To 5-methoxy-2-methyl-3-indolyl acetic acid 2-(trimethylsilyl)ethyl ester (2.00 g) in THF (20.0 mL) was added HMPA (2.0 mL). To the resulting mixture at -78° C. was added a 0.5M toluene solution of KHMDS (13.8 mL). After a period of 0.5 h, 2,4,6-trichlorobenzoyl chloride (1.03 mL) was added and the mixture was stirred 0.5 h at -78° C. then 0.5 h at 0° C. An aqueous solution of NH4Cl was then added and extracted with EtOAc. After purification by flash chromatography (10% EtOAc in hexane) the title compound was obtained (2.80 g) and used as such for the next step.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:44])(=[O:43])=[N:17][C:18](=[O:42])[C:19]2[CH:24]=[C:23]([C:25]#[C:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]([C:36]4[O:37][CH:38]=[CH:39][C:40]=4[CH3:41])=[O:35])[CH:28]=3)[CH:22]=[N:21][CH:20]=2)=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:44])(=[O:43])=[N:17][C:18](=[O:42])[C:19]2[CH:24]=[C:23]([C:25]#[C:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]([C:36]4[O:37][CH:38]=[CH:39][C:40]=4[CH3:41])=[O:35])[CH:28]=3)[CH:22]=[N:21][CH:20]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CO[Si](C)(C)C(C)(C)C)cc3)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CO)cc3)c2)c1
Reaction time: 1 h
Yield: 94 %

Procedure:
N-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl](methyl)oxido--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)nicotinamide (0.722 g, 1.15 mmol) was dissolved in THF (2.3 mL). The resulting solution was treated with 1M solution of TBAF in THF (2.3 mL, 2.30 mmol) causing the mixture to turn black in color. The mixture was allowed to stir for 1 h, subsequently dissolved in EtOAc (10 mL) and extracted with H2O (3×15 mL). The organic layer was dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude product was purified via column chromatography (gradient eluant mixture of EtOAc in Hexanes: 0% to 100% EtOAc) to afford the title compound in 94% yield (0.350 g, 0.682 mmol).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[C:28]3[C:27]4[C@@H:26]([CH2:29]C=O)[CH2:25][CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CO[CH:34]([O:37][CH3:38])[O:35][CH3:36].CC1C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:38][O:37][CH:34]([O:35][CH3:36])[CH2:29][C@H:26]1[CH2:25][CH2:24][C:23]2[S:22][C:21]3[N:20]=[CH:19][N:18]=[C:17]([O:16][CH:13]4[CH2:12][CH2:11][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:7])([CH3:6])[CH3:8])[CH2:15][CH2:14]4)[C:28]=3[C:27]1=2
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC=O)CC4)CC1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
For the preparation of the starting material compound 43.1, see Example 43. Into a 50-mL round-bottom flask containing a solution of tert-butyl N-methyl-N-(4-[[(3R)-3-(2-oxoethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (460 mg, 1.03 mmol, 1.00 equiv) in methanol (15 mL) was added trimethoxymethane (548 mg, 5.16 mmol, 5.00 equiv) and 4-methylbenzene-1-sulfonic acid (18 mg, 0.10 mmol, 0.10 equiv) at room temperature under nitrogen. The reaction mixture was stirred for 4 hr at ambient temperature. After completion, the reaction was quenched with saturated aqueous NaHCO3 and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:8) to afford the desired tert-butyl N-(4-[[(3R)-3-(2,2-dimethoxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (470 mg, 93%) as a colorless oil. LC-MS (ES): m/z 562 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:33])([O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:31](=[O:32])[NH:30][CH:29]=[N:28]2)=[CH:23][CH:22]=1)[CH:17]([F:19])[F:18]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:30]1[CH:29]=[N:28][N:27]([C:24]2[CH:25]=[CH:26][C:21]([O:20][C:16]([F:33])([F:15])[CH:17]([F:19])[F:18])=[CH:22][CH:23]=2)[C:31]1=[O:32])[CH3:13]
Reactant: O=c1[nH]cnn1-c1ccc(OC(F)(F)C(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1cnn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 57 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.15 g of (1S)-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.27 g of 2-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 1.20 g of 4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-2-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-3(2H,4H)-1,2,4-triazolone was obtained as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[N:15]=[C:5]2[C:6]([N:10]3[CH2:13][CH:12]([OH:14])[CH2:11]3)=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1.N1CC(O)C1.Cl[C:22]1[CH:30]=[C:29]2[C:25]([C:26]([CH3:33])([CH3:32])[C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1>>[OH:14][CH:12]1[CH2:11][N:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][C:22]4[CH:30]=[C:29]5[C:25]([C:26]([CH3:33])([CH3:32])[C:27](=[O:31])[NH:28]5)=[CH:24][CH:23]=4)[N:15]=3)[CH:9]=[CH:8][N:7]=2)[CH2:13]1
Reactant: CC1(C)C(=O)Nc2cc(Cl)ccc21
Reactant: Nc1nc2c(N3CC(O)C3)nccn2n1
Agent: OC1CNC1
Product: CC1(C)C(=O)Nc2cc(Nc3nc4c(N5CC(O)C5)nccn4n3)ccc21

Procedure:
1-(2-Amino-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-azetidin-3-ol, available by nucleophilic substitution of 8-chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine with azetidin-3-ol using general procedure 3, is reacted under amination conditions described in general procedure 2 with 6-chloro-3,3-dimethyl-1,3-dihydro-indol-2-one giving the title compound as a solid.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:7]([NH:9][CH2:10][C:11]([O:13]CC1C=CC=CC=1)=[O:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]>CO.[Pd]>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)O

Procedure:
The 64 g BocAsnGlyOBzl from above is dissolved in 500 ml MeOH and hydrogenated for 20 hours with 5 g 10% Pd-C as catalyst. The catalyst is removed by filtration and the solvent removed to give BocAsnGlyOH. This is dissolved in 200 ml DMF cooled to -20° C. and then activated with 20 g HoSu and 35 g DCC for 2 hours. 59 g BocGlyValOBzl is deBoced in HCl-EtAc, the HCl-EtAc removed by evaporation and the resulting oil taken up in 100 ml DMF and neutralized with 24 ml TEA. This is then added to the preactivated BocAsnGlyOSu. The mixture is stirred overnight, DCU removed by filtration and the DMF removed by evaporation. The residue is taken up in EtAc washed with sat. Nacl, sat. NaHCO3, and 10% citric acid. After drying the EtAc with MgSO4, it is removed by evaporation to give a powder, which is dried in a desiccator. Yield: 60 g (70%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[SH:11].CS[C:14](SC)=[C:15]([C:18]1[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=1)[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C1C=CN=CC=1.C(O)C.C(Cl)Cl>[C:6]([C:5]1[CH:9]=[CH:10][C:2]2[NH:1][C:14](=[C:15]([C:18]3[N:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:20][N:19]=3)[C:16]#[N:17])[S:11][C:3]=2[CH:4]=1)([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1S
Reactant: CSC(SC)=C(C#N)c1nccc(C(F)(F)F)n1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: N#CC(=C1Nc2ccc(C(=O)O)cc2S1)c1nccc(C(F)(F)F)n1
Temperature: 160 °C
Yield: 44.5 %

Procedure:
A mixture of 4-amino-3-mercaptobenzoic acid (768 mg, 4.5 mmol), 3,3-bis(methylthio)-2-(4-trifluoromethylpyrimidin-2-yl)acrylonitrile (1.45 g, 5.0 mmol, 1.1 eq.), 4-dimethylaminopyridine (550 mg, 4.5 mmol, 1 eq.), and potassium carbonate (622 mg, 4.5 mmol, 1 eq.) in ethanol (20 mL) was heated at 160° C. for 0.4 hr in a microwave. The mixture was cooled to room temperature, diluted with DCM, and washed with 1M hydrochloric acid. The DCM fraction was decanted, filtered, and concentrated under vacuum to give 2-[6-carboxybenzothiazol-2(3H)-ylidene]-2-(4-trifluoromethyl-pyrimidin-2-yl)acetonitrile (729 mg, 40% yield) as a brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]3[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:27]([NH:31][S:32]([C:35]1[S:36][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:39]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[S:36][C:37]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]4[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:38][CH:39]=1)(=[O:33])=[O:34])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2ccnc(Cl)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)ccn2)s1

Procedure:
5-{4-[4-Difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic-acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.7) (0.39 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example C.1) (0.414 g, 1.2 mmol) according to the general procedure III. Obtained as an off-white solid (0.36 g), which was subsequently deprotected.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH:42]([NH2:52])[CH2:43][CH2:44][CH2:45][C:46]2[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=2)[CH:34]=1>O1CCCC1>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:52][CH:42]([CH2:41][CH2:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)[CH2:43][CH2:44][CH2:45][C:46]2[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=2)=[O:10])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Reactant: NC(CCCc1cccnc1)CCCc1cccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NC(CCCc2cccnc2)CCCc2cccnc2)c2ccc(OC)cc2)cc1
Yield: 77.3 %

Procedure:
As before in Example 134, a solution of (E)-5,5-bis(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.94 g) and alpha-[3-(3-pyridinyl)propyl]-3-pyridinebutanamine (1.21 g) in tetrahydrofuran (25 mL) was stirred for 20 hours at 50° C. and then was worked up in the normal manner. The crude was purified by HPLC (ethyl acetate-triethylamine; 19:1) and was then lyophilized from benzene to give 1.95 g of (E)-5,5-bis(4-methoxyphenyl)-N-[1-[3-(3-pyridinyl)propyl]-4-(3-pyridinyl)butyl]-2,4-pentadienamide as a glass.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.O>CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[C:18]([N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)NCCCCNc1cc(F)ccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCNc1cc(-n2ccnc2)ccc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
1,4-Diaminobutane (4.19 g) was dissolved in tetrahydrofuran (THF: 300 ml) to which, at -10° C., was subsequently added dropwise 2,4-difluoronitrobenzene (3.00 g) dissolved in THF (100 ml). The reaction solution was warmed up to room temperature, stirred for 3 hours and then mixed with di-tert-butyl dicarbonate (8.22 g). The reaction solution was further stirred overnight, the thus formed insoluble matter was separated by filtration, the resulting filtrate was concentrated, and a mixed solution (150 ml) of n-hexane:ethyl acetate=1:2 was added to the residue. The thus formed insoluble matter was again separated by filtration and then the filtrate was concentrated under a reduced pressure. The resulting yellow solid was purified by a silica gel column chromatography (n-hexane:ethyl acetate=1:2) to give N-(4-tert-butoxycarbonylaminobutyl)-5-fluoro-2-nitroaniline (4.67 g). The resulting aniline compound (3.20 g) and imidazole (4.00 g) were dissolved in DMSO (50 ml). The solution was stirred at 150° C. for 4 hours, spontaneously cooled down to room temperature and, after addition of water (500 ml), extracted with ethyl acetate and then washed with water. The organic layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting solid substance was washed with water and dried under a reduced pressure to give N-(4-tert-butoxycarbonylaminobutyl)-5-(1H-imidazol-1-yl)-2-nitroaniline (3.13 g). In an atmosphere of hydrogen, the thus formed product (3.00 g) was subjected to 4 hours of reduction in ethanol under ordinary pressure, using palladium-carbon as the catalyst. The reaction solution was filtered and concentrated under a reduced pressure. Then, oxalic acid (2.16 g) and 4 N hydrochloric acid (40 ml) were added to the residue, followed by heating under reflux for 8 hours. The reaction solution was filtered, and the resulting filtrate was concentrated to about half of the volume. The thus precipitated crystals were collected by filtration and dried under a reduced pressure to give 1-(4-aminobutyl)-7-(1H-imidazol-1-yl)-2,3(1H,4H)-quinoxalinedione dihydrochloride (2.87 g).