Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=3)[CH:18]2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][C:7]=1[CH3:8].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[ClH:50].[N:51]1([CH2:57][C:58](O)=[O:59])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1.C(N(CC)CC)C>>[ClH:50].[ClH:50].[CH3:1][C:2]1[C:3]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27][C:58](=[O:59])[CH2:57][N:51]4[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]4)[CH:23]=3)[CH:18]2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][C:7]=1[CH3:8]
Reactant: O=C(O)CN1CCCCC1
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3cc(O)ccc3C2C)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3cc(OC(=O)CN4CCCCC4)ccc3C2C)c1C

Procedure:
The same procudures as in Example 167 were repeated using 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50 mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol), 1-piperidineacetic acid hydrochloride (28.5 mg, 0.158 mmol), and triethylamine(46 μl, 0.330 mmol) to afford the titled compound.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C@@H:7]([CH3:29])[CH2:8][O:9]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:3]1.Cl>>[F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C@@H:7]([CH3:29])[CH2:8][OH:9])[CH2:3]1
Reactant: C[C@@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)N1CC[C@@H](F)C1
Agent: Cl
Product: C[C@@H](CO)N1CC[C@@H](F)C1

Procedure:
(R)-3-Fluoro-1-((S)-1-(trityloxy)propan-2-yl)pyrrolidine (732 mg, 1.87 mmol) and HCl (2N in Et20, 1.4 mL, 2.8 mmol) were stirred at room temperature for 5 h. The solvent was decanted off, and the solid was dissolved in DCM (30 mL). The solution was washed (sat'd K2CO3), dried (Na2SO4), and concentrated under reduced pressure. The crude material was purified on a silica gel column to yield (S)-2-(R)-3-fluoropyrrolidin-1-yl)propan-1-ol (115 mg) as a clear oil. 1H NMR (DMSO-d6): δ 5.26-5.00 (m, 1H), 4.42 (t, 1H), 3.50 (m, 1H), 3.22 (m, 1H), 2.90-2.65 (m, 3H), 2.45-2.20 (m, 2H), 2.15-1.75 (m, 2H), 1.00 (d, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]2[S:19][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:21][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:33])C(=O)C1>C(Cl)Cl>[Br:33][C:12]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]2[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[S:19][C:10]=2[C:11]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)cn2C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(Br)n2C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution (0.1 M) of methyl 4-(tert-butoxycarbonyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in DCM was cooled to 0° C. and treated with NBS (1.1 eq.) then it was left to warm to RT. The reaction was quenched with aqueous Na2S2O3 (saturated solution) and extracted with AcOEt. The organic phase was washed with aqueous Na2S2O3 (saturated solution) and brine then dried and concentrated, affording the title compound (98%) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[CH:15]=[C:16]([C:22]([CH3:24])=O)[C:17]([O:19]CC)=[O:18])C>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:22]([CH3:24])=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=[N:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Reactant: NNc1ccc([N+](=O)[O-])cc1
Product: Cc1c(C(=O)O)cnn1-c1ccc([N+](=O)[O-])cc1

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 1 using 4-nitrophenylhydrazine and ethyl 2-ethoxymethyleneacetoacetate, the title compound was obtained, melting point: 202° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH2:14][C:15]1[CH:32]=[CH:31][C:18]2[NH:19][C:20]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([O-])=[O:27])=[CH:24][CH:23]=3)=[N:21][C:17]=2[CH:16]=1>>[NH2:14][C:15]1[CH:32]=[CH:31][C:18]2[NH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[O:27])=[CH:29][CH:30]=3)=[N:21][C:17]=2[CH:16]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Nc1ccc2[nH]c(-c3ccc(C(=O)[O-])cc3)nc2c1
Product: Nc1ccc2[nH]c(-c3ccc(C(=O)Nc4ccc(N5CCOCC5)cc4)cc3)nc2c1

Procedure:
Compound 453 was prepared from 4-morpholinoaniline and 4-(5-amino-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C24H23N5O2: 414.19; found: 413.97.
Reaction SMILES: [F:1][C:2]([F:33])([C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH2:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][CH2:9][C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].[CH2:34]=O.Cl>C(O)=O>[F:1][C:2]([F:33])([C:23]([F:31])([F:32])[C:24]([F:29])([F:30])[C:25]([F:26])([F:27])[F:28])[CH2:3][CH2:4][CH2:5][N:6]([CH2:7][CH2:8][CH2:9][C:10]([F:21])([F:22])[C:11]([F:19])([F:20])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH3:34]
Reactant: C=O
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCNCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: O=CO
Product: CN(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 90 °C
Yield: 88 %

Procedure:
A solution of bis(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)amine (3.0 g) and formic acid (90%, 1.5 g) was cooled in an ice-water bath and 8 ml of formaldehyde (37% weight) was added. The solution was slowly heated to 90° C. and maintained overnight. (Foaming and gas evolution at 60-75° C.) Concentrated hydrochloric acid (1 ml) was added and 7 ml of solution were removed by distillation. The remaining solution was cooled and treated with KOH (aq. 10%) to pH 11. The mixture was extracted with methylene chloride (3×50 ml). The combined methylene chloride extracts were washed with water (2×50 ml), dried over sodium sulfate, and concentrated on vacuum to give a residue. Distillation of the residue at reduced pressure gave 2.7 g of bis(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)methylamine, yield 88%. 19F NMR (CDCl3) -81.7 (m, 6F), -115.1 (m, 4F), -125.1 (m, 4F), -126.6 (m, 4F) ppm. 1H NMR (CDCl3) 2.40 (t, J=6 Hz, 4H), 2.19 (s, 3H), 2.16 (m, 4H), 1.76 (m, 4H) ppm. 13C NMR (CDCl3) 18.4, 28.7 (t, J=23 Hz), 41.3, 56.5, 108-123 (m) ppm. MS (m/e) 532 (M+ -F, 7.5%), 382 (1.0%), 304 (100%), 195 (0.6%), 169 (0.8%), 119 (2.5%), 69 (9.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH2:18][CH2:19][OH:20])[CH:17]=2)=O)=[C:4]([CH3:32])[CH:3]=1.Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH2:18][CH2:19][OH:20])[CH:17]=2)=[N:34]\[OH:35])=[C:4]([CH3:32])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(CCO)c1)c1ccc(S(C)(=O)=O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(CCO)c1)c1ccc(S(C)(=O)=O)cc1

Procedure:
In analogy to example 151, step 3, 5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)-1-(2-hydroxyethyl)pyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as an off-white solid, MS (ESI+): m/z=489.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=1)([O-])=O>CO.[Pd]>[F:15][C:12]([F:13])([F:14])[CH:11]([CH3:16])[O:10][C:7]1[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: CC(Oc1ccc([N+](=O)[O-])cn1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CC(Oc1ccc(N)cn1)C(F)(F)F
Yield: 98.1 %

Procedure:
(rac)-5-Nitro-2-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine (2.23 g) in methanol (30 ml) was hydrogenated over Pd/C (10%, 500 mg) at RT and at atmospheric pressure for 12 h. The catalyst was filtered off and the solvent removed in vacuo to give the desired (rac)-6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-3-ylamine (1.91 g) as a brown oil. MS (ESI): 270.0 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[N:8]=[N:7][C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]2[NH:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[F:28].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:81][N:82]1[CH2:87][CH2:86][NH:85][CH2:84][CH2:83]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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(N(C)C)=O>[CH2:13]([O:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5]([NH:20][C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[F:28])=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:7]=[N:8]2)=[CH:3][C:2]=1[N:85]1[CH2:86][CH2:87][N:82]([CH3:81])[CH2:83][CH2:84]1)[CH3:14]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1nnc2cc(OCC)c(Br)cc2c1Nc1cc(C)ccc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1nnc2cc(OCC)c(N3CCN(C)CC3)cc2c1Nc1cc(C)ccc1F
Temperature: 90 °C
Yield: 31.7 %

Procedure:
To a 50 mL round bottom flask charged with a magnetic stir bar and ethyl 6-bromo-7-ethoxy-4-[(2-fluoro-5-methylphenyl)amino]cinnoline-3-carboxylate (0.100 g, 0.223 mmol) (Method 28) was added 2.5 mL of anhydrous dimethylacetamide. Pd2(dba)3 (50 mg, 0.55 mmol), racemic BINAP (70 mg, 0.11 mmol), cesium carbonate (150 mg, 0.45 mmol), and 1-methylpiperazine (0.334 mmol) were added to the reaction. The mixture was heated to 90° C. for 4 h before being cooled to rt and filtered though a pad of diatomaceous earth. The filtrate was concentrated in vacuo giving the crude product which was purified on 12 g silica using EtOAc/MeOH (4:1) as eluent yielding 0.033 g (32%) of the title compound as a yellow solid. m/z 468.
Reaction SMILES: [Na+].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O-:10])=[O:9].Br[C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH:17]=[O:18]>CS(C)=O>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH:17]=[O:18])(=[O:10])=[O:9]
Reactant: O=Cc1sccc1Br
Reactant: O=S([O-])c1ccccn1
Agent: [Na+]
Solvent: CS(C)=O
Product: O=Cc1sccc1S(=O)(=O)c1ccccn1
Temperature: 125 °C
Yield: 6.4 %

Procedure:
A mixture of pyridine-2-sulfinate sodium salt (8.5 g), 3-bromothiophene-2-carbaldehyde (6.5 g) and dimethyl sulfoxide (50 mL) (split equally into four microwave vials) was heated by microwave irradiation at 125° C. for 45 minutes. The combined mixtures were diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 0:1 by volume) to afford the title compound as a yellow solid (0.55 g).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[I:7][C:8]1[N:15]2[C:11]([S:12][C:13]([S:16][CH3:17])=[N:14]2)=[N:10][CH:9]=1>CO.O>[I:7][C:8]1[N:15]2[C:11]([S:12][C:13]([S:16]([CH3:17])=[O:1])=[N:14]2)=[N:10][CH:9]=1
Reactant: CSc1nn2c(I)cnc2s1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)c1nn2c(I)cnc2s1
Reaction time: 1 h

Procedure:
Oxone(r), monopersulfate compound (263.99 mg; 0.43 mmol; 1.00 eq.) was added to a solution of 5-iodo-2-methylsulfanyl-imidazo[2,1-b][1,3,4]thiadiazole (127.60 mg; 0.43 mmol; 1.00 eq.) in MeOH (1.50 ml) and water (1.50 ml) at room temperature. After 1 h, the reaction was finished. Water was added and the reaction was extracted 2 times with dichloromethane. The combined organic extracts were dried over magnesium sulphate, filtered and concentrated to give 106.9 mg of the desired product as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:11])[C:9]#[CH:10])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C.O>C1COCC1.CN(C=O)C>[C:12]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:11])[C:9]#[CH:10])=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: C#CC(O)c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: C#CC(O)c1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-Amino-phenyl)-2-propyn-1-ol (3.0 mmol) (from Step A above) was dissolved in dry THF (20 mL) and DMF (1 mL). Acetic anhydride (4.2 mmol) was added dropwise followed by triethylamine (3.0 mmol). The reaction was stirred at room temperature for 2 h, after which time water (30 mL) was added, and the THF was evaporated in vacuo. The aqueous layer was extracted with ethyl acetate (3×50 mL), and the combined organic layers were dried over magnesium sulfate and concentrated. The resulting product, 3-(4-acetamidophenyl)-3-hydroxy-1-propyne, was purified via flash column chromatography (SiO2, 230-400 mesh) with ethyl acetate/hexane.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:16]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O[C@H]1CC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reaction time: 8 h

Procedure:
Trans-4-aminocyclohexanol (2.6 g, 22.6 mmol) was suspended in 60 mL DCM, then 4 mL (28.7 mmol) triethylamine was added. The mixture was cooled in ice bath, and trityl chloride (6.3 g, 22.6 mmol) was added. The mixture was stirred overnight, allowing it to slowly warm up. Saturated NaHCO3 was added to quench the chloride, and product was extracted with EtOAc three times. The combined organic layer was washed with brine, and dried over Na2SO4. Column chromatography with 20-40% EtOAc in hexanes provided 5.3 g (66%) white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:19][S:20]([C:23]2[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:26]([OH:33])=[C:25]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:24]=2)(=[O:22])=[O:21])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N+:38]([O-])=O.[CH:41](O)=O>[Pd]>[NH:1]1[C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:19][S:20]([C:23]3[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:26]([OH:33])=[C:25]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:24]=3)(=[O:22])=[O:21])[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]3)=[O:11])=[CH:4][C:3]=2[N:38]=[CH:41]1
Reactant: O=CO
Reactant: CC1CCN(C(=O)C(Cc2ccc(N)c([N+](=O)[O-])c2)NS(=O)(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CC1
Agent: [Pd]
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CC1

Procedure:
Prepared from N-[1-((4-amino-3-nitro-phenyl)-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethyl]-3,5-di-tert.butyl-4-hydroxy-benzenesulphonamide and cyclising with formic acid in the presence of palladium/charcoal analogously to Example 1.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:28]=[C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)[S:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[CH:48]=[N:47][CH:46]=[C:45]2[NH:49][CH:50]=[CH:51][C:44]=12>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:41][C:36]([N:33]1[CH2:34][CH2:35][N:30]([CH2:29][C:27]2[S:26][C:9]3[N:10]=[C:11]([C:43]4[CH:48]=[N:47][CH:46]=[C:45]5[NH:49][CH:50]=[CH:51][C:44]=45)[N:12]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:8]=3[N:28]=2)[CH2:31][CH2:32]1)([CH3:40])[C:37]([NH2:39])=[O:38]
Reactant: Brc1cncc2[nH]ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C(N)=O)CC3)sc2n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4cncc5[nH]ccc45)nc3s2)CC1
Temperature: 140 °C
Yield: 9.6 %

Procedure:
A mixture of 2-[4-(7-morpholin-4-yl-5-(tributylstannanyl)thiazolo[5,4-d]pyrimidin-2-ylmethyl)piperazin-1-yl]isobutyramide (167 mg, 0.24 mmol), 4-bromo-1H-pyrrolo[2,3-c]pyridine (62 mg, 0.31 mmol), tetrakis(triphenylphosphine)palladium (28 mg, 10 mol %) and CuI (55 mg, 0.28 mmol) in dioxane (2.5 mL) was purged with argon gas then heated at 140° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH/DCM. The resulting residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 15:85) to give 131 as an pale yellow solid (12 mg, 10%). LCMS (Method F): RT 4.70 min, [M+H]+ 522.2. 1H NMR (DMSO, 400 MHz): δ 11.94 (s, 1H); 9.10 (s, 1 H); 8.88 (s, 1 H); 7.82 (s, 1 H); 7.35 (s, 1 H); 7.15 (s, 1 H); 7.04 (s, 1 H); 4.37 (s, 4 H); 3.95 (s, 2 H); 3.82 (t, J=4.6 Hz, 4 H); 2.68 (s, 4 H); 2.56 (s, 4 H); 1.13 (s, 6H)
Reaction SMILES: [CH3:1][O:2][Si:3](OC)(OC)[O:4][CH3:5].[CH2:10]([Si:13]([CH2:22][CH:23]=[CH2:24])([CH2:19][CH:20]=[CH2:21])[CH2:14][CH2:15][CH2:16][Mg]Br)[CH:11]=[CH2:12]>C(OCC)C>[CH2:19]([Si:13]([CH2:10][CH:11]=[CH2:12])([CH2:14][CH:15]=[CH2:16])[CH2:22][CH2:23][CH2:24][SiH:3]([O:4][CH3:5])[O:2][CH3:1])[CH:20]=[CH2:21]
Reactant: C=CC[Si](CC=C)(CC=C)CCC[Mg]Br
Reactant: CO[Si](OC)(OC)OC
Solvent: CCOCC
Product: C=CC[Si](CC=C)(CC=C)CCC[SiH](OC)OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 67 %

Procedure:
Under a nitrogen atmosphere, tetramethoxysilane (5) (0.482 ml, 3.268 mmol) was cooled down to 0° C., then diethyl ether solution of 10 ml (7.2 mmol) of 0.72M 3-(triallylsilyl)propylmagnesium bromide (24) was added dropwise, then stirred at room temperature for 15 hours. The reacted mixture was cooled down to 0° C., quenched with water, then saturated ammonium chloride aqueous solution was added until the salt was completely dissolved. The obtained organic layer was separated, and the obtained water layer was extracted with diethyl ether, the collected organic layer was each washed with saturated sodium bicarbonate aqueous solution and saturated saline solution in this order, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, obtaining a crude product. The crude product was purified through short silica gel column chromatography (eluent: hexane/ethyl acetate=20/1), obtaining bis {(3-(triallylsilyl)propyl}dimethoxysilane (29′) represented by the following chemical reaction equation (yield: 1.04 g, yield (%): 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH:12]([CH3:16])[CH2:13][C:14]#[N:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.B>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH:12]([CH3:16])[CH2:13][CH2:14][NH2:15])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(CC#N)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: B
Solvent: C1CCOC1
Product: CC(CCN)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 83.9 %

Procedure:
To a solution of (3RS, 4RS)-4-(4-chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methylbutyronitrile (2 g, 5.42 mmol) in THF (30 ml) was added borane (1M solution in THF, 6.5 ml, 6.5 mmol) and the mixture was heated at 50° C. for 20 hours. The mixture was cooled to room temperature and quenched with methanol (50 ml) and HCl (2M, 5 ml), then heated at reflux for one hour. The cooled reaction mixture was concentrated in vacuo and purified by flash chromatography eluting with 2% to 10% methanol in dichloromethane, to give as a mixture of diastereoisomers (3RS, 4RS)-4-(4-chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methylbutylamine as a white solid (1.7 g, 84%).
Reaction SMILES: [F-].[NH4+].C([Si](C)(C)[O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]([CH3:17])=[N:15][CH:14]=[N:13]1)(C)(C)C>CO>[CH3:17][C:16]1[N:12]([CH2:11][CH2:10][CH2:9][OH:8])[N:13]=[CH:14][N:15]=1
Reactant: Cc1ncnn1CCCO[Si](C)(C)C(C)(C)C
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ncnn1CCCO
Yield: 92.3 %

Procedure:
To a solution of ammonium fluoride (10.4 g, 280 mmol) in methanol (110 ml) was added a solution of 3-(tertbutyldimethylsilyloxy)-1-(5-methyl-[1,2,4]-triazol-1-yl)propane (7.2 g, 28 mmol) in methanol (30 ml). The mixture was refluxed for 4.5 hours. After cooling, silica (100 g) was added and the volatiles were removed under vacuum. The residue was added onto a column of silica and eluted with a mixture of methylene chloride/ethyl acetate (1/1) followed by methylene chloride/methanol (9/1) to give 3-(5-methyl-[1,2,4]-triazol-1-yl)propan-1-ol (3.65 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CCOC(=O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (1.5 g, 4.27 mmol) and ethyl 2-aminoacetate (696 mg, 5.12 mmol). The title compound was obtained as a solid (1.1 g, 59% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.36 (1H, t), 8.98 (2H, s), 8.47 (1H, s), 4.11 (2H, q), 3.97 (2H, s), 1.19 (3H, t). MS m/z: 434.08, 436.06 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.Cl>>[N:24]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:13]=[CH:14]/[C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNC1
Reactant: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2s1
Agent: Cl
Product: C(=C/c1ccccc1OCCCCN1CCCC1)\c1nc2ccccc2s1
Yield: 33 %

Procedure:
The title compound was prepared in accordance with Example 38 starting with (H) of Example 38 (3.0 g, 8.7 mmol) and using pyrrolidine in place of dipropylamine to produce 1.1 g (33% yield) of the title compound as the HCl salt, mp 220°-222° C. IR(KBr): 3410, 1600 cm-1. MS: 379(MH+). 1H NMR (CD3OD): δ 8.02-6.91 (m, 10H), 4.12 (t, J=5.2 Hz, 2H), 3.23 (m, 6H), 2.54 (m, 4H), 2.21 (m, 4H).