Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([SH:12])[CH:6]=[CH:5]2.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:23])([F:25])[F:24])[CH:15]=1)[CH:6]=[CH:5]2
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: Sc1ccc2cc(Br)ccc2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Sc2ccc3cc(Br)ccc3c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-bromonaphthalene-2-thiol (956 mg) and 4-fluoro-2-trifluoromethyl benzonitrile (756 mg) in dimethylformamide (15 ml), at ambient temperature, was treated dropwise with triethylamine (504 mg). After stirring at ambient temperature for 3 hours the reaction mixture was diluted with ethyl acetate (100 ml), washed with water (3×25 ml) and brine (25 ml), dried (MgSO4) and evaporated to give a yellow oil. Crystallisation from methanol (20 ml) gave 4-(6-bromonaphth-2-ylthio)-2-trifluoromethylbenzonitrile (1.176 g, mp 114-116° C.;
Reaction SMILES: [P:1]([O-:16])([O-:15])([O:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:14])[C:11]=2[Cl:13])[NH:6][CH:5]=1)=[O:2].[Na][Na]>CO.C(=O)([O-])[O-]>[CH:8]1[C:7]2[NH:6][CH:5]=[C:4]([O:3][P:1]([OH:15])([OH:16])=[O:2])[C:12]=2[C:11]([Cl:13])=[C:10]([Br:14])[CH:9]=1
Reactant: O=P([O-])([O-])Oc1c[nH]c2ccc(Br)c(Cl)c12
Agent: O=C([O-])[O-]
Agent: [Na][Na]
Solvent: CO
Product: O=P(O)(O)Oc1c[nH]c2ccc(Br)c(Cl)c12

Procedure:
0.100 g 5-bromo,4-chloro,3-indolyl phosphate, disodium salt dissolved in 0.5M methanol, diluted to 1 ml in carbonate buffer.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](CN4CCOCC4)=[CH:20][CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1[C:48]([NH2:49])=[C:47]([NH:50][C@@H:51]2[C@@H:56]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.C(OC(N1CCN(C2C=CC(C=O)=CC=2)CC1)=O)(C)(C)C.C(=O)(OC(C)(C)C)N.Cl>O1CCOCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([N:49]4[CH2:48][CH2:47][NH:50][CH2:51][CH2:56]4)=[CH:22][CH:23]=3)[NH:15][C:12]2=[N:13][CH:14]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: CC(C)(C)OC(N)=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(N5CCNCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 43 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4-(4-Formyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester were reacted to produce an initial tert-butyl carbamate condensation product. This material was treated with 4N hydrochloric acid in dioxane at 40° C. overnight. Concentration followed by reverse phase chromatography on a Gilson chromatograph afforded fractions which were lyophilized to afford the title compound (43%). 1H NMR (d6-DMSO): 13.19 (br s, 1H), 8.77 (m, 2H), 8.04 (s, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.13-7.45 (m, 4H), 6.38 (m, 2H), 5.17 (t, J=8 Hz, 1H), 3.49 (m, 4H), 3.26 (m, 4H), 2.91 (s, 1H), 2.80 (s, 1H), 2.62 (d, J=8 Hz, 1H), 2.23 (d, J=9 Hz, 1H), 1.40 (d, J=9 Hz, 1H). MS: 465.09 (M+H). HPLC retention time: 1.79 minutes (G Method).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20]C)=[C:15]([O:18]C)[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.B(Br)(Br)[Br:25]>C(Cl)Cl>[BrH:25].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:20])=[C:15]([OH:18])[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:22][CH:23]=1
Reactant: COc1cc2c(cc1OC)C(COc1ccc(Cl)cc1)NCC2
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Br
Product: Oc1cc2c(cc1O)C(COc1ccc(Cl)cc1)NCC2
Reaction time: 17.5 h
Yield: 73.9 %

Procedure:
To a solution of 1-(4-chlorophenoxy)methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (90 mg) in anhydrous methylene chloride (5 ml) was added boron tribromide (203 mg) at -55°C under cooling and stirring, and then the reaction temperature was gradually elevated to at 5°C over 17.5 hours. After the reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml) and water (0.5 ml), and the solution was warmed at 60° to 80°C for 10 minutes and then the solution was concentrated. The amorphous residue was dissolved in acetone, and to the solution was added ether, and the mixture was allowed to stand. The precipitated crystals were collected by filtration and dried to give 1-(4-chlorophenoxy)methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (77 mg), mp 232° to 233°C. The product was identified with a sample by I.R. spectrum and N.M.R. spectrum.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18](O)[CH2:19][Si](C)(C)C)=[C:12]([Br:25])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]=[CH2:19])=[C:12]([Br:25])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CC(O)CCc1ccc(S(=O)(=O)c2ccccc2)cc1Br
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCCc1ccc(S(=O)(=O)c2ccccc2)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 4-(4-benzenesulfonyl-2-bromo-phenyl)-1-trimethylsilanyl-butan-2-ol (4.38 g) in DCM (80 mL) was added BF3.OEt2 (3.76 mL) at 0° C. under N2 atmosphere. The reaction was stirred at 0° C. for 1 h it was then quenched by addition of NaHCO3 (saturated solution). The mixture was extracted twice with DCM and the combined extracts were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (hexane/EtOAc, 9/1) to afford 4-benzenesulfonyl-2-bromo-1-but-3-enyl-benzene (3.38 g, 93% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]1[C:15]([O:18][CH3:19])=[N:16][N:17]=[C:10]1[C:9](Cl)=[N:8]2)=[O:4].[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH2:29])=[CH:23][CH:22]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]1[C:15]([O:18][CH3:19])=[N:16][N:17]=[C:10]1[C:9]([NH:29][CH2:28][CH2:27][C:24]1[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=1)=[N:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)nc(Cl)c1nnc(OC)n12
Reactant: NCCc1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)nc(NCCc1ccncc1)c1nnc(OC)n12
Temperature: 50 °C
Reaction time: 15 h

Procedure:
A mixture of 4-chloro-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid methyl ester (80 mg), 2-(4-pyridyl)ethylamine (50 mg), and sodium bicarbonate (45 mg) in DMF (2 mL) was stirred at 50° C. for 15 hrs. The mixture was cooled to 23° C., and then diluted with water and EtOAc. A precipitate formed which was isolated by filtration to afford 1-methoxy-4-(2-pyridin-4-ylethylamino)-[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid methyl ester. MS (M+H)+=379.3.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([N:8]=[C:9]=[O:10])[CH2:3]1.Cl.Cl.[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([N:21]2[C:25](=[O:26])[C:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][NH:22]2)[CH:16]=1.C(N(C(C)C)CC)(C)C>ClCCCl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([N:21]3[C:25](=[O:26])[C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:23][NH:22]3)[CH:16]=2)=[O:10])[CH2:3]1
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Reactant: CC1CCCC(N=C=O)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC1CCCC(NC(=O)NCc2ccnc(-n3[nH]cc(-c4cccnc4)c3=O)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
13.9 mg (100 μmol) of 3-methylcyclohexyl isocyanate are initially charged, 34.0 mg (100 mol) of the compound from Example 4A, dissolved in 0.6 ml of 1,2-dichloroethane, and 25.8 mg (200 μmol) of diisopropylethylamine are added and the mixture is stirred at RT overnight. The mixture is then concentrated, the residue is taken up in DMSO, the precipitate is filtered off and the filtrate is purified by preparative HPLC (Method 3).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([NH2:21])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: [BH3-]C#N
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 50 °C
Yield: 61.5 %

Procedure:
7-Nitro-3,4-dihydro-2(1H)-naphthalenone (200 mg, 1.1 mmol) was combined with ammonium acetate (807 mg, 10.5 mmol), sodium cyanoborohydride (86 mg, 1.4 mmol) and MeOH (5 mL) and heated to 50° C. for 15 h. The reaction was cooled and concentrated under vacuum and the residue was partitioned between EtOAc and water. The organic layer was washed with 5% aqueous K2CO3, brine and dried over Na2SO4. The crude was concentrated under vacuum and purified by silica gel flash column chromatography (0-100% (90% DCM/9% MeOH/1% NH4OH)/DCM). Purification provided 130 mg (65%) of the desired amine as a brown oil. 1H NMR (400 MHz, DMSO-d6) δ 7.90-7.89 (m, 2H), 7.31 (d, J=8.5 Hz, 1H), 3.06-2.88 (m, 3H), 2.84-2.72 (m, 1H), 2.54-2.44 (m, 2H), 1.81 (d, J=35.2 Hz, 2H), 1.51-1.42 (m, 1H).
Reaction SMILES: [CH:1]1[N:10]([C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:9]2[C:3](=[C:4]([NH2:20])[NH:5][C:6]([N:8]=2)=[S:7])[N:2]=1.[OH-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29]>>[OH2:15].[CH2:29]([S:7][C:6]1[N:5]=[C:4]([NH2:20])[C:3]2[N:2]=[CH:1][N:10]([C:9]=2[N:8]=1)[C@@H:11]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]1[OH:19])[CH2:28][CH2:27][CH2:26][CH:25]=[CH2:24].[CH2:29]([S:7][C:6]1[N:5]=[C:4]([NH2:20])[C:3]2[N:2]=[CH:1][N:10]([C:9]=2[N:8]=1)[C@@H:11]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]1[OH:19])[CH2:28][CH2:27][CH2:26][CH:25]=[CH2:24]
Reactant: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C=CCCCCBr
Agent: [Na+]
Agent: [OH-]
Product: C=CCCCCSc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Product: O
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
2-Thioadenosine (0.2 g, 0.67 mmol) was dissolved in 0.25M NaOH (8 ml, 2 mmol). 6-Bromo-1-hexene (0.45 ml, 3.3 mmol) was added, and the solution was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure (bath temp. 33° C.) and extracted with ether (2×2 ml). The aqueous phase was neutralized with 18% HCl and extracted with ethyl acetate (3×4 ml). The homogeneous product was obtained after drying and solvent removal as a yellowish solid (0.14 g, 55% yield, mp 94° C., trituration with ether). 1H NMR (CD3OD)d: 8.16 (s, 1H, H-8), 5.91 (d, J=5.8 Hz, 1H, H-1'), 5.8 (dm, 1H, olefinic), 4.93 (ddd, J=11, 9.7, 1 Hz, 2H, olefinic), 4.72 (`t`, 1H, J=5 Hz H-2'), 4.31 (m, 1H, H-3'), 4.11 (m, 1H, H-4'), 3.83 (m, 2H, H-5'), 3.16 (m, 2H, CH2S), 2.10 (m, 2H, CH2), 1.74 (m, 2H, CH2), 1.56 (m, 2H, CH2) ppm. Anal. calc. for C16H23N5O4S.0.5H2O: C, 49.22; H, 6.20; N, 17.93. Found: C, 49.46; H, 5.99; N, 17.36.
Reaction SMILES: O[Li:2].O.[NH2:4][C:5]1[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8]>O.CO>[NH2:4][C:5]1[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:6]=1[C:7]([O-:9])=[O:8].[Li+:2]
Reactant: [Li]O
Reactant: COC(=O)c1ccc(Cl)nc1N
Solvent: O
Solvent: CO
Product: Nc1nc(Cl)ccc1C(=O)[O-]
Product: [Li+]
Temperature: 70 °C
Reaction time: 24 h
Yield: 114.3 %

Procedure:
A solution of LiOH.H2O (1.38 g, 33 mmol) in water (33 mL) was added in one portion to a suspension of methyl 2-amino-6-chloronicotinate (6.08 g, 27 mmol) in MeOH (110 mL). The reaction mixture was stirred at 70° C. for 24 hours, and gradually became homogeneous. The solvents were removed under reduced pressure, and after the resulting white solid was dried under vacuum (<1 mmHg) to constant weight, 5.51 g (95%) of lithium 2-amino-6-chloronicotinate was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[S:7][C:8](Br)=[CH:9][CH:10]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[S:7][C:8]([C:26]2[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)s1)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)s1)NC(=O)OC(C)(C)C

Procedure:
Suzuki coupling. To a solution of (S)-3-(5-bromo-thiophen-2-yl)-2-tert-butoxycarbonylamino-propionic acid methyl ester in toluene (10 mL) was added 4-cyanobenzeneboronic acid, Pd(PPh3)4, and 1N Na2CO3 solution (4 mL). The mixture was heated at reflux for 7 h. After completion of the reaction, the aqueous layer was drained. The organic was washed with 10% Na2CO3 and 1 N HCl. The organic was dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The residue was then purified by column chromatography (hexanes-EtOAc) to provide (S)-2-tert-butoxycarbonylamino-3-[5-(4-cyano-phenyl)-thiophen-2-yl]-propionic acid methyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:10][N:9]=1)#[N:2].Br[C:53]1[C:58]([O:59][CH3:60])=[CH:57][CH:56]=[C:55]([C:61]([CH3:63])=[CH2:62])[N:54]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:27]=1[C:53]1[C:58]([O:59][CH3:60])=[CH:57][CH:56]=[C:55]([C:61]([CH3:63])=[CH2:62])[N:54]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[CH:10][N:9]=1)#[N:2]
Reactant: COc1cc(CN(Cc2cc(C#N)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)OC(C)(C)C)cn2)c(B2OC(C)(C)C(C)(C)O2)cc1OC
Reactant: C=C(C)c1ccc(OC)c(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)c1ccc(OC)c(-c2cc(OC)c(OC)cc2CN(Cc2cc(C#N)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)OC(C)(C)C)cn2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
Tert-butyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[4,5-dimethoxy-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (60 mg) is dissolved in 1,4-dioxane (1.5 ml) and thereto are added 2-bromo-6-isopropenyl-3-methoxy-pyridine (38 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (7 mg) and cesium carbonate (55 mg), and the mixture is stirred under nitrogen atmosphere at 80° C. overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated and the organic layer is filtered by NH— silica gel and the mixture is extracted with ethyl acetate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=85:15→70:30) to give tert-butyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(6-isopropenyl-3-methoxy-pyridin-2-yl)-4,5-dimethoxy-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (17 mg). MS (m/z): 734 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[Cl:12][CH2:13][CH2:14][CH2:15]I.[Na+].[Cl-].[CH3:19][N:20]([CH:22]=O)C>O>[Cl:12][CH2:13][CH2:14][CH2:15][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1.[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:13][CH2:14][CH2:22][NH:20][CH3:19]
Reactant: CN(C)C=O
Reactant: COc1cccc(O)c1
Reactant: ClCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CNCCCOc1cccc(OC)c1
Product: COc1cccc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, a solution of 3-methoxyphenol (2.00 g, 16.11 mmol) in DMF (10 mL) was slowly added over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.70 g of an 80% dispersion in mineral oil, 23.33 mmol) in DMF (15 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1 h. To this slurry was added drop-wise over 5 min, 1-chloro-3-iodopropane (3.95 g, 19.32 mmol), and the resulting brown mixture was stirred at ambient temperature for 4 h. Cold water (25 mL) was carefully added, followed by saturated NaCl solution (25 mL). The resulting mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered, concentrated by rotary evaporation to a residue that was dried briefly under high vacuum producing a light-brown oil (3.27 g, quantitative yield).
Reaction SMILES: [C:1]1([S:7]([Cl:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:11]1C=CC=CC=1.C(OC(=O)N[CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:38]3[O:37][CH:36]=[CH:35][C:34]=3[CH:33]=[C:32]([NH2:39])[CH:31]=2)[CH2:26][CH2:25]1)(C)(C)C>C(Cl)Cl>[ClH:10].[NH2:11][CH:28]1[CH2:29][CH2:24][CH2:25][CH2:26][N:27]1[C:30]1[C:38]2[O:37][CH:36]=[CH:35][C:34]=2[CH:33]=[C:32]([NH:39][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(N)cc3ccoc23)CC1
Reactant: c1ccncc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Product: Cl
Product: NC1CCCCN1c1cc(NS(=O)(=O)c2ccccc2)cc2ccoc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzenesulfonyl chloride (64.0 mg, 0.36 mmol) and pyridine (219 μL) were added to tert-butyl[1-(5-amino-1-benzofuran-7-yl)piperidin-4-yl]carbamate (100.0 mg, 0.30 mmol; Intermediate 49) in DCM (1 mL). The mixture was shaken at room temperature for 1 h, solvent was removed in vacuo and the residue was purified by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. N-deprotection and conversion into the hydrochloride salt was performed by treatment with 2 M HCl in ether. This furnished 31.3 mg (28%) of the title product. HPLC 100%, RT: 1.612 (System A; 10-97% MeCN over 3 min). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.69-1.70 (m, 2H) 2.00-2.01 (m, 2H) 2.76 (t, J=11.30 Hz, 2H) 3.18-3.26 (m, 1H) 6.54 (d, J=1.88 Hz, 1H) 6.82 (d, J=2.20 Hz, 1H) 6.86 (d, J=1.88 Hz, 1H) 7.52 (t, J=7.54 Hz, 2H) 7.57-7.68 (m, 1H) 7.71-7.72 (m, 2H) 7.88 (d, J=2.20 Hz, 1H) 8.14 (s, 3H) 10.03 (s, 1H). LC-MS 372 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[OH-].[Na+]>C(O)=O.C(N(CC)CC)C.[C].[Pd]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1
Reactant: c1cnc2[nH]ccc2c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CCN(CC)CC
Product: c1cnc2c(c1)CCN2
Temperature: 70 °C
Reaction time: 17 h
Yield: 60.4 %

Procedure:
1H-Pyrrolo[2,3-b]pyridine (1.0 g, 8.46 mmol) and 10% palladium-carbon (500 mg) were dissolved in a mixture of formic acid (10 mL) and triethylamine (10 mL), and the solution was stirred at 70° C. for 17 hours. To this reaction mixture was further added 10% palladium-carbon (270 mg), and the mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature, then an aqueous solution of 5N sodium hydroxide was added thereto, the solution was extracted with ethyl acetate and tetrahydrofuran, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1), and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (614 mg, 5.11 mmol, 60%) was obtained as a pale yellow solid.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:26][C:27](=[O:29])[CH3:28])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>O1CCCC1>[Br:50][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:26][C:27](=[O:29])[CH3:28])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1nc(-c2ccc(CCCO)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(-c2ccc(CCCBr)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of N-{4-[4-(3-hydroxypropyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide (75 mg) in tetrahydrofuran (0.7 ml) were added triphenylphosphine (68.5 mg) and carbon tetrabromide (86.7 mg) at 0° C., and the mixture was stirred for 1 h at 20° C. The reaction-mixture was purified by preparative thin-layer chromatography over silica gel with hexane/ethyl acetate (1:2) as an eluent to give N-{4-[4-(3-bromopropyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide as colorless oil.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH2:11]([N:13](CC)[CH2:14]C)[CH3:12].C(OC(=O)C)(=O)C>O.CCOCC>[ClH:1].[ClH:1].[CH3:14][NH:13][C:11]1[NH:9][C:6]2[C:7]([CH:12]=1)=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2
Reactant: Cc1ccc(NN)cc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CNc1cc2cc(C)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5 g of 1-(4-methylphenyl)hydrazine hydrochloride are dissolved in water and then triethylamine is added until the salt has been neutralized. Extraction is carried out with AcOEt and then the extract is evaporated to dryness. The precipitate formed is dissolved in 30 ml of ether and then a solution of 4.6 ml of acetic anhydride dissolved in 30 ml of ether is added dropwise. The mixture is stirred at 0° C. for 15 minutes and then the precipitate formed is filtered off to produce 3 g of the expected compound.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.C[O:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]2)=[C:14](Cl)[N:13]=1)=[O:11]>>[CH:3]1([CH2:6][O:7][C:14]2[N:13]=[C:12]([C:10]([OH:11])=[O:9])[CH:17]=[CH:16][C:15]=2[N:18]2[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]2)[CH2:5][CH2:4]1
Reactant: OCC1CC1
Reactant: COC(=O)c1ccc(N2CCC(F)(F)C2)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: O=C(O)c1ccc(N2CCC(F)(F)C2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (0.27 g, 8 mmol) was added in portions to cyclopropylmethanol (CAN 2516-33-8, 6 mL) and the mixture was stirred at room temperature for 2 hours. 6-Chloro-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid methyl ester (0.45 g, 1.6 mmol) was added to the mixture and the resulting solution was stirred in a sealed tube at 110° C. overnight. After concentration under reduced pressure, water (15 mL) was added to the residue and the solution was acidified with hydrochloric acid (6 N). The aqueous solution was extracted with ethyl acetate (3×20 mL) and the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the target compound which was used directly in the next step without further purification; MS (EI): m/e=299.1 [M+H]+.