Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([C:20]([NH:22][CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[O:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)=[CH:7][CH:6]=1.[H-].[Na+].[H][H].Cl[C:35]1[CH:40]=[N:39][CH:38]=[CH:37][N:36]=1>CN(C=O)C>[N:36]1[CH:37]=[CH:38][N:39]=[CH:40][C:35]=1[O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([C:20]([NH:22][CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[O:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1ccc(OCCO)cc1
Reactant: Clc1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1ccc(OCCOc2cnccn2)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
1-[4-(2-Hydroxyethoxy)phenyl]-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide (100 mg, 0.26 mmol) and sodium hydride (6 mg, 0.26 mmol) were dissolved in anhydrous DMF (2 mL) under N2 atmosphere. The reaction mixture was heated to 60° C. until hydrogen gas evolution ceased. 2-Chloropyrazine (35 mg, 0.31 mmol, 28 μL) was then added drop-wise and the reaction was heated to 100° C. After 18 h, the reaction mixture was concentrated in vacuo and purified by mass-directed purification to provide 1-{4-[2-(Pyrazin-2-yloxy)ethoxy]phenyl}-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide (OSIP484814AA) as a white powder. 1H NMR (d6-DMSO, 400 MHz): δ 9.17 (brt, J=6.0 Hz, 1H), 8.60 (s, 1H), 8.58 (d, J=1.6 Hz, 1H), 8.47 (dd, J=5.2, 1.2 Hz, 1H), 8.40 (d, J=0.8 Hz, 1H), 8.37 (d, J=1.2 Hz, 1H), 8.26 (s, 2H), 7.90 (dd, J=8.6, 1.8 Hz, 1H), 7.76 (ddd, J=8.2, 1.8 Hz, 1H), 7.65-7.55 (m, 3H), 7.37 (ddd, J=8.0, 4.8, 0.8 Hz, 1H), 7.24 (ddd, J=9.2, 2.2, 2.2 Hz, 2H), 4.69 (m, 2H), 4.54 (d, J=4.4 Hz, 2H), 4.47 (m, 2H). MS(ES+): m/z 467 (100) [MH+].
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][N:8]=[C:7]([CH3:10])[N:6]=1.[F:11][CH:12]([F:27])[C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[C:22]([CH3:24])[C:21](O)=[C:20]([CH3:26])[CH:19]=2)[N:14]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:10][C:7]1[N:6]=[C:5]([CH2:4][CH2:3][CH2:2][O:1][C:21]2[C:20]([CH3:26])=[CH:19][C:18]([C:15]3[N:14]=[C:13]([CH:12]([F:11])[F:27])[O:17][N:16]=3)=[CH:23][C:22]=2[CH3:24])[S:9][N:8]=1
Reactant: Cc1nsc(CCCO)n1
Reactant: Cc1cc(-c2noc(C(F)F)n2)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nsc(CCCOc2c(C)cc(-c3noc(C(F)F)n3)cc2C)n1
Temperature: 20 °C
Yield: 81 %

Procedure:
A mixture of 5-(3-hydroxypropyl)-3-methyl-1,2,4-thiadiazole (242 mg, 1.53 mmol), 4-(5-difluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol described in allowed U.S. patent application Ser. No. 07/869,287, incorporated herein by reference (400 mg, 1.67 mmol), and DEAD (290 mg, 1.67 mmol) was dissolved in 16 mL of THF. To the above solution was added triphenylphosphine (438 mg, 1.67 mmol) at 0° C. and the mixture was allowed to warm to 20° C. overnight. The solvent was removed in vacuo, an aqueous sodium bicarbonate solution was added, and the mixture was extracted with methylene chloride (7×). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (10 cm column, ethyl acetate/hexane, from 1/6 to 1/4) followed by recrystallization from ethyl acetate/hexane to afford 471 mg (81%) of 3-methyl-5-[3-[4-(5-difluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl]-1,2,4-thiadiazole, as a white crystalline solid, m.p. 62°-64° C. 3-Methyl-5-[3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-1,2,4-thiadiazole (I,Thi=3-methyl-1,2,4-thiadiazol-5-yl, Y=1,3-propylene, R1 =R2 =methyl, R3 =5-methyl-1,2,4-oxadiazol-3-yl)
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:27]=[CH:26][C:13]3/[C:14](=C/C#N)/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH-:32].[Na+].Cl.[CH2:35]([OH:37])[CH3:36]>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:27]=[CH:26][C:13]3/[C:14](=[CH:36]/[C:35]([OH:32])=[O:37])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCO
Reactant: [OH-]
Reactant: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Agent: Cl
Agent: [Na+]
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)O
Yield: 89 %

Procedure:
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (260 mg, 0.64 mmol) obtained in Example 1 was dissolved in ethanol (2.5 mL), 10 mol/L aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred under reflux for 24 hr. The mixture was neutralized with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=90/10) to give the title compound (compound 2) (243 mg, 89%).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH2:18]([NH2:21])[CH2:19][CH3:20]>C(O)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])=[N:21][CH2:18][CH2:19][CH3:20])#[N:2]
Reactant: CCCN
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Solvent: CCO
Product: CCCN=C(NC#N)NCCSCc1[nH]cnc1C
Yield: 71.4 %

Procedure:
A solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (2.69 g.) and n-propylamine (1.1 g.) in ethanol (50 ml.) was heated under reflux for 6 hours. Concentration, followed by chromatographic purification on a column of silica gel with ethyl acetate-isopropyl alcohol (4:1) as eluant and final recrystallisation from aqueous isopropyl alcohol afforded N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]N"-propylguanidine (2.0 g.) m.p. 108°-110°. (Found: C, 51.4; N, 7.4; N, 30.0; S, 11.4. C12H20N6S requires: C, 51.4; H, 7.2; N, 30.0; S, 11.4).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:4]=1.Cl.[C:18]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:21])[CH2:19][OH:20].C(N(C(C)C)CC)(C)C>CS(C)=O.O>[OH:20][CH2:19][C:18]([N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]3[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=3)[CH:4]=2)[CH2:24][CH2:23]1)=[O:21]
Reactant: N#Cc1cnc(Nc2cc(CCl)ccn2)s1
Reactant: O=C(CO)N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cnc(Nc2cc(CN3CCN(C(=O)CO)CC3)ccn2)s1

Procedure:
2-{[4-(Chloromethyl)pyridin-2-yl]amino}-1,3-thiazole-5-carbonitrile (180 mg, 0.72 mmole) and 1-glycoloylpiperazine hydrochloride (259 mg, 1.44 mmole) were combined in DMSO (2 mL). To this was added diisopropylethylamine (0.38 mL, 2.15 mmole) at RT. After 3 hr the mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (gradient, 5-15% EtOH/EtOAc then 5-10% MeOH/CHCl3) gave the title compound as a pale yellow solid: 1H NMR (d6-DMSO) δ12.19 (s, 1 H), 8.33 (d, 1 H, J=5.1 Hz), 8.32 (s, 1 H), 7.14 (s, 1 H), 7.0 (d, 1 H, J=5.2 Hz), 4.54 (t, 1 H, J=5.6 Hz), 4.08 (d, 2 H, J=5.6 Hz), 3.55 (s, 2 H), 3.49 (s, 2 H), 3.36 (s, 2 H), 2.38 (s, 4 H); MS [M+H]+=359.1285.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]([NH2:27])=O)=[CH:9]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1.[C:50]([O:55][CH2:56][CH3:57])(=[O:54])[C:51]#[C:52][CH3:53].C(P(CCCC)CCCC)CCC>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]1[S:37][CH:52]([CH2:51][C:50]([O:55][CH2:56][CH3:57])=[O:54])[CH2:53][N:27]=1)=[CH:9]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=O)cc2c1
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(OCCOC)cc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 50 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (920 mg), Lawesson's reagent (690 mg) and tetrahydrofuran (20 mL) was stirred at 50° C. for 2 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2:1-1:9, volume ratio) to give a yellow amorphous solid. A mixture of the obtained amorphous solid, ethyl but-2-ynoate (620 mg), tributylphosphine (450 mg), toluene (30 mL) and tetrahydrofuran (15 mL) was stirred at 50° C. for 1 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:1, volume ratio). The obtained compound was further subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (1:1, volume ratio) to give the title compound (500 mg, yield 42%) as a yellow oil
Reaction SMILES: [Cl:1][C:2]1[C:3](C#N)=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[NH:5][C:6]=1[Cl:7].[CH3:18][C:19](C)([O-:21])C.[K+].BrC(O)C.[NH:28]1C=CC=[CH:29]1>O1CCOCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH2:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)([C:29]#[N:28])[N:5]([CH2:18][CH2:19][OH:21])[C:6]=1[Cl:7]
Reactant: c1cc[nH]c1
Reactant: N#Cc1c(-c2ccc(Cl)c(Cl)c2)[nH]c(Cl)c1Cl
Reactant: CC(C)(C)[O-]
Agent: CC(O)Br
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC1(c2ccc(Cl)c(Cl)c2)CC(Cl)=C(Cl)N1CCO

Procedure:
To a stirred mixture of 2.0 g (6.5 mmol) of 4,5-dichloro-2-(3,4-dichlorophenyl)-pyrrole-3-carbonitrile and 0.88 g (7.8 mmol) of potassium tert-butoxide heated at reflux in 50 mL of dioxane is added 0.98 g (7.8 mmol) of bromoethanol. The mixture is stirred at reflux for 12 hours, cooled, diluted with 50 mL of water, and extracted several times with chloroform. The combined chloroform extracts are dried over magnesium sulfate and concentrated in vacuo to leave a solid which, on warming and dissolving in ethyl acetate, deposits on cooling mostly starting pyrrole. Concentration of the mother liquor and recrystallization of the residual solid from 20% ethyl acetate in hexane gives 0.31 g of a white solid, mp 143°-145° C.; IR 5077A.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1([CH2:6][O:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:5][CH2:4]1.[NH2:20][C:21]([NH2:23])=[S:22]>CCO>[C:14]1([CH3:17])[CH:13]=[CH:12][C:11]([S:8]([OH:10])(=[O:7])=[O:9])=[CH:16][CH:15]=1.[F:19][C:2]([F:1])([F:18])[C:3]1([CH2:6][S:22][C:21](=[NH:20])[NH2:23])[CH2:4][CH2:5]1
Reactant: NC(N)=S
Reactant: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CC2)cc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O)cc1
Product: N=C(N)SCC1(C(F)(F)F)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A mixture of toluene-4-sulfonic acid 1-trifluoromethyl-cyclopropylmethyl ester (2 g, 6.796 mmol) and thiourea (0.52 g, 6.831 mmol) in 5 mL of EtOH was stirred at 90° C. for 3 hours before being cooled to RT and evaporated to give 2.5 g of 2-(1-trifluoromethyl-cyclopropylmethyl)-isothiourea p-toluenesulfonic acid salt (>95% yield).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:24]2[CH2:28][NH:27][C:26](=[O:29])[CH2:25]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].[CH2:30](O)[CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:30]([O:15][C:16]1[CH:17]=[C:18]([CH:24]2[CH2:28][NH:27][C:26](=[O:29])[CH2:25]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OCC=Cc1ccccc1
Reactant: COc1ccc(C2CNC(=O)C2)cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C2CNC(=O)C2)cc1OCC=Cc1ccccc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 72.2 %

Procedure:
Diisopropylazodicarboxylate (61 mg, 0.6 mmol) is added to a solution of 4-(3-hydroxy-4-methoxyphenyl)-2-pyrrolidone (63 mg, 0.3 mmol), cinnamyl alcohol (43 mg, 0.3 mmol) and triphenyl phosphine (157 mg, 0.6 mmol) in 3 ml of tetrahydrofuran and the reaction mixture is stirred at 70° C. After 12 hours, the same work-up procedure as in Example 1 yields 70 mg (70%) of 4-(3-cinnamyloxy-4-methoxyphenyl)-2-pyrrolidone: 1H NMR (300 MHz, CDCl3) δ 7.40 (d, J=6.8 Hz, 2H), 7.31 (t, J=6.8 Hz, 2H), 7.25 (d, J=7.2 Hz, 1H), 6.86-6.81 (m, 2H), 6.71 (d, J=15.6 Hz, 1H), 6.42 (m, 1H), 5.92 (b, 1H), 4.76 (dd, J=6.0, 1.2 Hz, 2H), 3.87 (s, 3H), 3.71 (t, J=8.8 Hz, 1H), 3.64-3.56 (m, 1H), 3.35 (t, J=8.8 Hz, 1H).
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17][C:18]1([CH3:25])[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]1>BrC(Br)C.C1COCC1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2([OH:24])[CH2:21][CH2:22][CH2:23][C:18]([CH3:25])([CH3:17])[CH2:19]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1(C)CCCC(=O)C1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: CC(Br)Br
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(C)CCCC(O)(c2ccc(OCc3ccccc3)cc2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
In a RB flask (250 mL) was placed magnesium turnings (2.08 g, 85.9 mmol), which were stirred under vacuum without solvent overnight. To the stirred magnesium turnings was added anhydrous THF (10 mL). To the resulting mixture at 50° C. was added several drops of dibromoethane, followed by 4-benzyloxybromobenzene (11.8 g, 42.9 mmol) in 40 ml of THF. After addition was complete, the reaction mixture was heated at 60° C. for 3 hours until a brownish-grey slurry was formed. The reaction mixture was cooled in an ice-bath and 3,3-dimethyl-cyclohexanone (3.87 g, 30.67 mmol) in THF (15 mL) was added dropwise. The reaction mixture was stirred at room temperature for one hour. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc/aqueous NH4Cl. The aqueous phase was extracted three times with EtOAc. The organic phase was combined and dried (Na2SO4). Silica gel chromatography (EtOAc/heptane) provided 5.08 g of 1-(4-benzyloxy-phenyl)-3,3-dimethyl-cyclohexanol as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.BrCC1CCCCO1.[Cl:17][C:18]1[C:19]2[O:39][CH2:38][C:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[C:20]=2[C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[CH:27]=1>>[Cl:17][C:18]1[C:19]2[O:39][CH2:38][C:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=4)[C:29]3=[O:37])[C:20]=2[C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[CH:27]=1
Reactant: BrCc1ccccn1
Reactant: O=C1Nc2ccccc2C12COc1c(Cl)cc3c(c12)OCCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1c(Cl)cc3c(c12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 6-chloro-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 6-chloro-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one was obtained (81%) as a colorless solid: mp 197-199° C.; 1H NMR (300 MHz, CDCl3) δ 8.60 (d, J=2.1 Hz, 1H), 7.60 (ddd, J=7.5, 7.5, 1.5 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.25-7.15 (m, 3H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.83 (d, J=7.5 Hz, 1H), 6.79 (s, 1H), 5.35 (d, J=16.2 Hz, 1H), 5.00 (d, J=9.3 Hz, 1H), 4.89 (d, J=16.2 Hz, 1H), 4.74 (d, J=9.0 Hz, 1H), 4.16-3.86 (m, 4H); 13C NMR (75 MHz, CDCl3) δ175.9, 155.8, 151.7, 149.5, 141.8, 138.6, 138.3, 136.7, 130.9, 128.9, 123.6, 123.4, 122.6, 121.4, 118.2, 116.8, 109.4, 106.8, 81.7, 64.5, 63.8, 57.7, 46.3; MS (ES+) m/z 421.2 (M+1), 423.2 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[H][H]>C(O)C.[Ni]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: c1cnc2c(c1)CCN2
Yield: 59.6 %

Procedure:
A solution of 7-azaindole (20.0 g, 169 mmol) in ethanol (200 ml) was treated with wet Raney Nickel (4 g, 50% water) and stirred in a hydrogen atmosphere at 5 atmospheres pressure at 95° C. over 2 days. The reaction mixture was filtered through diatomaceous earth and the filtrate evaporated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate followed by increasingly polar mixtures of methylene chloride and methanol (saturated with ammonia) to give 7-azaindoline (12.1 g, 79%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O.C(COC)OC>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO>[C:19]([NH:18][C:16]1[S:17][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([O:8][C:6]3[CH:5]=[C:4]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[N:3]=[C:2]([C:40]4[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=4)[N:7]=3)[C:14]=2[N:15]=1)(=[O:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(Cl)n3)cccc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(C4=CCN(C(=O)OC(C)(C)C)CC4)n3)cccc2s1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of N-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzo[d]thiazol-2-yl}-acetamide (279 mg, 0.6 mmol, Example 7(d)), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (309 mg, 1.0 mmol, ChemShop), PdCl2(PPh3)2 (42 mg, 0.06 mmol, Aldrich), Na2CO3.H2O (74 mg, 0.6 mmol), dimethoxyethane (0.7 mL), H2O (0.3 mL) and EtOH (0.2 mL) was heated in a microwave synthesizer at 120° C. with stirring for 10 min. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2×30 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (30% EtOAc/hexane) to give the title compound. MS (ESI, pos. ion) m/z: 612 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].Cl.[CH3:14][NH:15][CH3:16].C(=O)(O)[O-].[K+].O>CN(C=O)C>[CH3:14][N:15]([CH3:16])[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: CNC
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc([N+](=O)[O-])cc1C#N
Temperature: 80 °C
Yield: 100 %

Procedure:
1.66 g (10.0 mmol) of 2-fluoro-5-nitrobenzonitrile, 1.22 g (15.1 mmol) of dimethylamine hydrochloride and 3.46 g (25.1 mmol) of potassium bicarbonate is dissolved, under an argon atmosphere, in DMF (30 ml) then the reaction medium is heated at a temperature of 80° C. for 18 hours. The reaction mixture is cooled down to 0° C. and ice-cooled water is added. The reaction mixture is extracted with ethyl acetate and the organic phase is washed successively with 50 ml of water and 50 ml of salt water, dried over magnesium sulphate, filtered and concentrated under vacuum. The evaporation residue is purified by trituration with isopropyl ether and the solid obtained is filtered and rinsed with isopentane in order to obtain after drying 2.0 g of a solid yellow product (yield 100%). Melting point: 109-110.5° C.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C@@H:8]([C:13]1[C:14]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[C:15]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:21]=3[S:20][C:16]2=[N:17][C:18]=1[CH3:19])[C:9]([O:11]C)=[O:10])([CH3:6])([CH3:5])[CH3:4]>>[C:3]([O:7][C@@H:8]([C:13]1[C:14]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=2)=[C:15]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:21]=3[S:20][C:16]2=[N:17][C:18]=1[CH3:19])[C:9]([OH:11])=[O:10])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C(F)(F)F)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2sc3c(c2c(-c2ccc(C(F)(F)F)cc2)c1[C@H](OC(C)(C)C)C(=O)O)CCCC3
Temperature: 60 °C
Yield: 56.3 %

Procedure:
1 M Aqueous sodium hydroxide solution (1.6 mL, 1.6 mmol) was added to a solution of (S)-methyl 2-(tert-butoxy)-2-(2-methyl-4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro benzo[4,5]thieno[2,3-b]pyridin-3-yl)acetate (75 mg, 0.15 mmol) in 1:1 tetrhydrofuran/industrial methylated spirit (4 mL) at room temperature. The resulting mixture was heated at 60° C. 1.5 h. The resulting solution was concentrated in vacuo and the residue was dissolved in water (10 mL). The aqueous solution was adjusted to pH 4 by the addition of 2 M aqueous hydrochloric acid solution and the resulting suspension was extracted with dichloromethane (20 mL). The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give the crude product as a pale yellow solid. This was purified by flash column chromatography on silica eluting with methanol in dichloromethane (5%) to give the title compound (40.3 mg, 56%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:5][O:6][C:7](=[O:19])[NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12]2.CN1CC[O:28][CH2:27]C1.CCN=C=NCCCN(C)C.[CH:42]1[CH:43]=[CH:44][C:45]2[N:50](O)[N:49]=[N:48][C:46]=2[CH:47]=1>CN(C=O)C.O>[Cl:23][C:21]1[CH:20]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:22]=1)[CH2:5][O:6][C:7](=[O:19])[NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([C:27]([C:42]1[CH:43]=[CH:44][C:45]3[NH:50][N:49]=[N:48][C:46]=3[CH:47]=1)=[O:28])[CH2:13][CH2:12]2
Reactant: On1nnc2ccccc21
Reactant: O=C(Nc1ccc2c(c1)CCNC2)OCc1cc(Cl)cc(Cl)c1
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc2c(c1)CCN(C(=O)c1ccc3[nH]nnc3c1)C2)OCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C

Procedure:
Starting material 47 (46 mg, 0.1 mmol), 1H-1,2,3-benzothiazole-5-carboxyllic acid (22 mg, 0.1 mmol) and 4-methyl morpholin (40 μL, 0.4 mmol) were dissolved in 2 ml DMF. Then EDCI (38 mg, 0.2 mmol) and HOBt (26 mg, 0.2 mmol) were added and the mixture was stirred over night at ambient temperature. The reaction mixture was mixed with water and the resulting precipitate was filtered and dried in vacuo at 45° C. The desired product 48 could thereby be isolated as light brown solid (34 mg, 0.07 mmol, 52%).