Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@:10]1([CH:50]([OH:53])[CH2:51][CH3:52])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@:10]([CH:50]([OH:53])[CH2:51][CH3:52])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@@](C(O)CC)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@@](C(O)CC)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 274.2 %

Procedure:
To a solution of 1-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]propan-1-ol 3a (42 mg, 0.06 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 5 mL) were added o-dichlorobenzene (41.16 mg, 0.28 mmol) and 10% Pd/C (5.72 mg, 0.006 mmol) in turn. The mixture was stirred at room temperature under H2 for 4 hours and filtered. The filtered cake was washed with a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL×2). The combined filtrates were concentrated in vacuo. The residue was purified to give the title compound 3 as a pale yellow solid (76.5 mg, 51.0%, HPLC: 94.6%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 465.1[M+H]+; and 1H NMR (400 MHz, CDCl3) δ(ppm): 7.35 (m, 2H), 7.32 (m, 1H), 7.06 (d, 2H), 6.77 (d, 2H), 4.19 (d, 1H), 4.10 (d, 1H), 3.96 (m, 4H), 3.76 (m, 3H), 3.68 (m, 1H), 1.54 (m, 2H), 1.36 (t, 3H), 0.95 (t, 3H).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[C:8]([N:10]=O)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CO>CCO.C(Cl)Cl.[Pd]>[C:1]([C:5]1[NH:6][C:7]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[C:8]([NH2:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2[nH]c(C(C)(C)C)nc2N=O)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(-c2[nH]c(C(C)(C)C)nc2N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
A suspension of Intermediate 51b (150 mg, 0.617 mmol) and Pd/C (10%, 15 mg) in EtOH (10 mL) was stirred at RT under H2 for 2 h. The flask was evacuated and purged with N2 thrice, then the mixture filtered through Celite, and the filter-cake washed with EtOH (10 mL). The combined organics were concentrated in vacuo to leave a red-brown gum. FCC, using 1-6% MeOH in DCM, gave the title compound as a yellow-orange gum (96.3 mg, 68%). LCMS (Method 3): Rt 2.26 min, m/z 230 [MH+].
Reaction SMILES: Br[CH2:2][C:3]1[C:11]([F:12])=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4]=1[F:13].[C:14]([O-:17])(=[O:16])[CH3:15].[K+].O.C(OCC)(=O)C>CN(C)C=O>[C:14]([O:17][CH2:2][C:3]1[C:11]([F:12])=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4]=1[F:13])(=[O:16])[CH3:15]
Reactant: Fc1cc2sccc2c(F)c1CBr
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1c(F)cc2sccc2c1F
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 0.18 g of 5-bromomethyl-4,6-difluorobenzo[b]thiophene in 5 ml of N,N-dimethylformamide is added 0.23 g of potassium acetate, and the resulting mixture is stirred at 60° C. for one hour. The temperature of the thus stirred mixture is lowered to room temperature, and 10 ml of water and 10 ml of ethyl acetate are added thereto. Thereafter, the resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure, to obtain 0.14 g of colorless, oily 5-acetoxymethyl-4,6-difluorobenzo[b]thiophene.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5]1.C[CH2:17][N:18](CC)CC.CS(Cl)(=O)=O.CN.CCO>C(Cl)Cl>[CH3:17][NH:18][CH2:2][CH2:3][N:4]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5]1
Reactant: OCCN1CCn2c1nc1ccccc12
Reactant: CCN(CC)CC
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: CCO
Solvent: ClCCl
Product: CNCCN1CCn2c1nc1ccccc12
Temperature: 0 °C
Yield: 78.6 %

Procedure:
To a cooled (0° C.), stirred suspension of 1-N-(2-hydroxyethyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (882 mg, 4.34 mmol) in CH2Cl2 (18 mL) was added Et3N (0.67 mL, 4.77 mmol) and MsCl (0.37 mL, 4.77 mmol). The resulting solution was stirred at room temperature for 1 hour, washed with brine, dried (MgSO4) and concentrated to give an off-white solid. 33% CH3NH2 /EtOH (45 mL) was added and the solution was stirred at room temperature over the weekend. The mixture was concentrated, taken up in 10% aqueous HOAc (20 mL) and extracted with EtOAc. The extracts were dried (MgSO4) and concentrated to give 738 mg (79%) of an off-white solid m.p. 60°-63° C.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[C:13]([O:14][CH3:15])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1>C(O)(=O)C>[Br:1][C:6]1[CH:5]=[C:4]([F:3])[C:13]([O:14][CH3:15])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: BrBr
Reactant: COc1c(F)ccc2cccnc12
Solvent: CC(=O)O
Product: COc1c(F)cc(Br)c2cccnc12
Temperature: 40 °C

Procedure:
Bromine (0.48 ml) was added dropwise to a solution of 7-fluoro-8-methoxyquinoline (1.6 g) in glacial acetic acid (24 ml). The mixture was heated to 40° C. for 4 h and the reaction quenched with 5% aqueous sodium metabisulphite (100 ml). The solution was basified with 25% aqueous sodium hydroxide to pH13 and the product extracted with ethyl acetate (3×150 ml). The extracts were combined, dried over magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with 25% ethyl acetate in hexane to yield the desired product as a white solid (0.50 g).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)[CH3:3].S(OC)(O[CH3:18])(=O)=O.[O-2].[Mg+2]>C1(C)C=CC=CC=1>[NH2:1][CH:2]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[CH3:18])=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(N)c1ccc2c(c1)NCCC2
Reactant: COS(=O)(=O)OC
Agent: [Mg+2]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(N)c1ccc2c(c1)N(C)CCC2
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Example P-13:1.3 g of 7-(1-aminoethyl)-1,2,3,4-tetrahydro-quinoline, 0.73 gof dimethyl sulfate and 0.27 g of ground magnesium oxide in 50 ml of absolute toluene are placed in a sulfonation flask. The internal temperature is then increased to 100°-105° C. and the mixture is stirred at that temperature for 18 hours. After cooling, inorganic material is filtered off, 10 ml of cone. HCl are added to the toluene solution, and the batch is maintained at 70° C. for 2 hours. The batch is then neutralised with sodium hydroxide solution and the organic phase is removed. The aqueous phase is subsequently further extracted twice with ethyl acetate and the organic phases are dried over Na2SO4. After removal of the solvent under a water-jet vacuum, 1.2 g of crude product are obtained which can be purified by flash chromatography on silica gel (eluant: ethyl acetate/n-hexane 1: 1) to yield 1.05 g of 7-(1-aminoethyl)-1-methyl-1,2,3,4-tetrahydro-quinoline in the form of a red oil (1H-NMR).
Reaction SMILES: [OH-].[Na+].O.[CH:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11]1>CCCCCC>[OH:9][CH:4]([CH:11]1[CH2:12][CH2:13][CH2:14][C:10]1=[O:15])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC=O
Reactant: O=C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Product: CCCCC(O)C1CCCC1=O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
Into a 2-litter four-neck flask fitted with a thermometer, a reflux condenser and a stirrer were added sodium hydroxide (3.2 g) and water (300 ml). Then, a mixture of pentanal (86 g) and cyclopentanone (152 g) was added dropwise with stirring at 0-5° C. over a period of 2 hours. After the addition, the reaction mixture was stirred at room temperature for 1 hour to complete the reaction. Hexane (150 ml) was added to the reaction mixture and the layers were separated from each other. The resulting organic layer was washed with an aqueous solution (200 ml) of acetic acid (1 g) and then separated. The resulting organic layer was washed with saturated brine and separated. The organic layer was evaporated on a rotary evaporator under reduced pressure to recover hexane and unreacted cyclopentanone, whereby a crude product (173 g) was obtained. The product was distilled using a Claisen distillation apparatus to obtain 127 g of 2-(1-hydroxypentyl)cyclopentanone (boiling point: 115° C./933 Pa; GC purity: 95%). The remaining 5% was 2-pentylidenecyclopentanone which is a dehydration product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1)[N:8]=[CH:7]2.[OH:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=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.CN(C=O)C>[OH:19][C@H:16]1[CH2:17][CH2:18][C@H:13]([NH:12][C:9]2[N:8]=[CH:7][C:6]3[C:11](=[C:2]([C:24]4[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=4)[CH:3]=[CH:4][CH:5]=3)[N:10]=2)[CH2:14][CH2:15]1
Reactant: OB(O)c1ccc(O)cc1
Reactant: O[C@H]1CC[C@H](Nc2ncc3cccc(Br)c3n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Oc1ccc(-c2cccc3cnc(N[C@H]4CC[C@H](O)CC4)nc23)cc1
Temperature: 85 °C

Procedure:
To a flask charged with trans-4-[(8-bromoquinazolin-2-yl)amino]cyclohexanol (1.3 g, 4.035 mmol) was added Pd(PPh3)4 (233 mg, 0.202 mmol), K3PO4.3H2O (2.686 mg, 10.09 mmol), 4-hydroxybenzeneboronic acid (1.113 g, 8.07 mmol) and DMF (16 mL) under argon. The mixture was heated at 80-90° C. under argon overnight, then cooled to room temperature and filtered. The filtrate was concentrated under vacuum and purified by silica gel chromatography (eluted with EA:PE=2:1) to give the title compound as a yellow solid (1 g, 74%). 1 HNMR (DMSO-d6, 400 MHz): δ 9.50 (s, 1H), 9.01 (s, 1H), 7.72-7.61 (m, 3H), 7.31-7.20 (m, 2H), 6.83 (t, 2H, J=7.6 Hz), 4.53 (d, 1H, J=4 Hz), 3.70-3.55 (m, 1H), 3.45-3.36 (m, 1H), 1.99-1.84 (m, 4H), 1.35-1.14 (m, 4H).
Reaction SMILES: [CH3:1]/[CH:2]=[C:3]1\[C@H:4]2[CH:11]=[C:10]([CH3:12])[CH2:9][C@@:8]\1([NH2:13])[C:7]1[CH:14]=[CH:15][C:16]([NH:18][C:6]=1[CH2:5]2)=[O:17].[CH:19](=O)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(C)C.C1COCC1>[C:22]1([CH:21]=[CH:20][CH:19]=[N:13][C@@:8]23[C:7]4[CH:14]=[CH:15][C:16](=[O:17])[NH:18][C:6]=4[CH2:5][C@@H:4](/[C:3]/2=[CH:2]\[CH3:1])[CH:11]=[C:10]([CH3:12])[CH2:9]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=CC=Cc1ccccc1
Reactant: C/C=C1\[C@H]2C=C(C)C[C@@]1(N)c1ccc(=O)[nH]c1C2
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C/C=C1\[C@H]2C=C(C)C[C@]1(N=CC=Cc1ccccc1)c1ccc(=O)[nH]c1C2
Yield: 95.2 %

Procedure:
20 mg Huperzine A, and 77 mg cinnamaldehyde were refluxed in 2 mL isopropanol for 3 hours. Solvent was removed under vacuum. The crude reaction mixture was dissolved in 3 mL anhydrous THF and purified with prep. TLC (CHCl3: methanol=9:1) to give 28 mg of title product. MS: 357 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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]1[CH:4]=[C:5]([C:15]2[CH:21]=[CH:20][CH:19]=[C:17]([NH2:18])[CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Nc1cccc(Br)c1
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: COCCOC
Product: COc1ccc(-c2cccc(N)c2)cc1OC
Temperature: 25 °C
Yield: 63 %

Procedure:
3,4-dimethoxyphenyl boronic acid (0.126 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.067 g in 63% yield.
Reaction SMILES: CCC(CCCCC([NH:11]C(C(NC(C(NC(C(NC1C(=O)NC(CCN)C(=O)NC(CC2C=CC=CC=2)C(=O)NC(CC(C)C)C(=O)NC(CCN)C(=O)NC(CCN)C(=O)NC(C(O)C)C(=O)NCC1)=O)CCN)=O)C(O)C)=O)CCN)=O)C.OS(O)(=O)=O.[CH2:91]([N:93]([CH2:108][CH3:109])[CH2:94][CH2:95][S:96]([C:98]1[C:102]([N:103]2[CH:107]=[CH:106][N:105]=[CH:104]2)=[N:101][S:100][N:99]=1)=[O:97])[CH3:92].[N-]=[N+]=[N-].[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH2:108]([N:93]([CH2:91][CH3:92])[CH2:94][CH2:95][S:96]([C:98]1[C:102]([N:103]2[CH:107]=[CH:106][N:105]=[CH:104]2)=[N:101][S:100][N:99]=1)(=[NH:11])=[O:97])[CH3:109]
Reactant: CCN(CC)CCS(=O)c1nsnc1-n1ccnc1
Reactant: CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(Cc2ccccc2)NC(=O)C(CCN)NC1=O)C(C)O
Agent: O=S(=O)(O)O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCS(=N)(=O)c1nsnc1-n1ccnc1
Temperature: 25 °C

Procedure:
Concentrated sufuric acid (13 ml) is added dropwise to a stirred slurry of the compound of Example 11 (13 mmol) and sodium azide (52 mmol) in chloroform at -20° C. The reaction mixture is allowed to warm to ambient temperature and then heated at reflux temperature for 36 hr. The reaction mixture is then cooled to 0° C. and water (100 ml) added. The mixture is carefully basified with 50% sodium hydroxide solution. The chloroform layer is separated and the aqueous layer is extracted with methylene chloride. The combined organic layers are dried and concentratedto obtain the product which is purified by standard procedures.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]1[S:14][C:13]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[CH2:20][C:21]([O:23]C)=[O:22])=[CH:12][CH:11]=1.[OH-].[Na+].Cl>O1CCOCC1>[C:21]([CH2:20][C:19]1[CH:18]=[CH:17][S:16][C:15]=1[C:13]1[S:14][C:10]([C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH2:4][C:3]([OH:25])=[O:2])=[CH:11][CH:12]=1)([OH:23])=[O:22]
Reactant: COC(=O)Cc1ccsc1-c1ccc(-c2sccc2CC(=O)OC)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)Cc1ccsc1-c1ccc(-c2sccc2CC(=O)O)s1

Procedure:
Intermediate C (71 mg, 0.181 mmol) was dissolved in dioxane (2 ml) and 1 M NaOH (0.40 ml) and the mixture was stirred at rt overnight. The mixture was acidified by 1 M HCl and aqueous layer extracted with EtOAc. The organic layer was dried (MgSO4) and filtered. Yield: 57 mg (87%); yellow soid. 1H NMR (400 HMz, DMSO-d6): δ 3.73 (s, 4H), 7.09 (d, J 5.2 Hz, 2H), 7.23 (s, 2H), 7.53 (d, J 5.2 Hz, 2H), 12.52 (s, 2H).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11](C)(C)C)=[O:9])[C:5]2[CH:15]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[S:17][C:4]=2[C:3]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[CH:28]([C:30]1[CH:34]=[CH:33][S:32][C:31]=1B(O)O)=[O:29].[F-].[K+]>O1CCOCC1.CC(P(C(C)(C)C)C(C)(C)C)(C)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.[Pd]>[CH:22]1([C:3]2[C:4]3[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][C:5]=3[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]=2[C:31]2[S:32][CH:33]=[CH:34][C:30]=2[CH:28]=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=Cc1ccsc1B(O)O
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(Br)n2CC(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)Cn1c(-c2sccc2C=O)c(C2CCCCC2)c2sc(C(=O)OC)cc21
Reaction time: 8 h
Yield: 65 %

Procedure:
Methyl 5-bromo-6-cyclohexyl-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (prepared in analogy to Example 7, Step 2, substituting tert-butyl bromoacetate with methyl bromo acetate) and (3-formyl-2-thienyl)boronic acid (1.2 eq.) were dissolved in dioxane (0.1 M) and treated with spray-dried KF (3.3 eq.). The solution was degassed by bubbling argon and Pd(t-Bu3P)2 (0.24 eq.) was added, and the reaction mixture was left stirring overnight; the mixture was then absorbed on silica gel and the title compound isolated by chromatography (PE/EtOAc 9:1). Yield: 65%. 1H-NMR (400 MHz, CDCl3, 300 K, δ) 9.62 (s, 1H), 7.63 (s, 1H), 7.61 (d, 1H, J 5.5), 7.50 (d, 1H, J 5.5), 4.62 (s, 2H), 3.91 (s, 3H), 3.67 (s, 3H), 2.46-2.37 (m, 1H), 1.80-0.80 (m, 10H); MS (ES+) m/z 446 (M+H)+.
Reaction SMILES: C(C1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:22])[N:4]=1)#N.O.[C:24]([OH:27])(=[O:26])[CH3:25]>Cl.C(Cl)(Cl)Cl.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([O:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:22])[N:4]=[C:25]([C:24]([OH:27])=[O:26])[CH:8]=1
Reactant: CC(=O)O
Reactant: COc1cc(C#N)nc(Oc2c(Cl)cccc2C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(Oc2c(Cl)cccc2C(F)(F)F)nc(C(=O)O)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2-cyano-4-methoxy-6-[2-chloro-6-(trifluoromethyl) phenoxy] pyridine (2.88 g, 0.0088 mol) was suspended in about 20 ml of concentrated hydrochloric acid and about 10 ml of acetic acid. The obtained suspension was stirred at about 100° C. for about 4 hours. After being allowed to stand for cooling, the obtained reaction solution was mixed with water, and then distributed in chloroform-water. The obtained solution was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated, thereby obtaining an aimed product.
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:37][CH:38]1[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39]1.O>CN(C=O)C>[CH3:27][N:26]([CH2:37][CH:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)[S:25]([N:20]1[C:21]2([CH2:23][CH2:22]2)[CH2:24][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:18][CH2:19]1)(=[O:28])=[O:29]
Reactant: CNS(=O)(=O)N1CCN(c2ncnc3c2ccn3C(=O)OC(C)(C)C)CC12CC2
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CC1CCNC1)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 45 °C
Reaction time: 16 h

Procedure:
4-(4-Methylsulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 4) (0.71 mmol) was dissolved in dry DMF (0.5 mL) and added Cs2CO3 (1.42 mmol) and tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate (0.85 mmol). Stirred at 45° C. for 16 h and then added H2O (2 mL). Extracted with EtOAc (3×2 mL) and the combined organic phases were concentrated in vacuo. The residual oil was treated with a mixture of 1,1,1,3,3,3-hexafluoro-2-propanol: 2,2,2-trifluoroethanol (3:1, 4 mL) at 150° C. for 2 h. The crude reaction mixture was concentrated on celite in vacuo and purified by standard column chromatography using methanol in DCM as eluent. The obtained compound was recrystallized in methanol:EtOAc affording the title compound as solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:7]2)([O-])=O.Cl[Sn]Cl.O>CCO>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:8]1[NH:9][C:10]2[C:6]([CH:7]=1)=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=2
Reactant: O=[N+]([O-])c1ccc2[nH]c(-c3ccccn3)cc2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc2[nH]c(-c3ccccn3)cc2c1
Yield: 19.8 %

Procedure:
To a solution of 5-nitro-2-(pyridin-2-yl)-1H-indole (700 mg, 2.9 mmol) in EtOH (20 mL) was added SnCl2 (2.6 g, 12 mmol). The mixture was heated at reflux for 10 h. Water was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by chromatography on silica gel (5-10% ethyl acetate/petroleum ether) to afford 2-(pyridin-2-yl)-1H-indol-5-amine (120 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 9.33 (brs, 1H), 8.55 (dd, J=1.2, 3.6 Hz, 1H), 7.76-7.67 (m, 2H), 7.23 (d, J=6.4 Hz, 1H), 7.16-7.12 (m, 1H), 6.94 (d, J=2.0 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.71-6.69 (dd, J=2.0, 8.4 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[H-].[Na+].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]2[C:30]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)=[C:29](Cl)[N:28]=[CH:27][N:26]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[Cl-].[NH4+]>CC(N(C)C)=O>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH:24][C:25]2[C:30]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)=[C:29]([O:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:28]=[CH:27][N:26]=2)(=[O:22])=[O:23])=[CH:19][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1cccc(Oc2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: OCc1ccccn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCc2ccccn2)c1
Yield: 94.6 %

Procedure:
To a stirred solution of pyridine-2-methanol (130 mg) in dimethylacetamide (0.5 ml) is added gradually with stirring sodium hydride (62.7% dispersion-type, 60 mg) under ice-cooling, and thereto is added 4-tert-butyl-N-{6-chloro-5-(3-methoxyphenoxy)pyrimidin-4-yl}benzenesulfonamide (100 mg). The mixture is reacted at 100° C. for 30 minutes, and cooled. The pH value of the mixture is adjusted to pH 8 with saturated aqueous ammonium chloride solution. The mixture is extracted with ethyl acetate, and the extract is washed, dried, and concentrated to dryness under reduced pressure. The residue is crystallized from ethyl acetate to give 4-tert-butyl-N-{5-(3-methoxyphenoxy)-6-(2-pyridinylmethoxy)pyrimidin-4-yl}benzenesulfonamide (110 mg) as crystals.
Reaction SMILES: [CH3:1][N:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](=[O:7])[O:4][CH2:5][CH3:6]>[Rh].CC(O)C>[CH3:1][N:2]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:3](=[O:7])[O:4][CH2:5][CH3:6]
Reactant: CCOC(=O)N(C)c1ccccc1
Agent: [Rh]
Solvent: CC(C)O
Product: CCOC(=O)N(C)C1CCCCC1
Reaction time: 0.3 h

Procedure:
A mixture of 17.9 g. (0.10 mole) of ethyl N-methylcarbanilate, 100 ml. of 2-propanol, and 2.4 g. of 5% Rh on carbon was added to a 300 ml. Magne Drive autoclave. The vessel was sealed, purged first with nitrogen and then with hydrogen, and pressured with hydrogen to 600 psig. The autoclave was agitated at 30°-40° and 500-800 psig for 0.3 hr., when gas absorption stopped. The reaction product was removed and filtered through Celite filter aid to remove the catalyst. Most of the solvent was removed on a rotary evaporator under vacuum. Distillation gave a quantitative yield of ethyl N-methylcyclohexylcarbamate, b.p. 78°-82° at 2 mm., mostly 81°-2° at 2 mm. An elemental analysis was obtained on a middle cut from the distillation. Anal. Calcd. for C10H19O2N: C, 64.83; H, 10.34; N, 7.56. Found: C, 64.73; H, 10.32; N, 7.44.