Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4.[H-].[Na+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23]>CN(C=O)C.O>[CH3:1][C:2]1[CH:17]=[N:16][C:5]2[N:6]([CH2:21][C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4
Reactant: Cc1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: O=C(CCl)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)c1c(n2CC(=O)N2CCCCC2)CCN2CCCC12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 10-methyl-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine (80 mg, 0.352 mmol) in DMF (1 mL) was added a suspension of sodium hydride (42 mg, 1.05 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solution of 2-chloro-1-(piperidin-1-yl)ethanone (114 mg, 0.704 mmol) in DMF (1 mL) was added to the reaction mixture, and stirring continued for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel flash chromatography to yield 2-(10-methyl-2,3,5,6-tetrahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizin-7(11cH)-yl)-1-(piperidin-1-yl)ethanone;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]\[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1>CO.N1CCCCC1>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]\[CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1/C=C\CCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1/C=C\CCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A solution of tert-butyl (Z)-4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-enyl]piperazine1-carboxylate (0.0562 g, 0.139 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0203 g, 0.139 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-((Z)-4-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-enyl)piperazine-1-carboxylate (0.0672 g, 91%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]2[C:12]([CH3:15])=[CH:13][S:14][C:8]=2[N:7]([CH3:16])[C:6]1=[O:17].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[CH2:35]1[CH2:40][O:39][CH:38]=[CH:37][CH2:36]1.O>C(Cl)Cl>[CH3:16][N:7]1[C:8]2[S:14][CH:13]=[C:12]([CH3:15])[C:9]=2[C:10](=[O:11])[N:5]([CH2:4][CH2:3][CH2:2][O:1][CH:38]2[CH2:37][CH2:36][CH2:35][CH2:40][O:39]2)[C:6]1=[O:17]
Reactant: Cc1csc2c1c(=O)n(CCCO)c(=O)n2C
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: Cc1csc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.5 %

Procedure:
To a solution of 3-(3-hydroxypropyl)-1,5-dimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (9 g, 35.4 mmol) and PPTS (900 mg, 3.54 mmol) in DCM (90 mL) at 0° C. was added DHP (8.96 g, 0.106 mol) dropwise. The reaction was stirred at RT for 18 h, poured into water (30 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography and eluted with PE/EA (4:1) to give 1,5-dimethyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (11.2 g, 93.4% yield) as a yellow oil. LCMS: [MH+-THP] 255 and TR=1.473 min.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=1)[CH3:2].Cl[CH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([C:3]1[N:7]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:19][CH2:20][CH2:21][NH:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:12][CH2:13]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1C1CCNCC1
Reactant: Fc1ccc(NCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2ccccc2n1C1CCN(CCCNc2ccc(F)cc2)CC1
Temperature: 100 °C
Yield: 37 %

Procedure:
To a stirred solution of 2-ethyl-1-piperidin-4-yl-1H-benzimidazole (0.6 g) and (3-chloropropyl)-(4-fluorophenyl)amine (0.4 g) in DMF (7 ml) was added K2CO3 (1.1 g) and KI (0.1 g). The mixture was heated at 100° C. for 2 h, and then allowed to cool to rt. Water (50 ml) was added and the mixture extracted with ethyl acetate (80 ml), and the organic layer separated and washed with water. This was further dried and concentrated in vacuo. The oil was purified by flash chromatography (95:5 DCM:MeOH), and the solid recrystallised from ether to yield 0.3 g of the title compound as colourless crystals. Mp. 121-124° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[O:19][C:20](=[O:42])[CH2:21][CH2:22][NH:23][C:24](=[O:41])[C:25]1[CH:30]=[CH:29][C:28]([CH:31]([CH2:39]O)[CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:27][CH:26]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:39][CH:31]([C:28]3[CH:29]=[CH:30][C:25]([C:24]([NH:23][CH2:22][CH2:21][C:20]([OH:42])=[O:19])=[O:41])=[CH:26][CH:27]=3)[CH2:32][CH2:33][CH2:34][C:35]([F:36])([F:38])[F:37])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CO)CCCC(F)(F)F)cc1
Product: CC(C)(C)c1ccc(-c2ccc(OCC(CCCC(F)(F)F)c3ccc(C(=O)NCCC(=O)O)cc3)cc2)cc1

Procedure:
The title compound is prepared by essentially following the procedures as described in Example 8, using 4′-tert-butyl-biphenyl-4-ol and 3-[4-(5,5,5-trifluoro-1-hydroxymethyl-pentyl)-benzoylamino]-propionic acid methyl ester as starting materials. MS (ES): 554.2 [M+H]−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.OO.[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13]>O1CCCC1>[NH2:9][C:4]1[N:3]([O:15][C:12](=[O:14])[CH3:13])[C:2](=[NH:1])[N:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Cl)nc(N)n1
Agent: OO
Solvent: C1CCOC1
Product: CC(=O)On1c(N)cc(Cl)nc1=N
Temperature: 40 °C
Yield: 11 %

Procedure:
5 g (0.035 mole) of 2,6-diamino-4-chloropyrimidine are dissolved in 50 ml of anhydrous tetrahydrofuran. 7 ml of a 70% aqueous hydrogen peroxide solution and 16 ml of acetic anhydride are added dropwise while stirring at a temperature of 40° C. in half an hour. The mixture is stirred at 60° C. for further two hours. After evaporating the tetrahydrofuran 50 ml of water are added to the residue, then it is kept in a refrigerator for a night. Thus 4.00 g (57%) of the aimed compound separate. Further 0.77 g (11%) of this compound is obtained by filtering the product achieved by the second separation.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([OH:38])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:40](OC(=O)C)(=[O:42])[CH3:41].N1C=CC=CC=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([O:38][C:40](=[O:42])[CH3:41])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4[C@@H](O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@H](O)[C@H]2[C@@H](CC[C@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]32C)[C@@H]2C[C@@H]3O[C@]4(CC[C@@H](C)CO4)[C@@H](C)[C@@H]3[C@@]12C

Procedure:
(3β,5α,11β,12β,25R)-3-(t-butyldimethylsilyloxy)spirostan-11,12-diol was selectively acetylated with acetic anhydride, pyridine and dimethylaminopyridine in methylene chloride to give the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:2]2[N:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:14]=[C:13]([O:12][CH3:11])[C:18]=1[O:19][CH3:20]
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cnc3[nH]ccc3n2)cc(OC)c1OC
Temperature: 110 °C
Yield: 88.5 %

Procedure:
A flask was charged with 2-bromo-5H-pyrrolo[2,3-b]pyrazine (9.5 g, 48 mmol), 3,4,5-trimethoxyphenylboronic acid (13.22, 62 mmol), and K2CO3 (19.9, 144 mmol). Dioxane (213 ml) and water (71 ml) were added, and the solution was vacuum degassed under argon. [1,1′-bis(Diphenylphosphino)ferrocene]dichloro-palladium(ll) (3.92 g, 4.8 mmol) was added, and the reaction mixture was refluxed (110° C.) overnight. The reaction mixture was filtered through a plug of celite using dichloromethane, and the filtrate was concentrated giving a black oil. The oil was purified by silica gel chromatography using 5%-60% EtOAc in hexanes as eluant to provide 12.12 g (89%) of 2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>CC(N(C)C)=O.ClCCl>[CH:19]1([NH:22][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[N:3]=2)[CH2:21][CH2:20]1
Reactant: CCOC(=O)c1cc(F)c(N2CCCC2)nc1Cl
Reactant: NC1CC1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(F)c(N2CCCC2)nc1NC1CC1
Temperature: 90 °C

Procedure:
A solution of ethyl 2-chloro-5-fluoro-6pyrrolidinyl-3-pyridinecarboxylate (Example C-2, 500 mg, 1.83 mmol) and cyclopropylamine (2 mL) in DMA (1 mL) was sealed in a pressure bottle and heated at 90° C. for 1 day. The reaction mixture was diluted with dichloromethane (40 mL), washed with water and dried on sodium sulfate. Flash chromatography on a silica gel column using dichloromethane/hexane (3:2) as eluent provided 270 mg of the title compound as an oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:19])([F:18])[C:7]1[CH:17]=[CH:16][C:10](/[CH:11]=[CH:12]/[C:13](O)=[O:14])=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)Cl>[F:5][C:6]([F:19])([F:18])[C:7]1[CH:17]=[CH:16][C:10](/[CH:11]=[CH:12]/[C:13]([Cl:3])=[O:14])=[CH:9][CH:8]=1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)/C=C/c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (335 ml, 4.6 mmol) was added at 0° C. to 4-trifluoromethyl-E-cinnamic acid (1 g, 4.6 mmol) and pyridine (375 ml, 4.6 mmol) in dry CH2Cl2. The mixture was then stirred for 1 h without cooling, again cooled to 0° C. and filtered with the exclusion of moisture. The filtrate (10 ml) contained the title compound and was used in aliquots for the next reaction step.
Reaction SMILES: [Zn](C)[CH3:2].[CH2:4]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH:20]=[O:21])[CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH2:4]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([C@@H:20]([OH:21])[CH3:2])[CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=CC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: C[Zn]C
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOCC
Product: C[C@H](O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
Using Schlenck glassware and air-free conditions, anhydrous ethyl ether freshly distilled from sodium/benzophenone (2.43 mL) was added to catalyst 13 prepared according to Example 11, protocol 1. Freshly distilled titanium tetraisopropoxide (0.430 mL, 1.46 mmol) was added, and the reaction was cooled to −78° C. Commercial Me2Zn (1.21 mL, 2 M in toluene) was added, and the reaction was stirred at −78° C. for 1 hour. Aldehyde 9 (0.300 g, 1.21 mmol) in Et2O (0.3 mL) was added, and the reaction was warmed to −30° C. and stirred overnight. The reaction was then quenched at −30° C. with saturated aqueous NH4Cl. Et2O was added, and the reaction was filtered through Celite wet with Et2O. The reaction was dried with sodium sulfate, filtered, concentrated, and purified using an ISCO CombiFlash column (silica, 2:1 Hexane:EtOAc) to obtain 15 (0.162 g, 51%). HLPC analysis of the product presented in the Figures. 1H NMR (CDCl3, 300 MHz) 7.43-7.31 (5H, broad s), 5.16 (2H, s), 4.30-3.60 (2H, broad m), 3.63 (1H, dq, J=6.4, 6.4 Hz), 3.30-2.70 (2H, broad s), 2.15-1.90 (1H, broad s), 1.84-1.72 (1H, m), 1.76-1.56 (1H, m), 1.58-1.36 (2H, m), 1.23 (3H, d, J=6.4 Hz) ppm. 13C NMR (CDCl3, 75 MHz) 155.81, 137.04, 128.61, 128.08, 127.93, 68.35, 67.19, 46.61, 45.02, 43.25, 27.08, 24.37, 20.95 ppm. LRMS m/z 263.68 (M+, C15H21NO3, requires 263.15.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39]>CN(C)C=O>[CH2:38]([NH:40][C:41]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH2:22][CH2:21][N:20]([C:23]4[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=4)[C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:42])[CH3:39]
Reactant: CCN=C=O
Reactant: Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 55 %

Procedure:
Compound A-09 (4-(3-hydroxyphenyl)-2-(morpholin-4-yl)-7-(pyridin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (34 mg, 0.09 mmol) obtained in Example 1-A-09 was dissolved in dimethylformamide (1 mL), and diisopropylethylamine (32 μL) and ethyl isocyanate (32 μL) were added, followed by stirring at 60° C. for 12 hours. The reaction mixture was poured onto water, followed by extraction with dichloromethane, and the organic layer was dried over sodium sulfate. After the drying agent was filtered off, followed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol), to obtain the desired compound (colorless powder, 22 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[O:5][CH:6]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:5][CH:6]=1
Reactant: O=Cc1cc(Br)co1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Brc1coc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of 4-bromofuran-2-carbaldehyde (500 mg, 2.85 mmol) and pyrrolidine (0.47 mL, 5.74 mmol) and CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (1.2 g, 5.71 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc (100 mL) and the organic layer was washed with brine then dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (silica, 0-5% MeOH in CH2Cl2) to afford the sub-title compound (400 mg, 61%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:33])[C:14]1[CH:19]=[C:18]([CH:20]=C)[C:17]([F:22])=[C:16]([F:23])[C:15]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=1[F:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:35].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Si:1]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:33])[C:14]1[CH:19]=[C:18]([CH:20]=[O:35])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=1[F:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(C(=O)NOCCO[Si](C)(C)C(C)(C)C)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCONC(=O)c1cc(C=O)c(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 50.9 %

Procedure:
N-[2-(t-Butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-vinyl-benzamide (6.35 g, 10.7 mmol) prepared in Process A was dissolved in a mixed solvent of THF (100 ml) and water (30 ml). Aqueous solution of osmium tetroxide (0.1 mM, 2 ml, 0.2 mmol), and sodium metaperiodate (9.0 g, 42.1 mmol) were added at 10° C., and the mixture was stirred at room temperature for 17 hours. Insoluble material was removed through a celite column, and the solution was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (300 g, n-hexane/ethyl acetate (5:1)) to give N-[2-(t-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-formyl-benzamide (3.24 g, 51%) as a brown solid.
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH:5]1[NH:14][C:15]([C:17]1[C:18](Cl)=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:16])[CH2:11]2>CC(N(C)C)=O.CCOC(C)=O>[CH:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH:5]1[NH:14][C:15]([C:17]1[C:18]([S:2][CH3:1])=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:16])[CH2:11]2
Reactant: C[S-]
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(Cl)nc1Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CSc1nc(Cl)ccc1C(=O)NC1C2CC3CC(C2)CC1C3
Temperature: 60 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
Sodium thiomethoxide (0.409 g, 5.84 mmol) was added to N-(2-adamantyl)-2,6-dichloro-pyridine-3-carboxamide (2 g, 6.15 mmol) in DMA (10 mL) at 20° C. under nitrogen. The resulting suspension was stirred at 60° C. for 3 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (3×20 mL), and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product which was purified by crystallisation from EtOAc/isohexane to afford N-(2-adamantyl)-6-chloro-2-methylsulfanyl-pyridine-3-carboxamide (1.150 g, 55.5%) as a white solid
Reaction SMILES: [OH:1][C:2]1[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:20]1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=1.CN(C)C=O>O>[CH3:29][O:28][C:22]1[CH:23]=[C:24]([O:26][CH3:27])[N:25]=[C:20]([O:1][C:2]2[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[N:21]=1
Reactant: COC(=O)c1ccc(C)nc1O
Reactant: COc1cc(OC)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)nc1Oc1nc(OC)cc(OC)n1
Yield: 8 %

Procedure:
5.0 g (0.03 mol) of methyl 2-hydroxy-6-methylnicotinate, 5.0 g (0.03 mol) of potassium carbonate, 5.7 g (0.03 mol) of 2-chloro-4,6-dimethoxypyrimidine and 50 ml of N,N-dimethylformamide were weighed, and were reacted at 100° C. for 4 hours. The reaction mixture was then poured into water, and was extracted with 100 ml of ethyl acetate. The organic layer was then washed with water and a saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 0.73 g of the aimed product.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:20].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C)C=O>[C:2]([CH:3]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])([OH:20])=[O:1]
Reactant: COC(=O)CCCC=CC1C2CCC(C2)C1CO
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCC=CC1C2CCC(C2)C1C(=O)O
Temperature: 20 °C
Reaction time: 9 h
Yield: 65 %

Procedure:
A solution of 25.0 g (0.1 mole) of methyl 6-(3-hydroxymethyl-bicyclo[2.2.1]hept-2-yl)-hex-5-enoate in 60 ml of absolute dimethylformamide is added to 132.0 g (0.35 mole) of pyridinium dichromate in 200 ml of absolute dimethylformamide at 20° C. The reaction mixture is stirred at 20° C. for 9 hours, left to stand for 14 hours and then poured into 1.9 liters of water and extracted with diethyl ether. After drying over Na2SO4, the mixture is evaporated in vacuo and the residue is chromatographed on silica gel, using methylene chloride/methanol (95:5) to give 17.3 g of methyl 6-(3-carboxy-bicyclo-[2.2.1]hept-2-yl)-hex-5-enoate (yield: 65%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1I.Br[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]>>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: Clc1ccc(I)c(Cl)c1
Product: O=[N+]([O-])c1cc(Br)ccc1-c1ccc(Cl)cc1Cl

Procedure:
2,4-Dichloroiodobenzene and 2,5-dibromonitrobenzene were reacted under Ullmann conditions to give 4-bromo-2',4'-dichloro-2-nitrobiphenyl, m.p. 112°-115° C. This was reduced with stannous chloride to give 2-amino-4-bromo-2',4'-dichlorobiphenyl, b.p. 170°-175° C./0.2 mm. This was subjected to the Schiemann reaction using fluoroboric acid to give 4-bromo-2',4'-dichloro-2-fluorobiphenyl, m.p. 63°-65° C. This was reacted with cuprous cyanide in dimethyl formamide to give 2',4'-dichloro-4-cyano-2-fluorobiphenyl, m.p. 98°-103° C. which was then reacted with methylmagnesium iodide followed by hydrolysis with dilute hydrochloric acid to yield 4-acetyl-2',4'-dihloro-2-fluorobiphenyl, m.p. 65°-67° C.