Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[C:13]2[CH:16]([F:18])[F:17])[CH:11]=[CH:10][CH:9]=[N:8]3)=[CH:4][CH:3]=1.[C-:19]#[N:20].[Na+].CCOC(C)=O.CCCCCC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([C:19]#[N:20])([CH:16]([F:18])[F:17])[C:14]=2[CH:15]=1
Reactant: [C-]#N
Reactant: FC(F)c1c2cc(Cl)ccc2nc2ncccc12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#CC1(C(F)F)c2cc(Cl)ccc2Nc2ncccc21
Reaction time: 15 h
Yield: 52.9 %

Procedure:
Method KKK To a stirred solution of 7-chloro-9-(difluoromethyl)-4-azaacridine (91) (1.28 g, 4.84 mmol) in anhydrous DMF (30 mL) at room temperature was added NaCN (711 mg, 14.51 mmol). After 15 h at room temperature, the reaction was quenched with H2O (150 mL), and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 30% EtOAc-hexane) furnished 92 (747 mg, 53% yield) as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH:32]1([NH2:35])[CH2:34][CH2:33]1>>[CH:32]1([NH:35][C:4](=[O:5])[C:3]2[CH:8]=[CH:9][C:10]([O:12][C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:11][C:2]=2[OH:1])[CH2:34][CH2:33]1
Reactant: COC(=O)c1ccc(OC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1O
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc(OC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1O

Procedure:
Methyl 2-hydroxy-4-(trityloxy)benzoate (340 mg, 0.83 mmol) was dissolved in cyclopropylamine (3 mL) and left at room temperature for a week. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (0-20% ethyl acetate in petroleum ether) to give the subtitled compound (210 mg).
Reaction SMILES: [CH:1](NC1CCCCC1)(C)C.[CH3:11][C:12]([CH3:26])=[C:13]([N:18]1[C@H:21]([CH2:22][CH:23]=[CH2:24])[CH2:20][C:19]1=[O:25])[C:14]([O:16][CH3:17])=[O:15].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:11][C:12]([CH3:26])=[C:13]([N:18]1[C@H:21]([CH2:22][CH:23]=[CH2:24])[C@H:20]([CH3:1])[C:19]1=[O:25])[C:14]([O:16][CH3:17])=[O:15]
Reactant: CC(C)NC1CCCCC1
Reactant: C=CC[C@@H]1CC(=O)N1C(C(=O)OC)=C(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@@H]1[C@H](C)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
1.55M Butyl lithium-hexane solution (1.66 ml) was added to a solution of N-isopropylcyclohexylamine (0.29 ml) in tetrahydrofuran (3 ml) at -70° C., and the mixture was stirred for 20 minutes at -70° C. and allowed to warm up to 0° C. This mixture was added to a solution of methyl 3-methyl-2-[(4R)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (100 mg) in tetrahydrofuran (3 ml) at -70° C., and the mixture was stirred for 1 hour at -70° C. and allowed to warm up to -30° C. during 30 minutes. 1N Hydrochloric acid (3.6 ml) was added to the reaction mixture at -70° C., and the mixture was diluted with ethyl acetate (30 ml). The solution was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (5:1-2:1) to give methyl 3-methyl-2-[(3S,4R)-3-methyl-2-oxo-4-allylazetidin-1-yl]but-2-enoate (20 mg); IR (CH2Cl2): 1740, 1715 cm-1 ; NMR (CDCl3) δ: 1.23 (d, 3H, J=8 Hz), 1.95 (s, 3H), 2.19 (s, 3H), 1.36 (t, 2H, J=7 Hz), 3.36 (dq, 1H, J=6, 8 Hz), 3.75 (s, 3H), 4.04 (dt, 1H, J=6, 7 Hz), 4.9-5.2 (m, 2H), 5.4-5.9 (m, 2H); and methyl 3-methyl-2-[(3R,4R)-3-methyl-2-oxo-4-allylazetidin-1-yl]but-3-enoate (28 mg); IR (CH2Cl2): 1740 cm-1. NMR (CDCl3) δ: 1.27 and 1.29 (a pair of d, 3H, J=8 Hz), 1.83 (broad s, 3H), 2.1-2.9 (m, 2H), 2.85 (dq, 1H, J=2, 8 Hz), 3.2-3.4 (m, 1H), 3.74 and 3.76 (a pair of s, 3H), 4.8-5.2 (m, 5H), 5.5-6.0 (m, 1H); and a mixture of methyl 3-methyl-2-[(3R,4R)-3-methyl-2-oxo-4-allylazetidin-1-yl]but-2 -enoate and methyl 3-methyl-2-[(3S,4R)-3-methyl-2-oxo-4-allylazetidin-1-yl]but-3-enoate (36 mg): IR (CH2Cl2): 1740 cm-1.
Reaction SMILES: [O:1]([CH2:8][C:9](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]([NH:23][NH2:24])=O)=[CH:20][C:15]=2[NH:14][CH:13]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1.O=P(Cl)(Cl)Cl>>[O:1]([CH2:8][C:9]1[S:34][C:21]([C:19]2[CH:18]=[CH:17][C:16]3[NH:12][CH:13]=[N:14][C:15]=3[CH:20]=2)=[N:23][N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(OCc2nnc(-c3ccc4[nH]cnc4c3)s2)cc1

Procedure:
The compound was synthesized starting from phenoxyacetic acid (153 mg; 1 mmol), benzimidazol-5-carbohydrazide (176 mg; 1 mmol), Lawesson's reagent (606 mg; 1.5 mmol) and POCl3 (0.137 ml; 1.5 mmol) as described in method 3; yield: 0.031 g (10.1%); MS m/z: 309.0 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 5.64 (s, 2H); 6.99-7.03 (m, 1H); 7.09-7.12 (m, 2H); 7.32-7.36 (m, 2H); 7.84 (d, 1H, 3J=8.3 Hz); 7.98 (dd, 1H, 4J=1.7 Hz, 3J=8.3 Hz); 8.31 (d, 1H, 4J=1.7 Hz); 8.90 (s, 1H); HPLC (METHOD [A]): rt 12.07 min (95.9%)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:21])[S:5][C:6]=1[C:7]([OH:9])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCCC1>[CH2:37]([NH:44][C:7]([C:6]1[S:5][C:4]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:21])=[N:3][C:2]=1[CH3:1])=[O:9])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1nc(N2CCN(c3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1nc(N2CCN(c3ccccc3)C2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7 %

Procedure:
To a solution of 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylic acid (0.30 g, 1.00 mmol) and 4-methylmorpholine (0.15 mL, 1.10 mmol) in tetrahydrofuran (50 mL) was added isobutyl chloroformate (0.15 mL, 1.3 mmol) at 0° C. The resulting mixture was stirred at ambient temperature for 2 hours and benzylamine (0.20 mL, 1.80 mmol) was added. The reaction mixture was kept stirring for 17 hours at ambient temperature. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the title compound as a white powder in 7% yield (0.030 g): mp 234-236° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, J=5.7 Hz, 1H), 7.60 (d, =7.8 Hz, 2H), 7.39-7.12 (m, 8H), 4.35 (d, J=5.7 Hz, 2H), 4.14-3.92 (m, 4H), 2.46 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.6, 156.7, 152.7, 150.7, 139.5, 138.9, 128.8, 128.1, 127.1, 126.6, 123.3, 118.3, 117.8, 42.4, 42.3, 41.2, 17.0; MS (ES+) m/z 393.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[NH:9][C:8]1=[O:17])[C:5]#[N:6].[C-:19]#[N:20].[K+].O>CO>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:7]1([C:19]#[N:20])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[NH:9][C:8]1=[O:17])[C:5]#[N:6]
Reactant: [C-]#N
Reactant: COC(=O)C(C#N)=C1C(=O)Nc2ccc(Cl)cc21
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)C(C#N)C1(C#N)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 86 %

Procedure:
A stirred suspension of crude (5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-cyanoacetic acid methyl ester, intermediate 1 (56.0 g, 0.21 mol) in methanol (750 ml) was treated, in portions, with potassium cyanide (13.8 g, 0.21 mol) followed by water (45 ml). The mixture was stirred at ambient temperature for 7 hours and the resultant black solution was left to stand overnight. The solvent was removed in vacuo, water (500 ml) was added and the mixture acidified by the addition of 2M hydrochloric acid [CAUTION: TRACES OF CYANIDE MAY STILL BE PRESENT!]. The mixture was extracted with dichloromethane (3×300 ml). The combined extracts were washed with water (2×300 ml) and dried (MgSO4). The solvent was removed in vacuo to give the crude (5-chloro-3-cyano-2-oxo-2,3-dihydro-1H-indol-3-yl)-cyanoacetic acid methyl ester as a pale-brown solid (53.3 g, 86%). This was a mixture of diastereomers, which was sufficiently pure by 1H NMR for subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:15][N:14]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:36]1[N:41]=[C:40]([NH2:42])[N:39]=[C:38]([NH2:43])[CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[NH:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:36]3[N:41]=[C:40]([NH2:42])[N:39]=[C:38]([NH2:43])[CH:37]=3)=[CH:20][CH:19]=2)=[N:15][N:14]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: Oc1ccc(-c2nnc(Nc3cc(C(F)(F)F)ccc3Cl)o2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4cc(C(F)(F)F)ccc4Cl)o3)cc2)nc(N)n1
Temperature: 80 °C
Yield: 56.5 %

Procedure:
4-(5-{[2-chloro-5-(trifluoromethyl)phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (177.85 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (200.0 mg, 1.0 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 6-chloro-2,4-diamino-pyrimidine (86.7 mg, 0.6 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 180° C. for 30 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 50 mL of EtOAc and ca. 50 mL of saturated aqueous NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as an off-white solid (131.1 mg). Yield 56.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][C:12](=[O:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])[C:5]([OH:7])=O.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[CH2:44]([O:46][C:47]([CH2:49][N:50]1[C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=2[NH:54][CH2:53][CH2:52][C:51]1=[O:61])=[O:48])[CH3:45].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][C:12](=[O:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])[C:5]([N:54]1[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[N:50]([CH2:49][C:47]([O:46][CH2:44][CH3:45])=[O:48])[C:51](=[O:61])[CH2:52][CH2:53]1)=[O:7]
Reactant: Cc1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)O)cc1Cl
Reactant: CCOC(=O)CN1C(=O)CCNc2ccccc21
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)CCN(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3C)c(Cl)c2)c2ccccc21
Temperature: 25 °C
Yield: 77.5 %

Procedure:
To a solution of 3-chloro-4-[2-(2-methylphenyl)benzoylamino]benzoic acid (309 mg), diphenyl chlorophosphate (251 mg), 1-ethoxycarbonylmethyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (210 mg) in tetrahydrofuran (15 ml) was added triethylamine (172 mg) at 0° C. The resulting mixture was allowed to warm to ambient temperature where it was maintained for 5 hours. The solvent was evaporated and diluted with ethyl acetate and washed with water, diluted hydrochloric acid, saturated sodium bicarbonate aqueous solution and brine. The organic layer was dried over magnesium sulfate and concentrated to give 5-{3-chloro-4-[2-(2-methylphenyl)benzoylamino]benzoyl}-1-ethoxycarbonylmethyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (390 mg) which was purified by recrystallization from a mixture of ethyl acetate and n-hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].C(N(CC)CC)C.[Cl:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26](Cl)=[O:27].O>C1COCC1>[Cl:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12])=[O:27]
Reactant: O=C(Cl)CCOCCCl
Reactant: COC(=O)c1ccc(N)c(C)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)CCOCCCl)c(C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.70 g (10.3 mmol) methyl 4-amino-3-methyl-benzoate in 10 ml THF are combined with 2.84 ml (20.6 mmol) triethylamine and stirred for 20 minutes at ambient temperature. Then a solution of 1.78 g (10.4 mmol) 3-(2-chloro-ethoxy)-propionic acid-chloride in 25 ml THF is added dropwise and the mixture is stirred for a further 2.5 hours at ambient temperature. Then water is added and the mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down completely i. vac. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate=7:3->6:4).
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1.[C:17]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]([O:11][CH3:17])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(O)c(C2CCCC2)cc1Br
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
To a solution of 4-bromo-2-cyclopentyl-5-nitro-phenol (310 mg, 1.08 mmol) and Cs2CO3 (529 mg, 1.62 mmol) in DMF (2.0 mL) was added iodomethane (769 mg, 337 μL, 5.42 mmol) dropwise. The reaction was stirred at 50° C. under inert atmosphere for 16 h. The reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. Purification by silica gel chromatography (0-20% ethyl acetate/hexane) provided 1-bromo-5-cyclopentyl-4-methoxy-2-nitrobenzene as a light yellow oil (288 mg, 89% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.65 (d, J=6.6 Hz, 2H), 3.87 (s, 3H), 3.29-3.21 (m, 1H), 1.99-1.91 (m, 3H), 1.81-1.50 (m, 5H).
Reaction SMILES: [Br-].[F:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[CH2:36]([CH:41]1[CH2:46][CH2:45][CH:44]([CH:47]2[CH2:52][CH2:51][CH:50]([CH2:53][CH:54]=O)[CH2:49][CH2:48]2)[CH2:43][CH2:42]1)[CH2:37][CH2:38][CH2:39][CH3:40].CCOCC>C1COCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:7]=[CH:8]\[CH2:54][CH2:53][CH:50]2[CH2:51][CH2:52][CH:47]([CH:44]3[CH2:43][CH2:42][CH:41]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:46][CH2:45]3)[CH2:48][CH2:49]2)=[CH:28][CH:29]=1
Reactant: CCCCCC1CCC(C2CCC(CC=O)CC2)CC1
Reactant: Fc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC1CCC(C2CCC(CC/C=C\c3ccc(F)cc3)CC2)CC1
Yield: 57.8 %

Procedure:
4-fluorophenethyltriphenylphosphoniumbromide (4.2 g, 9 mmol) was dried and then dissolved in THF (10 ml), followed by stirring under ice cooling, adding potassium-t-butoxide (1.0 g, 9 mmol) slowly to the obtained reaction solution, stirring at room temperature for 2 hours after the completion of dropping, adding a THF (50 ml) solution of 4-(4-pentylcyclohexyl)-cyclohexylacetoaldehyde (2.7 g, 9.7 mmol) and further stirring for 5 hours, adding ether after the completion of reaction, filtering off the obtained white crystals deposited, concentrating the filtrate under reduced pressure, and purifying the obtained brown oil by means of silica gel column chromatography, to obtain a mixture (2.0 g, 5.2 mmol) of 1-(4-fluorophenyl)-4-(4-(4-pentylcyclohexyl)cyclohexyl)-2Z-butene with its E-isomer.
Reaction SMILES: [OH-].[Na+:2].[Br:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][S:15][CH2:14][CH2:13]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]([O:22]CC)=[O:21])[C:7]2=[CH:8][CH:9]=1.O>CCO>[Br:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][S:15][CH2:14][CH2:13]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]([O-:22])=[O:21])[C:7]2=[CH:8][CH:9]=1.[Na+:2]
Reactant: CCOC(=O)CN1C(=O)C2(CCSCC2)c2cc(Br)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])CN1C(=O)C2(CCSCC2)c2cc(Br)ccc21
Temperature: 60 °C
Reaction time: 14 h

Procedure:
5 M Sodium hydroxide solution (0.748 mL, 3.74 mmol) was added to a solution of ethyl (5-bromo-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)acetate from Step D (479 mg, 1.25 mmol) in EtOH(2 mL) and the mixture was heated to 60° C. After 14 h, H2O (5 mL) was added to the reaction and the resulting precipitate was collected by filtration to give the desired product. MS: m/z=357 (M+1).
Reaction SMILES: [CH2:1]1[C:15](=O)[C:14]2[C:5](=[C:6]([OH:18])[C:7]3[C:12]([C:13]=2[OH:17])=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3](=O)[CH2:2]1.[NH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([CH2:28][OH:29])[CH2:23]1>C(O)C>[OH:29][CH2:28][CH:24]1[CH2:25][CH2:26][CH2:27][N:22]([CH2:21][CH2:20][NH:19][C:15]2[C:14]3[C:13](=[O:17])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6](=[O:18])[C:5]=3[C:3]([NH:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH:24]([CH2:28][OH:29])[CH2:23]3)=[CH:2][CH:1]=2)[CH2:23]1
Reactant: O=C1CCC(=O)c2c1c(O)c1ccccc1c2O
Reactant: NCCN1CCCC(CO)C1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)c2c(NCCN3CCCC(CO)C3)ccc(NCCN3CCCC(CO)C3)c21

Procedure:
Although not shown in scheme 3, the method follows that of HAQ70 using leucoquinizarin (0.23 g, 0.95 mmol), [1-(2-aminoethyl)-piperidin-3-yl-]methanol (0.06 g, 3.8 mmol) and ethanol (25 mL). The title compound was yielded as a dark-blue solid (0.15 g, 29%). M.p. 112-114° C.; δH(250 MHz; CDCl3); 1.15 (m, 2H, 2×CH2CHCH2OH), 1.5-1.75 (m, 6H, 2×CH2CH2CH and 2×CH2CH2CH2), 1.85 (m, 2H, 2×CH2CH2CH), 2.3 (m, 4H, 4×ring-H), 2.5 (s (broad), 4H, 2×ring-H, 2×OH), 2.65 (t, 4H, J=5 Hz, 2×HNCH2CH2N), 2.75 (2×d, 2H, J=3 Hz and 12 Hz, 2×ring-H), 3.42 (q, 4H, J=5 Hz, 2×HNCH2CH2N), 3.55 (2×d, 2H, J=5 Hz and 12 Hz, 2×CHCH2OH), 3.7 (2×d, 2H, J=9 Hz and 12 Hz, 2×CHCH2OH), 7.1 (s, 2H, C(2)H and C(3)H), 7.6 (m, 2H, C(6)H and C(7)H), 8.3 (m, 2H, C(5)H, C(8)H) and 10.75 (t, 2H, C(1)NH and C(4)NH); δC(62.9 MHz; CDCl3); 24.08, 26.92, 37.90, 40.52, 54.43, 56.95, 57.75, 65.70, 109.89, 123.87, 126.13, 132.09, 134.46, 146.6 and 182.36; FAB MS, m/z(M+H)+ 521; IR υmax/cm−1; 3400 (OH), 3090 (Ar—CH), 2960-2800 (CH2, CH3), 1650, 1585, 1550, 1520, 1265, 1175 and 1125; Anal. calcd for C30H40N4O4: C, 69.21; H, 7.74; N, 10.76. Found: C, 69.22; H, 7.88; N, 10.69.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:22])[N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[C:13](Br)[CH:14]=1)#[N:2].[CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[CH2:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:22])[N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[C:13]([CH:24]=[CH:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:14]=1)#[N:2]
Reactant: C=Cc1ccccn1
Reactant: N#Cc1ccccc1-c1cc(Br)cn(-c2ccccc2)c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1-c1cc(C=Cc2ccccn2)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 15 %

Procedure:
A mixed liquid of 100 mg of 3-(2-cyanophenyl)-1-phenyl-5-bromo-1,2-dihydropyridin-2-one, 100 mg of 2-vinylpyridine, 6 mg of palladium acetate, 17 mg of tri-(o-tolyl)phosphine and 3 ml of triethylamine was stirred at 130° C. for 2 hours in nitrogen atmosphere. After cooling to room temperature, ethyl acetate was added thereto. The extract was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane), to give 16 mg of the title compound as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=1[F:18].[NH2:19][C:20]1[C:21]([N:29]2[CH2:34][C@H:33]([CH3:35])[C@@H:32]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C@H:31]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:30]2)=[C:22]2[CH2:28][CH2:27][O:26][C:23]2=[N:24][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Si:37]([O:36][C@@H:32]1[C@@H:33]([CH3:35])[CH2:34][N:29]([C:21]2[C:20]([NH:19][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:18])=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:14]=3)=[O:17])=[CH:25][N:24]=[C:23]3[O:26][CH2:27][CH2:28][C:22]=23)[CH2:30][C@H:31]1[NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])([C:40]([CH3:43])([CH3:41])[CH3:42])([CH3:38])[CH3:39]
Reactant: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (13.3 mg, 0.0525 mmol), tert-butyl ((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (16.7 mg, 0.0349 mmol) and HATU (46.2 mg, 0.122 mmol) was added DMF (2.0 mL) followed by DIPEA (70.0 μL, 0.402 mmol). The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to afford the sub-title compound as a brown solid (24.9 mg). LCMS calc. for C36H47F3N5O5Si (M+H)+: m/z=714.3. found 714.3.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[H-].[Na+].[CH2:10](Br)[C:11]#[CH:12].O>O1CCCC1>[CH2:12]([N:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1)[C:11]#[CH:10]
Reactant: C#CCBr
Reactant: O=Cc1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCn1ccc(C=O)c1
Reaction time: 0.17 h

Procedure:
2.924 g of pyrrole-3-carboxaldehyde (J. Org. Chem. 1981, Vol. 46, p. 839) dissolved in 45 ml of tetrahydrofuran and 1.488 g of sodium hydride as 50% in oil were admixed and then were stirred for 10 minutes cold, then for 40 minutes at room temperature. After cooling, 2.5 ml of propargyl bromide were added with stirring at 5 C. for 90 minutes. A further 2 ml of propargyl bromide were added with stirring at 5° C. for 1 hour and the mixture was poured into water and extracted with methylene chloride. The solvent was distilled off at atmospheric pressure to obtain 2.868 g of 1-(2-propynyl)-1H-pyrrole-3-carboxaldehyde which was purified by chromatography on silica gel and elution with a 65-35 hexane-ethyl acetate mixture to obtain 2.868 g of the said product.