Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].CN(N=O)C(N[N+]([O-])=O)=N.[N+](=[CH2:15])=[N-].[F:16][C:17]1[CH:18]=[C:19]([C:30]23[CH2:37][CH2:36][C:33]([CH2:38][CH2:39]/[CH:40]=[CH:41]/[C:42]([O:44][CH3:45])=[O:43])([CH2:34][CH2:35]2)[CH2:32][O:31]3)[CH:20]=[C:21]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:22]=1>C1COCC1.O.CCOCC>[F:16][C:17]1[CH:18]=[C:19]([C:30]23[CH2:35][CH2:34][C:33]([CH2:38][CH2:39][CH:40]4[CH2:15][CH:41]4[C:42]([O:44][CH3:45])=[O:43])([CH2:36][CH2:37]2)[CH2:32][O:31]3)[CH:20]=[C:21]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:22]=1
Reactant: COC(=O)/C=C/CCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Reactant: C=[N+]=[N-]
Agent: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CC1CCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a vigorously stirred 0° C. biphasic solution of Et2O (10 mL), 40% aq. KOH (2 mL, 14.0 mmol) and water (2 mL) was added portionwise N-methyl-N′-nitro-N-nitrosoguanidine (0.844 g, 2.87 mmol) over 15 min. When addition had been completed, the ether layer was separated and dried with KOH pellets. The contents were allowed to stand for 5 min, then redried over fresh KOH pellets. To 5 mL of the diazomethane solution (˜50% of total volume) was added a 0° C. solution of (E)-methyl 5-(1-(3-fluoro-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)pent-2-enoate (0.3 g, 0.717 mmol) in THF (2 mL). A mixture of PdOAc2 (0.016 g, 0.072 mmol) in THF (2 mL) was added slowly and the reaction was stirred at 0° C. for 15 min and then the remainder of the diazomethane solution (˜5 mL) was added slowly. The reaction was allowed to warm to rt and stirred for 1 h, then was filtered and then concentrated in vacuo. The residual crude oil was chromatographed (SiO2; gradient from 0% to 30% EtOAc/hexane over 10 min) to give the title compound (0.26 g, 0.601 mmol, 84% yield) as a clear oil. 1H NMR (CDCl3) δ: 6.86 (t, J=1.8 Hz, 1H), 6.74 (ddd, J=10.1, 2.4, 1.5 Hz, 1H), 6.68 (dt, J=10.5, 2.3 Hz, 1H), 5.40 (t, J=3.2 Hz, 1H), 3.93-3.84 (m, 1H), 3.83-3.76 (m, 2H), 3.68 (s, 3H), 3.62 (dtt, J=11.4, 4.1, 1.9 Hz, 1H), 2.03-1.94 (m, 5H), 1.88-1.81 (m, 2H), 1.75-1.56 (m, 7H), 1.43-1.16 (m, 7H), 0.75-0.68 (m, 1H); 19F NMR (CDCl3) δ: −112.1.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29]C)=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl.C(O)(C)C>C(Cl)Cl>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3cc(F)ccc3F)ccc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(c1ccc(OCCN2CCCCCC2)cc1)c1c(-c2cc(F)ccc2F)ccc2cc(O)ccc12
Yield: 46.1 %

Procedure:
Dissolve [4-(2-azepan-1-yl-ethoxy)-phenyl]-[2-(2,5-difluoro-phenyl)-6-methoxy-naphthalen-1-yl]-methanone (1.74 g, 3.37 mmol) in 20 mL methylene chloride and chill in ice. Add to this solution 2.0 mL of boron tribromide (5.3 g, 21.2 mmol) and allow to come to room temperature. Pour into a two phase solution of saturated sodium bicarbonate and 3/1 chloroform/isopropanol. Separate the organic layer, wash with water and dry over 3 Å sieves. Evaporate the solvent and purify on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient. Evaporate the solvent to yield 780 mg (46%) of the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[N+](=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N-]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH3:22][N:12]1[C:13](=[O:21])[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@H:11]1[CH2:10][CH2:9][C@@H:8]1[C@@H:18]2[CH2:19][CH2:20][C@@:3]2([CH3:4])[C@H:5]1[CH2:6][CH2:7][C@@H:2]2[O:1][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3CC[C@@H]12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a solution of 17β-hydroxy-4-methyl-5α-4-azaandrostan-3-one (2.37 g, 7.75 mmole) in methylene chloride (50 ml) was added ethyl diazoacetate (5.5 g, 48 mmole) and rhodium diacetate dimer (50 mg) intermittently in small portions during 60 hours resulting in ca. 35% conversion to product. The mixture was passed through a flash silica gel column eluted with 1.5% MeOH in CH2Cl2 to give the semi-purified product which was repurified via another flash silica gel column eluted with 60-95% EtOAc in hexane to give the title product. (Rf=0.3/EtOAc) mp. 39°-41° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:38](=S)=[S:39]>C(O)C>[CH2:23]([NH:22][C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:5]2[C:4]3[CH:3]=[C:2]4[NH:1][C:38](=[S:39])[N:12]([CH2:13][CH3:14])[C:11]4=[CH:10][C:9]=3[N:8]=[CH:7][N:6]=2)[CH2:16][CH2:17]1)=[S:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1N
Reactant: S=C=S
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCn1c(=S)[nH]c2cc3c(N4CCN(C(=S)NCc5ccccc5)CC4)ncnc3cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of 502.7 mg (1.19 mmol) of 4-(6-amino-7-ethylamino-4-quinazolinyl)-N-benzyl-1-piperazinethiocarboxamide obtained in Example 461 in 10 ml of ethanol were added 1.66 ml (11.9 mmol) of triethylamine and 10 ml (166 mmol) of carbon disulfide, followed by overnight stirring at room temperature in an atmosphere of argon. After the solvent was evaporated, the residue was purified by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([OH:23])[CH2:20][CH:19]([CH3:21])[O:18][CH:17]([CH3:22])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([O:23][CH3:24])[CH2:20][CH:19]([CH3:21])[O:18][CH:17]([CH3:22])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CC(O)(c2cccc(OCc3ccccc3)c2)CC(C)O1
Reactant: CI
Product: COC1(c2cccc(OCc3ccccc3)c2)CC(C)OC(C)C1

Procedure:
Using the procedure described in Example 3, the more polar isomer of 4-(3-benzyloxyphenyl)-4-hydroxy-2,6-dimethyltetrahydropyran (described in the portion of Example 52 which is concerned with the preparation of starting materials) was reacted with methyl iodide to give 4-(3-benzyloxyphenyl)-4-methoxy-2,6-dimethyltetrahydropyran, (77%, more polar isomer), as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH:17]([CH3:19])[CH3:18])[C:8]=2[S:7][C:6]=1[CH2:20]Br)=[O:4].[NH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[NH2:23]>C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Zn]>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH:17]([CH3:19])[CH3:18])[C:8]=2[S:7][C:6]=1[CH2:20][C:5]1[C:6]([CH3:20])=[N:23][N:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:13]=1[CH3:8])=[O:4]
Reactant: NNc1ccccn1
Reactant: COC(=O)c1c(CBr)sc2c1c(=O)n(C)c(=O)n2C(C)C
Agent: CC(=O)/C=C(/C)O
Agent: [Zn]
Product: COC(=O)c1c(Cc2c(C)nn(-c3ccccn3)c2C)sc2c1c(=O)n(C)c(=O)n2C(C)C

Procedure:
Prepared from 6-(bromomethyl)-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid methyl ester, zinc acetylacetonate hydrate and 2-hydrazinopyridine by the method of example 1 part e) to give the sub-title compound.
Reaction SMILES: C([O:5]C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[S:24][CH:23]=[N:22][C:21]=2[Cl:25])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[OH-:5].[NH4+:8].[Cl:25][C:21]1[N:22]=[CH:23][S:24][C:20]=1[CH2:19][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)CN(Cc1scnc1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(Cc1scnc1Cl)C1CCNCC1
Product: [NH4+]
Temperature: 0 °C
Yield: 178.7 %

Procedure:
Add 4-{[(4-chloro-thiazol-5-yl)methyl]-isobutyl-amino}-piperidine-1-carboxylic acid tert-butyl ester (23.49 g, 60.6 mmol) to dichloromethane (140 mL) and cool to 0° C. Slowly add trifluoroacetic acid (47.0 mL, 610 mmol) and stir for 15 minutes at 0° C. and three hours at room temperature. Cool the reaction to 0° C. and slowly add chilled 2 N NaOH (400 mL). Extract with ethyl acetate (3×200 mL), wash with 2 N NaOH (100 mL) and then with brine (100 mL). Dry the ethyl acetate over sodium sulfate and then filter off the sodium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 1.2% concentrated ammonium hydroxide/12% ethanol/chloroform then with 2% concentrated ammonium hydroxide/20% ethanol/chloroform to yield 15.59 g (89%) of [(4-chloro-thiazol-5-yl)methyl]-isobutyl-piperidin-4-yl-amine: mass spectrum (ion spray): m/z=288.1 (M+1); 1H NMR (CDCl3): δ=8.63 (s, 1H), 3.80 (s, 2H), 3.17-3.14 (m, 2H), 2.59-2.47 (m, 3H), 2.32 (d, 2H), 1.79-1.65 (m, 4H), 1.50-1.40 (m, 2H), 0.91 (d, 6H).
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]([OH:17])=O)[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[NH2:18][C@@H:19]([CH3:43])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21]>>[CH2:37]([O:36][CH:35]([O:39][CH2:40][CH3:41])[C@@H:34]([N:22]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)[C:20](=[O:21])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)=[O:13])[CH3:43])[CH3:42])[CH3:38]
Reactant: CN(CC(=O)O)NC(=O)NCc1ccncc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(pyridin-4-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-6) 99 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-11) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:11]([O:13][C:14](=[O:29])[CH:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(O)(=O)C.O>[CH2:11]([O:13][C:14](=[O:29])[CH:15]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:12]
Reactant: CCCCCCCCCCCCC(Br)C(=O)OCC
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCC(Oc1cccc([N+](=O)[O-])c1)C(=O)OCC
Temperature: 80 °C

Procedure:
A mixture of 250 g (1.79 mol) of m-nitrophenol, 602 g (1.79 mol) of Alphabromo-myristic acid ethyl ester, 248 g (1.79 mol) of potassium carbonate, and 1350 ml of dimethylformamide is heated to 80° C. for 3 h with stirring. The mixture is then poured out slowly into a mixture of 2300 ml of water and 250 ml of acetic acid. The product is extracted with dichloromethane. The solvent is removed by evaporation.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.Cl.[NH2:14]O.C([O-])([O-])=O.[K+].[K+].[C:22]([O:25]C(=O)C)(=O)[CH3:23]>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]2[N:14]=[C:22]([CH3:23])[O:25][N:10]=2)([CH3:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: NO
Reactant: CC(C)(C#N)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1nc(C(C)(C)c2ccc(Br)cc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
To a solution of 2-(4-bromophenyl)-2-methylpropionitrile (3 g, 13.38 mmol)) in EtOH (40 mL) was added hydroxylamine HCl (4.65 g, 66.93 mmol) and K2CO3 (9.25 g, 66.93 mmol). The reaction mixture was stirred at room temperature overnight. The resultant white precipitate was eliminated by filtration and the filtrate was concentrated to a yellow oil which was dissolved in pyridine (16 mL). Acetic anhydride (3.79 mL, 40.14 mol) was added and the reaction was stirred to reflux for 2 hours. The solution was quenched with 2N HCl (50 mL) and extracted 3 times with EtOAc (20 mL). The organics were combined, and dried with Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (40% EtOAc in Hexanes) to yield the product as a white foam (0.88 g, 30%). 1H NMR (CDCl3): δ 1.71 (s, 6H); 2.53 (s, 3H), 7.18-7.54 (m, 4H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:8]3[CH:9]=[C:10]([C:20]4[C:25]([Cl:26])=[CH:24][N:23]=[C:22](Cl)[N:21]=4)[N:11]([CH2:16][O:17][CH2:18][CH3:19])[C:12]=3[CH:13]=[CH:14][CH:15]=2)=[O:6])[CH2:3][CH2:2]1.Cl.[NH2:29][C@@H:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[OH:35].CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:26][C:25]1[C:20]([C:10]2[N:11]([CH2:16][O:17][CH2:18][CH3:19])[C:12]3[CH:13]=[CH:14][CH:15]=[C:7]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])[C:8]=3[CH:9]=2)=[N:21][C:22]([NH:29][C@@H:30]2[CH2:34][CH2:33][CH2:32][C@H:31]2[OH:35])=[N:23][CH:24]=1
Reactant: CCOCn1c(-c2nc(Cl)ncc2Cl)cc2c(C(=O)NC3CC3)cccc21
Reactant: N[C@@H]1CCC[C@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CCOCn1c(-c2nc(N[C@@H]3CCC[C@H]3O)ncc2Cl)cc2c(C(=O)NC3CC3)cccc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 93.6 %

Procedure:
A mixture of N-cyclopropyl-2-(2,5-dichloropyrimidin-4-yl)-1-(ethoxymethyl)-1H-indole-4-carboxamide (30 g, 75 mmol), (1R,2R)-2-aminocyclopentanol hydrochloride (12.3 g, 90 mmol) and DIPEA (37.5 mL, 225 mmol) in DMSO (150 mL) is stirred at 80° C. for 16 h, then poured into water (1 L), and extracted with EA (2×500 mL). The combined extracts are washed with aqueous saturated sodium chloride (500 mL), dried over Na2SO4 and concentrated in vacuo. The residue is purified by chromatography on silica gel to give 2-{5-chloro-2-[(1R,2R)-2-hydroxycyclopentylamino]pyrimidin-4-yl}-N-cyclopropyl-1-(ethoxymethyl)-1H-indole-4-carboxamide (33 g, 93%). MS (m/z): 470 (35Cl) and 472 (37Cl) (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:38](COCC[Si](C)(C)C)[C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]5[CH2:36][CH2:35]5)=[O:32])=[C:26]([Cl:37])[CH:25]=4)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:38][C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]5[CH2:36][CH2:35]5)=[O:32])=[C:26]([Cl:37])[CH:25]=4)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ncnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccc(OCc5ccccc5)cc4)cc23)cc1Cl)NC1CC1
Yield: 85.4 %

Procedure:
After dissolving 38 mg of 1-{4-[6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenyl}-3-cyclopropylurea in 0.8 ml of tetrahydrofuran, 0.2 ml of tetrabutylammonium fluoride (1 M tetrahydrofuran solution) was added dropwise and the mixture was refluxed for 2 hours. It was then returned to room temperature, water was added, and liquid separation and extraction were performed with ethyl acetate and tetrahydrofuran. The organic layer was washed with water and saturated saline, concentrated and dried under reduced pressure to obtain 26 mg of the title compound.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:9][CH:10]=[C:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:18])[CH2:16][OH:17])[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(OCC)C>C(Cl)Cl>[C:1]([O:4][CH:5]([CH2:9][CH:10]=[C:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:18])[CH2:16][O:17][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CC(=O)OC(CC=C(C)CCCC(C)CO)C(C)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OC(CC=C(C)CCCC(C)COC1CCCCO1)C(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
324 mg (1.20 mmol) of a raw product of 3-acetoxy-11-hydroxy-6,10-dimethyl-5-undecen-2-one and 219 μl (202 mg, 2.40 mmol) dihydropyrane was dissolved in 8.5 ml DCM. After addition of 30 mg (0.12 mmol) pyridinium paratoluene sulfonate, the reaction mixture was stirred for 18 hrs at ambient temperature. Then, 25 ml diethylether was added, the resulting organic phase was washed once with 25 ml semiconcentrated NaCl solution, and dried over Na2SO4. After filtration and removal of the solvent in vacuo, the remaining product was purified by flash chromatography (parameters of the chromatography column: 2.0×20.0 cm, ethylacetate/petroleum ether=1:4) on silica gel.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[C:8]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3)[nH]c2c1
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Cn1c(-c2ccccc2)c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Tert-Butyl 3-cyclohexyl-2-phenyl-1H-indole-6-carboxylate (from Step 5) was dissolved in DMF (0.18 M). NaH (60% suspension in mineral oil, 1.5 eq.) was added and the resultant mixture stirred for 5 min at RT, then for another 5 min at 50° C. The solution was allowed to reach RT, and then neat 2-chloro-N,N-dimethylacetamide (1.6 eq.) was added dropwise. After 1 h analytical RP HPLC indicated complete conversion of the starting material. The mixture was diluted with EtOAc, and then washed with water (3×) and brine. Drying over Na2SO4 and evaporation gave a colorless solid, which was purified by flash chromatography on silica gel using PE/EtOAc (3:1, then 2:1) as the eluent. The resulting colorless solid was immediately dissolved in a mixture of DCM and TFA (0.05 M, 1:1, v/v). After stirring for 30 min at RT, the solvents were removed in vacuo to give after drying under high-vacuum, the title compound as a light yellow foam. 1H NMR (400 MHz, DMSO-d6, 300 K) δ 1.12-1.31 (m, 3H), 1.60-1.75 (m, 5H), 1.80-1.92 (m, 2H), 2.53-2.59 (m, 1H), 2.80 (s, 3H), 2.89 (s, 3H), 4.84 (s, 2H), 7.31 (d, J 6.4, 2H), 7.48-7.53 (m, 3H), 7.64 (d, J 8.4, 1H), 7.81 (d, J 8.4, 1H), 7.92 (s, 1H,); MS (ES+) m/z 405 (M+H)+
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26].O(C(C)(C)C)[K]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[C:18]([CH2:24][S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: O=S(=O)(CCl)c1ccccc1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1CS(=O)(=O)c1ccccc1
Temperature: -20 °C
Yield: 83 %

Procedure:
A stirred solution of 1-benzyl-4-(4-nitrophenyl)piperazine (5.95 g, 20.0 mmol) and chloromethylphenylsulfone (3.82 g, 20.0 mmol) in dry THF under nitrogen at −60° C. is treated with 1.0M KO-t-Bu in THF (44.0 mL, 44.0 mmol), warmed to −20° C. over a 1 h period, quenched with acetic acid and treated sequentially with water, saturated aqueous NaHCO3 and ether. The phases are separated and the aqueous phase is extracted with ether. The combined ethers are washed with water and brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed (silica gel, 1:1 and 1:0 ethyl acetate:hexanes as eluent) to give the title compound as a yellow solid, 7.52 g (83% yield), mp 145-146° C., characterized by NMR and mass spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([Cl:9])=[N:7][OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(OCC)C>[CH3:19][S:20]([O:8][N:7]=[C:6]([Cl:9])[C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:22])=[O:21]
Reactant: ON=C(Cl)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)ON=C(Cl)c1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 56.4 %

Procedure:
A solution of 9.8 g of 4-chlorobenzohydroximoyl chloride in 300 ml of diethyl ether was chilled to 5°. To it was quickly added 10.4 g of triethylamine and, after 5 minutes, a solution of 6.1 g of methanesulfonyl chloride in 30 ml of diethyl ether was added dropwise during 30 minutes. The mixture was stirred for 1 hour at 0°-5°, followed by 1 hour at ambient temperature. The mixture was again cooled to 5°, then filtered, and the filter cake was washed with cold ether. The filtrate and washes were combined and the other evaporated under reduced pressure to leave a yellow oil. The oil was crystallized from a mixture of benzene and hexane to give 7.8 g of N-(methanesulfonyloxy)-4-chlorobenzimidoyl chloride, m.p. 80°-82°.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[C:13](#[N:17])[CH2:14][C:15]#[N:16].C(NCC)C.O>CN(C=O)C>[NH2:17][C:13]1[O:1][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[C:14]=1[C:15]#[N:16]
Reactant: N#CCC#N
Reactant: COc1ccc(C(=O)CO)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2coc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a cooled solution of 2-hydroxy-4′-methoxyacetophenone (379 mg, 2.28 mmol) in DMF (0.75 ml) was added malononitrile (166 mg, 2.51 mmol) followed by diethylamine (0.1 ml, 0.97 mmol). The mixture was stirred at room temperature for 2 hours, and then poured into large amount of cold water. The precipitate was filtrated, washed with water, and dried under reduced pressure to give the intermediate of Example 1(A) (424 mg, 87%) as a brown solid. 1H NMR (400 MHz, CDCl3) ppm 3.83 (s, 3H), 4.73 (brs, 2H), 6.93 (m, 2H), 6.94 (s, 1H), 7.49 (m, 2H). LC/MS: m/z 215 (M+1)+.