Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.C([Li])CCC.CN(C)[CH:19]=[O:20]>O1CCCC1.CCCCCC.O>[CH:19]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1)=[O:20]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1C(=O)O
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-methylbenzoic acid (10 g) in tetrahydrofuran (100 mL), a solution of 1.6M n-butyl lithium in hexane (60 mL) was added at −70° C. After the reaction mixture was stirred for one hour at −40° C., a solution of N,N-dimethylformamide (10 mL) in tetrahydrofuran (10 mL) was added to the mixture at −70° C. After stirred for one hour at −70° C. and then warmed to room temperature, the mixture was poured onto ice and diluted with water. The aqueous layer was washed with hexane and acidified with concentrated hydrochloric acid, and the precipitate was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of 4-formyl-2-methylbenzoic acid (5 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14](O)=[O:15])[CH2:6][CH2:5]2.C1N=C[N:21](C(N2C=NC=C2)=O)C=1.N.CO>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH2:21])=[O:15])[CH2:6][CH2:5]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: N
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(N)=O)O2
Yield: 37.7 %

Procedure:
Following the amide coupling procedure described in protocol A, 498 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (1.99 mmol), 367 mg CDI (2.26 mmol) and 1.4 mL of 7.0M NH3 in MeOH (9.8 mmol) produced 187 mg of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([NH:30][C@H:31]([C:34]([O:36][CH3:37])=[O:35])[CH2:32][OH:33])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.COCCN(S(F)(F)F)CCOC.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:33][CH2:32][C@@H:31]([C:34]([O:36][CH3:37])=[O:35])[N:30]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@@H](CO)C(=O)OC)[nH]2)c1
Agent: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](C(=O)OC)CO3)[nH]2)c1
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
Methyl N-{[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]carbonyl}-L-serinate (1.91 g, 3.57 mmol) synthesized in Example (86a) was dissolved in methylene chloride (40 mL), and bis(2-methoxyethyl)aminosulfur trifluoride (0.85 mL, 4.64 mmol) was added dropwise at −78° C. After stirring for 30 minutes under nitrogen atmosphere, potassium carbonate (0.74 g, 5.35 mmol) was added, and stirring was carried out at 0° C. for 10 minutes, followed by further stirring at room temperature for 3 hours. A saturated aqueous sodium hydrogencarbonate solution (30 mL) was added, followed by extraction with methylene chloride (100 mL), and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-70%) to afford the desired compound (1.76 g, 93%) as a white powder.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[O:2].[NH2:15]C1C=CC(O)=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH2:15])=[O:14])=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[O:2]
Reactant: O=Cc1n[nH]c2cc(C(=O)O)ccc12
Reactant: Nc1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2c(C=O)n[nH]c2c1
Reaction time: 2 h

Procedure:
To a solution of 3-formyl-1H-indazole-6-carboxylic acid (1.6 g, 8.4 mmol) and 4-aminophenol (1.8 g, 16.8 mmol) in dry dimethylformamide (35 mL) was added HATU (3.8 g, 16.8 mmol) followed by triethylamine (1.4 mL, 10.1 mmol). The reaction was stirred at room and monitored by TLC and LC/MS. After two hours the reaction was complete. The solvent was removed by vacuum and the product was purified by flash column chromatography using ethyl acetate: petroleum ether 1:1 to pure ethyl acetate. N-4-Hydroxyphenyl)-3-formyl-1H-indazole-6-carboxamide was isolated as a tan colored solid. 1H NMR (DMSO-d4) δ 6.79 (2H, d, 8.9 Hz), 7.59 (2H, d, 8.9 Hz), 7.94 (1H, d, 9.8 Hz), 8.24 (1H, d, 8.2 Hz), 8.31 (1H, s), 9.31 (1H, br s), 10.27 (2H, s). MS (APCI pos) 282.1.
Reaction SMILES: ClCl.[CH:3]1[CH:8]=[C:7]2[C:9]([OH:20])=[C:10]3[C:15](=[C:16]([OH:17])[C:6]2=[CH:5][CH:4]=1)[C:14]([NH2:18])=[CH:13][CH:12]=[C:11]3[NH2:19].OS(O)(=O)=O.Cl.[NH2:27][C:28]1[C:41]2[C:40](=[O:42])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33](=[O:43])[C:32]=2[CH:31]=[CH:30][CH:29]=1.[K]>O>[CH:3]1[CH:8]=[C:7]2[C:9]([C:10]3[C:15]([C:16](=[O:17])[C:6]2=[CH:5][CH:4]=1)=[C:14]([NH:18][C:31]1[CH:30]=[CH:29][C:28]([NH2:27])=[C:41]2[C:40]([C:39]4[C:34]([C:33](=[O:43])[C:32]=12)=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:42])[CH:13]=[CH:12][C:11]=3[NH2:19])=[O:20]
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: Nc1ccc(N)c2c(O)c3ccccc3c(O)c12
Agent: Cl
Agent: ClCl
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1ccc(Nc2ccc(N)c3c2C(=O)c2ccccc2C3=O)c2c1C(=O)c1ccccc1C2=O
Reaction time: 0.5 h
Yield: 103.5 %

Procedure:
Chlorine is passed at 100° C. into a solution of 52.0 g of leuco-1,4-diaminoanthraquinone (94%) in 410 g of 96% strength H2SO4 until the leuco compound has just disappeared. Excess chlorine as well as hydrogen chloride is expelled by means of air. The batch is then allowed to cool down to room temperature, during which time 48.0 g of 1-aminoanthraquinone (98%) are added, and the mixture is then added dropwise to 410 g of water. 95.0 g of potassium peroxodisulphate are added in portions in the course of about 1 hour at 40°-50° C. to the paste. Stirring is allowed to continue for about 30 minutes at 30°-50° C., and the solids are filtered off with suction and washed with water until almost neutral. The press cake is washed with 300 ml of 10% strength NaHSO3 solution, and then with water, and dried at 100° C. 102.3 g of 4,4'-diamino-1,1'-dianthrimide (79% pure) are obtained; this result corresponds to 87% of theory.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:13]=[CH:14][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].[Zn]>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][C:15]2[CH:14]=[CH:13][C:12]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:11][C:10]=2[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:22][CH:21]=1
Reactant: COC(=O)Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)c(CNC(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(Oc2ccc(N)cc2)c(CNC(=O)OC(C)(C)C)c1
Yield: 100.2 %

Procedure:
Methyl 2-(3-((tert-butoxycarbonyl)aminomethyl)-4-(4-nitrophenoxy)phenyl)acetate (242 mg, 0.581 mmol) was diluted with THF (3 mL) followed by the addition of Zn dust (38.0 mg, 0.581 mmol). About 2 mL of saturated ammonium chloride was added dropwise. After stirring the reaction for 10 minutes, the reaction mixture was diluted with ethyl acetate and saturated sodium bicarbonate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 225 mg of methyl 2-(4-(4-aminophenoxy)-3-((tert-butoxycarbonyl)aminomethyl)phenyl)acetate.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([I:19])=[CH:16][CH:17]=2)[NH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[O:28]1[CH2:33][CH2:32]C(=O)[CH2:30][CH2:29]1>ClCCCl>[I:19][C:15]1[CH:14]=[C:13]2[C:18]([C:10]3[CH2:9][CH2:8][NH:7][C:6]4([C:11]=3[NH:12]2)[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2cc(I)ccc12
Reactant: O=C1CCOCC1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Ic1ccc2c3c([nH]c2c1)C1(CCOCC1)NCC3
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of [2-(6-Iodo-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester (500.0 mg, 1.294 mmol) was stirred into a mixture of DCE (2.0 mL) and TFA (2.0 mL) for 10 min. Tetrahydro-4H-pyran-4-one (360.0 uL, 3.88 mmol) was added. The reaction mixture was stirred at 40° C. for one hour, then at 50° C. for two hours and finally at 60° C. for one hour. The reaction solution was then concentrated down and the product was used in the next step without further purification. MS m/z 369 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:6][CH:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][C@H:27]1[CH3:33])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.CO>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C@@H:29]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:18])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[Cl:17])[CH:3]=2)[CH2:28][C@H:27]1[CH3:33])=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: C[C@@H]1CC(=O)CCN1C(=O)OC(C)(C)C
Reactant: Nc1cccc(NC(=O)c2ccc(F)cc2Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1C[C@H](Nc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1C(=O)OC(C)(C)C
Yield: 22.9 %

Procedure:
Dissolve N-(3-amino-phenyl)-2-chloro-4-fluoro-benzamide (Preparation 1, 200 mg, 0.756 mmol) and (2R)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (161 mg, 0.756 mmol) in tetrahydrofuran (5 mL). Add acetic acid (52 μl, 0.907 mmol) and sodium triacetoxyborohydride (192 mg, 0.907 mmol) and stir at room temperature for 18 hr. Heat the reaction to 45° C. for 4 hr. Cool the reaction to room temperature and load onto an SCX column with methanol. Wash the column with methanol, flush with 2M ammonia in methanol, and concentrate in vacuo. Purify by column chromatography (20%-75% ethyl acetate/hexane) to yield 80 mg (23%) of the title compound: mass spectrum (ion spray): m/z=462.4 (M+1); 1H NMR: δ (CDCl3, ppm) 7.76 (m, 2H), 7.20 (m, 1H), 7.15 (m, 1H), 7.10 (m, 1H), 6.70 (d, J=7.6 Hz, 1H), 6.40 (d, J=8.4 Hz, 1H), 4.20 (m, 1H), 3.82 (m, 2H), 3.67 (bs, 1H), 3.20 (m, 1H), 2.00 (m, 2H), 1.65 (m, 2H), 1.47 (s, 9H), 1.27, (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])[NH2:5].[CH3:18][N:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[C:22]2[CH:34]=[CH:35][N:36]([S:37]([C:40]3[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C:21]=2[C:20]1=[O:47].CC12CC3(C)P(C4C=CC=CC=4)C(C)(CC(C)(O3)O1)O2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:2]([C:23]2[C:22]3[CH:34]=[CH:35][N:36]([S:37]([C:40]4[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=4)(=[O:39])=[O:38])[C:21]=3[C:20](=[O:47])[N:19]([CH3:18])[CH:24]=2)[CH:3]=1
Reactant: Nc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Agent: [Pd]
Agent: CC12CC3(C)OC(C)(CC(C)(O1)P3c1ccccc1)O2
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(N)ccc4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Temperature: 60 °C
Yield: 72.3 %

Procedure:
A mixture of 3-bromo-4-(2,4-difluorophenoxy)aniline (5.0 g, 11.67 mmol), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (3.85 g, 12.84 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.399 g, 1.366 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.321 g, 0.350 mmol), and potassium phosphate (6.19 g, 29.2 mmol) in dioxane (50 mL) and water (12.5 mL) was degassed and back-filled with nitrogen several times. The reaction mixture was heated at 60° C. for 16 hours and then cooled to ambient temperature. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 60% ethyl acetate/hexanes) to provide 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (4.40 g, 72.3% yield).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:10].[Cl-].[C:12]([O:16][C:17](=[O:20])[CH2:18][Zn+])([CH3:15])([CH3:14])[CH3:13].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:10][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=1[CH2:18][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:20]
Reactant: N#Cc1ccc(Br)c(Cl)c1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc(C#N)cc1Cl
Temperature: 65 °C
Yield: 39.3 %

Procedure:
Combined 4-bromo-3-chlorobenzonitrile (0.600 g, 2.77 mmol) and (2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride (8.32 mL, 4.16 mmol) in THF (5.54 mL), then Pd(dba)2 (0.080 g, 0.139 mmol) and 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (0.109 g, 0.277 mmol) were added and the reaction was refluxed overnight at 65° C. The reaction was concentrated by rotary evaporation and purified on a silica gel column eluting with hexanes and EtOAc to give the title compound (274 mg, 39%) as a yellow oil. MS m/z [M+H]+ 252.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20].[CH:22]1([O:27][C:28]2[C:29]([O:38][CH3:39])=[N:30][CH:31]=[C:32]([CH:37]=2)[C:33](OC)=[O:34])[CH2:26][CH2:25][CH2:24][CH2:23]1.[Cl-].[NH4+]>O1CCCC1>[CH:22]1([O:27][C:28]2[CH:37]=[C:32]([C:33](=[O:34])[CH2:20][C:19]3[C:18]([Cl:21])=[CH:17][N:16]=[CH:15][C:14]=3[Cl:13])[CH:31]=[N:30][C:29]=2[O:38][CH3:39])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COC(=O)c1cnc(OC)c(OC2CCCC2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ncc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
n-Butyl lithium (4.9 mL of a 2.5M solution in hexanes) is added dropwise to a stirred solution of diisopropylamine (1.7 mL) in dry tetrahydrofuran (20 mL) at −78° C. under a nitrogen atmosphere. After 30 minutes. a solution of 3,5-dichloro-4-methylpyridine (1.95 g) in dry tetrahydrofuran (10 mL) is added dropwise and the solution stirred at −78° C. for a further 30 minutes. A solution of methyl 5-cyclopentyloxy-6-methoxynicotinoate (1.5 g) in dry tetrahydrofuran (15 mL) is added and the red mixture stirred and allowed to warm to room temperature during 4 hours. After stirring overnight at room temperature the mixture is treated with saturated aqueous ammonium chloride. The tetrahydrofuran layer is separated and the aqueous phase is extracted with ethyl acetate. The combined organic layers are washed with saline and dried over anhydrous magnesium sulphate. Concentration gives a light brown oil which is triturated with a mixture of n-pentane and methyl t-butyl ether to give 1-(5-cyclopentyloxy-6-methoxypyridin-3-yl)-2-(3,5-dichloropyrid-4-yl)ethanone (1 g) in the form of a beige solid, m.p. 118-9° C. [Elemental analysis:—C, 56.8; H, 4.82; Cl, 18.5; N, 7.40%. calculated:—C, 56.7; H, 4.76; Cl, 18.6; N, 7.35%.]
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C[Si]([N-][Si](C)(C)C)(C)C.[K+].S(O[CH2:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=1)(=O)(=O)C.C(OCC)(=O)C>O1CCCC1>[CH3:34][O:33][C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([O:29][CH3:30])[C:26]=1[O:31][CH3:32])[CH2:22][N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: O=C1CCCN1
Reactant: COc1cc(COS(C)(=O)=O)cc(OC)c1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(CN2CCCC2=O)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Combine 2-pyrrolidinone (2.85 g, 33.5 mmol) and tetrahydrofuran (70 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of potassium bis(trimethylsilyl)amide (67 mL, 0.5 M in toluene, 33.5 mol). After 45 minutes, add a solution of 3,4,5-trimethoxybenzyl mesylate (8.8 g, 32.02 mmol) in tetrahydrofuran (60 mL). After the addition of 3,4,5-trimethoxybenzyl mesylate is complete, heat to reflux. After 18 hours, cool the reaction mixture and partition between water and ethyl acetate. Separate the aqueous layer and extract 4 times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound: Rf=0.35 (silica gel, ethyl acetate).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[N:14]3[C:9](=[C:10]([CH2:15][O:16][Si](C(C)(C)C)(C)C)[CH:11]=[CH:12][C:13]=13)[C:8]([CH2:24][CH3:25])=[C:7]2[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)(=[O:3])[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>O1CCCC1>[C:1]([C:4]1[CH:5]=[C:6]2[N:14]3[C:9](=[C:10]([CH2:15][OH:16])[CH:11]=[CH:12][C:13]=13)[C:8]([CH2:24][CH3:25])=[C:7]2[C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:31]=1)(=[O:3])[CH3:2]
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(C)=O)c3ccc(CO[Si](C)(C)C(C)(C)C)c1n32
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(C)=O)c3ccc(CO)c1n32
Reaction time: 24 h
Yield: 59.2 %

Procedure:
4-Acetyl-2-(4-benzyloxyphenyl)-7-(tert-butyldimethylsilanyloxymethyl)-1-ethylpyrrolo[2,1,5-cd]indolizine (1.5 g, 2.79 mmol) and tetrabutylammoniumfluoride hydrate (2.92 g. 11.16 mmol) was dissolved in 20 ml of dry tetrahydrofuran and stirred for 24 hours. Diethyl ether (100 ml) was added and the organic layer was extracted with 100 ml of 15% acetic acid, 100 ml of saturated sodium hydrogen carbonate, 100 ml of water, washed with brine, dried over sodium sulfate, and evaporated to a red-brown solid. The crude product was purified by column chromatography over silica gel 60, using 10% of ethyl acetate in toluene as the eluent. Fractions containing the product were combined an the solvent was evaporated. The remaining solid was crystallised from toluene and petroleum ether to afford 0.7 g (59%) of the title compound. M.p. 190-191° C. MS(SP): m/z 423 (M+). 1H--NMR (DMSO-d6, 200 MHz) δ: 1.39 (t, 3 H); 2.64 (s, 3 H); 3.20 (q, 2 H); 5.18 (s, 2 H); 5.22 (s, 2 H); 7.25 (d, 2 H); 7.31-7.55 (m, 5 H); 7.75 (d, 2 H); 8.01 (d, 1 H); 8.20 (s, 1 H); 8.36 (d, 1 H). Analysis: Calculated for C28H25N1O3 : C, 79.41; H, 5.95; N, 3.31%; Found: C, 79.2; H, 5.7; N, 3.2%.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C@H:13]2[CH2:37][CH2:36][C@@:35]3([CH3:38])[C:15](=[CH:16][CH2:17][C@@H:18]4[C@@H:34]3[CH2:33][CH2:32][C@@:31]3([CH3:39])[C@H:19]4[CH2:20][CH2:21][C@@H:22]3[C@H:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:14]2)C(=O)C2=CC=CC=C12.C(N)CCC>CO.C(Cl)(Cl)Cl>[CH3:29][CH:27]([CH2:26][CH2:25][CH2:24][C@H:23]([C@@H:22]1[C@:31]2([CH3:39])[C@H:19]([C@H:18]3[C@H:34]([CH2:33][CH2:32]2)[C@:35]2([CH3:38])[C:15]([CH2:14][C@@H:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH2:5])[CH2:37][CH2:36]2)=[CH:16][CH2:17]3)[CH2:20][CH2:21]1)[CH3:30])[CH3:28]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCN5C(=O)c6ccccc6C5=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClC(Cl)Cl
Solvent: CCCCN
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCN)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 43.1 %

Procedure:
A solution of 6-phthalimido-1-(5-cholesten-3β-yloxy)hexane (500 mg) and n-butylamine (5 ml) in methanol (10 ml) and chloroform (5 ml) is heated under reflux for 1 hour. The solution is evaporated in vacuo to a residue that is put on a column of silica gel and eluted with CHCl3 -MeOH-NH4OH 90:10:1 (v/v/v). The ninhydrin positive fractions are combined and evaporated to give the title compound (170 mg, 43%).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[CH:23]=[C:22]([C:24]#[N:25])[N:21]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[C:19]=3[N:20]=2)=[N:12][CH:13]=1)(C)(C)C.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH:26]1([N:21]2[C:19]3[N:20]=[C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([CH2:7][OH:6])=[CH:13][N:12]=4)[N:16]=[CH:17][C:18]=3[CH:23]=[C:22]2[C:24]#[N:25])[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(Nc2ncc3cc(C#N)n(C4CCCC4)c3n2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#Cc1cc2cnc(Nc3ccc(CO)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a stirred solution of 2-[5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile in THF (2.0 mL) is added HF.pyridine (0.080 mL) at 0° C. The reaction mixture stirred at room temperature for 16 h before it is diluted with ethyl acetate, ished with saturated NaHCO3 solution, dried (MgSO4), filtered and concentrated. Trituration with diethyl ether gave 7-cyclopentyl-2-(5-hydroxymethyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, 68 mg, 53% yield (over 2 steps). MS(ESI) m/z 335.0 (M+H)+ (method A).
Reaction SMILES: I.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:15][NH:16][C:17]([S:22][CH3:23])=[N:18][CH2:19][CH2:20][CH3:21])OCCO2)=[CH:6][CH:5]=1.[ClH:24].C(=O)([O-])O.[Na+]>>[ClH:24].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]([CH2:19][CH2:20][CH3:21])[C:17]([S:22][CH3:23])=[N:16][CH:15]=2)=[CH:6][CH:5]=1
Reactant: CCCN=C(NCC1(c2ccc(OC)cc2)OCCO1)SC
Agent: Cl
Agent: I
Agent: O=C([O-])O
Product: CCCn1c(-c2ccc(OC)cc2)cnc1SC
Yield: 86 %

Procedure:
A mixture of 7 parts of methyl N-[2-(4-methoxyphenyl)-1,3-dioxolan-2-ylmethyl]-N'-propylcarbamimidothioate monohydroiodide and 30 parts of hydrochloric acid solution 10% is stirred and refluxed for 1.50 hours. The reaction mixture is cooled and neutralized with sodium hydrogen carbonate. The product is extracted with 1,1'-oxybisethane. The extract is dried, filtered and saturated with hydrogen chloride. The precipitated oil solidifies upon scratching. The product is filtered off and crystallized from a mixture of 2-propanol and 2,2'-oxybispropane, yielding 4 parts (86%) of 5-(4-methoxyphenyl)-2-(methylthio)-1-propyl-1H-imidazole monohydrochloride; mp. 149.2° C.