Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19][CH2:20][C:21](=[CH2:24])[CH2:22][OH:23]>ClCCl.CN(C)C1C=CN=CC=1>[Si:1]([O:19][CH2:20][C:21](=[CH2:24])[CH2:22][OH:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C=C(CO)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A solution of t-butyldiphenylsilylchloride (45 g, 165 mmol) in anhydrous dichloromethane (60 ml) is added dropwise to a stirred solution of 2-hydroxymethyl-2-propene-1-ol (12 g, 165 mmol) triethylamine (27.5 ml) and 4-dimethylaminopyridine (2 g) in anhydrous dichloromethane (300 ml) at 0° C. Then, the mixture is stirred at 20° C. overnight, washed with a saturated solution of ammonium chloride and brine. The title product is obtained by flash chromatography on silica gel (19.4 g, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[N:6]=[CH:5][CH:4]=[C:3]2[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccnc2c(C)cccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccnc2c(CBr)cccc12

Procedure:
4-Methoxy-8-methylquinoline (346 mg, 2 mmole), N-bromosuccinimide (365 mg, 2.05 mmole) and benzoyl peroxide (10 mg) in CCl4 (8 ml) were heated under reflux for 2.5 hours. The mixture was cooled and the succinimide was filtered off. The filtrate was washed with dilute aqueous NaHCO3 (1×) and water (1×), dried (Na2SO4) and evaporated to yield the sub-title compound as a pale yellow solid which was recrystallised from petroleum ether/cyclohexane to give colourless needles.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[NH2:15]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Clc1cc(Nc2ncnc3cc[nH]c23)ccc1OCc1ccccn1
Temperature: 140 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (63 mg) in 1-methyl-2-pyrrolidone (0.8 mL), was added 3-chloro-4-(pyridin-2-ylmethoxy)aniline (149 mg), and the mixture was heated to 140° C. and stirred for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted with a mixed solvent (25 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=10/0→8/2). The object fraction was concentrated under reduced pressure. Chloroform/diisopropyl ether (1/9) was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (112 mg) as pale-yellow powder crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])[C:3]1=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])[C:3]1=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CC(=O)OCCN1CCN(C)C1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)OCCN1CCN(C)C1=Nc1ccccc1N1CCOCC1

Procedure:
Reaction of 1-methyl-3-(2-acetoxyethyl)-2-imidazolidinone (13.4 g) in benzene (80 ml) with 4-(2-aminophenyl)morpholine (10.6 g) in benzene (80 ml) in the presence of phosphorus oxychloride (7 ml) for 30 hours at 80°-85° C. gave 4-((2-[1-methyl-3-(2-acetoxyethyl)-2-imidazolidinylideneamino]phenyl))morpholine.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8].I[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.CCCCCC>CN(C)P(N(C)C)(N(C)C)=O.[Cu]I>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:5]([O:4][CH3:3])[CH:6]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(I)cc1
Reactant: COc1cccc(N)c1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cccc(Nc2ccc(C)cc2)c1
Temperature: 55 °C

Procedure:
To a suspension of 0.11 g (4.6 mmol, hexane washed 3 x, 50-60% in oil) sodium hydride in 1.0 mL of hexamethylphosphoramide was cannulated a solution of 0.11 g (0.89 mmol) of 3-methoxyaniline in 2.0 mL hexamethylphosphoramide. The resulting mixture was heated at 55° C. for 20 min. To this was added 0.18 g (0.93 mmol) of copper(I) iodide and the mixture was heated at 55° C. for 1.5 hours. 4-iodotoluene was added and the reaction heated at 85° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, hexane was added and the reaction was then loaded onto a silica gel column. The mixture was purified by flash chromatography (100% hexane, 5% ethyl acetate in hexanes) to give the title compound as an orange oil. PNMR (300 MHz, CDCl3) d 2.30 (3 H, s), 3.76 (3 H, s), 5.65 (1 H, s), 6.43 (1 H, m), 6.57 (1 H, d, J=1.6 Hz), 6.58 (1 H, m), 7.01 (2 H, d, J=8.5 Hz), 7.09 (2 H, d, J=8.5 Hz), 7.15 (1 H, d, J=8.6 Hz).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1CCC[C@H]1C(O)=O.[SH:21][CH2:22][CH:23]([CH2:38][SH:39])[C:24](C1(C=CC=CC1)C[C@@H](C(O)=O)N)=[O:25]>>[SH:21][CH2:22][CH:23]([CH2:38][SH:39])[C:24]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:25]
Reactant: N[C@@H](CC1(C(=O)C(CS)CS)C=CC=CC1)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)C(CS)CS

Procedure:
By substituting L-phenylalanine for the L-proline in the procedure of Example 3B, and then submitting the product to the procedure of Example 4, 1-[2-acetylthiomethyl)-3-acetylthiopropanoyl]-L-phenylalanine and 1-[2-(mercaptomethyl)-3-mercaptopropanoyl]-L-phenylalanine are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:14]=[C:15]([O:23][CH3:24])[C:16]4[N:17]([C:19]([CH3:22])=[N:20][N:21]=4)[CH:18]=3)[C:11](=[O:25])[C:10](=O)[CH:9]2[C:27](=O)[CH2:28][CH3:29])=[CH:4][CH:3]=1.Cl.[F:32][C:33]([F:41])([F:40])[CH2:34][O:35][CH2:36][CH2:37][NH:38][NH2:39]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:27]([CH2:28][CH3:29])=[N:39][N:38]([CH2:37][CH2:36][O:35][CH2:34][C:33]([F:41])([F:40])[F:32])[C:10]=3[C:11](=[O:25])[N:12]2[C:13]2[CH:14]=[C:15]([O:23][CH3:24])[C:16]3[N:17]([C:19]([CH3:22])=[N:20][N:21]=3)[CH:18]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)C1C(=O)C(=O)N(c2cc(OC)c3nnc(C)n3c2)C1c1ccc(Cl)cc1
Reactant: NNCCOCC(F)(F)F
Agent: Cl
Solvent: CO
Product: CCc1nn(CCOCC(F)(F)F)c2c1C(c1ccc(Cl)cc1)N(c1cc(OC)c3nnc(C)n3c1)C2=O

Procedure:
The tile compound was prepared in analogy to the procedure described in Example 68 using 5-(4-chlorophenyl)-1-(8-methoxy-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-4-propionylpyrrolidine-2,3-dione (Step 84.5) and (2-(2,2,2-trifluoroethoxy)ethyl)hydrazine hydrochloride in MeOH and TEA. The crude material was first purified by silica gel chromatography (hexane/EtOAc/MeOH 75:25:5 to 5:1) followed by preparative achiral SFC (Propyl-pyridyl-urea, gradient 13-18% in 6 min_total 11 min). tR: 1.04 min (LC-MS 2); ESI-MS: 549 [M+H]+ (LC-MS 2).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1.[CH2:18](Br)[CH:19]=[CH2:20].CO>CN(C=O)C>[CH2:20]([N:9]1[C:10]2[CH:11]=[CH:12][C:4]([Cl:3])=[CH:5][C:6]=2[C:7]2[CH2:16][N:15]([CH3:17])[CH2:14][CH2:13][C:8]1=2)[CH:19]=[CH2:18]
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: C=CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% dispersion in oil, 240 mg, 6 mmol) in DMF (15 mL) at 0° C. was added 8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.1 g, 5 mmol) and the reaction mixture was stirred at 0° C. for 30 min, followed by addition of allyl bromide (0.51 mL, 6 mmol). The reaction mixture was allowed to warm to and was stirred at 25° C. for 3 h. MeOH was added and the reaction mixture was evaporated to dryness. The residue was purified by flash chromatography on silica gel using MeOH-DCM gradient. 1H NMR (DMSO-d6) δ (ppm): 7.53 (s, 1H), 7.47 (d, 1H), 7.15 (d, 1H), 5.94 (m, 1H), 5.1 (m, 1H), 4.83 (m, 1H), 4.78 (s, 2H), 4.25 (s, 2H), 3.44 (s, 2H), 3.02 (s, 2H), 2.86 (s, 3H).
Reaction SMILES: [I:1]I.N1C=CN=C1.O[CH2:9][C:10]1[N:11]=[C:12]([C@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])[O:13][CH:14]=1>C(Cl)Cl>[I:1][CH2:9][C:10]1[N:11]=[C:12]([C@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])[O:13][CH:14]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1nc(CO)co1
Reactant: II
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)c1nc(CI)co1
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a solution of TPP (873 mg, 3.33 mmol) in CH2Cl2 (10 mL), was added I2 (845 mg, 3.33 mmol), and stirred for 10 min. Imidazole (227 mg, 3.33 mmol) was added and stirred for an additional 10 min and then a solution of (R)-tert-butyl 1-(4-(hydroxymethyl)oxazol-2-yl)ethylcarbamate (537 mg, 2.22 mmol) in CH2Cl2 (15 mL) was added. After 2 h, the reaction mixture was washed successively with sat. aq. NaHCO3, aq. Na2S2O3, dried on Na2SO4 and concentrated under low pressure. The residue was chromatographed on silica gel (20% ethyl acetate/80% hexanes) to yield 84% of (R)-tert-butyl 1-(4-(iodomethyl)oxazol-2-yl)ethylcarbamate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[S:31])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].IC.[C:34](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11]([S:31][CH3:34])=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(SC)=NC1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-(4-cyanophenyl)-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 3; 1000 mg, 2.24 mmol), iodomethane (350.5 mg, 2.47 mmol) and potassium carbonate (341 mg, 1.82 mmol) are dissolved in 20 ml acetone. The reaction mixture is stirred at room temperature overnight and the solvent is removed in vacuo. The product is purified by column chromatography (silica gel; eluent: cyclohexane-ethyl acetate, gradient 90:10 to 50:50).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([CH:42]=[CH:43][CH:44]=1)[CH2:7][O:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]1)=[O:3].[CH3:45][O:46][CH2:47][CH2:48][NH:49][CH3:50]>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][O:25][CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:14]2[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][CH:9]2[O:8][CH2:7][C:6]2[CH:42]=[CH:43][CH:44]=[C:4]([C:2](=[O:3])[N:49]([CH2:48][CH2:47][O:46][CH3:45])[CH3:50])[CH:5]=2)=[CH:16][CH:17]=1
Reactant: CNCCOC
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc(C(=O)Cl)c2)cc1
Product: COCCN(C)C(=O)c1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1

Procedure:
Analogously to Example 127a, 0.355 g tert-butyl 3-(3-chlorocarbonylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.106 g of 2-methoxy-N-methylethylamine are reacted. The title compound is obtained as a colourless oil. Rf=0.10 (1:1 EtOAc-heptane); Rt=5.65.
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][O:4][CH2:5]2.[C:7]1([Mg]Br)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Cu]I.C1COCC1>[C:7]1([C@@H:2]2[CH2:3][O:4][CH2:5][C@H:6]2[OH:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Br[Mg]c1ccccc1
Reactant: C1OCC2OC12
Agent: [Cu]I
Solvent: C1CCOC1
Product: O[C@@H]1COC[C@H]1c1ccccc1

Procedure:
A second batch was obtained according to the above procedure reacting 3,4-epoxy-tetrahydrofuran (1.0 g, 11.62 mmol), phenylmagnesium bromide (3.872 mL, 11.62 mmol), CuI (155.67 mg, 0.813 mmol) and dry THF (total volume of 3.6 mL). The residues obtained from the above two batches was mixed and purified by flash chromatography (silica; DCM in MeOH 0/100 to 10/90). The desired fractions were collected and evaporated in vacuo to give I-42 (5.5 g, 74%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[Li]CCCC.[CH3:16][O:17][C:18](=[O:29])[C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1Br>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:20]1[C:19]([C:18]([O:17][CH3:16])=[O:29])=[CH:24][C:23]([N+:25]([O-:27])=[O:26])=[CH:22][CH:21]=1
Reactant: COc1cccc(OC)c1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1c(OC)cccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 1,3-dimethoxybenzene (115.2 ml, 0.88 mol) in anhydrous THF (600 ml) was cooled to 0° C. and treated with n-BuLi (382.4 ml, 0.95 mol, 2.5M solution in hexane) dropwise while maintaining the temperature of the reaction mixture between 0° C. and 5° C. The reaction mixture was allowed to warm to room temperature, stirred for 2 hours and recooled to 0° C. Anhydrous ZnCl2 (141.6 g, 1.04 mol) was added as a solid in portions while maintaining the reaction temperature below 5° C. After adding all the ZnCl2, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours (clear solution). The reaction mixture was recooled to 0° C. and methyl-2-bromo-5-nitrobenzoate (208 g, 0.80 mol) was added as a solid in one portion, followed by the addition of dichloro-bis-(triphenylphosphine)palladium(II) (7 g, 9.90 mmol). Additional THF (200 ml) was added and the reaction mixture was allowed to warm to room temperature. Reaction is exothermic with exotherm starting around 20° C. The reaction mixture was stirred while maintaining the reaction temperature below 45° C. until methyl-2-bromo-5-nitrobenzoate was less than 0.1% peak area detected by HPLC. Solid product started precipitating out typically after 30 minutes. Isopropyl acetate (400 ml) was added and the reaction mixture was stirred for another 30 minutes. The solid was filtered and washed with isopropyl acetate (300 ml), dried at 40° C. under reduced pressure to provide the title compound (203 g, 80%). mp 157° C.; Anal. Calcd. for C16H15NO6: C, 60.57; H, 4.77; N, 4.41; Found C, 60.30; H, 4.76; N, 4.34. 1H NMR [(CD3)2SO] δ3.65 (3H, s); 3.66 (6H, s), 6.73 (1H, s), 6.77 (1H, s), 7.36 (1H, m), 7.59 (1H, d), 8.36 (1H, dd) and 8.52 (1H, d); 13C [(CD3)2SO] δ52.1, 55.6, 63.4, 89.9, 104.2, 115.7, 123.7, 125.3, 130.1, 133.0, 134.4, 141.4, 146.0, 156.2, 165.6. The 13C signal for two methoxy groups at 55.6 are overlapping; IR (KBr): 1740 and 1600 cm−1; MS (APCI) m/z: 318 (M+H)+, m/z 335 (M+NH4)+, 340 (M+Na)+; FAB-HRMS: found, 318.0989, required 318.0978.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][C:9]=3[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:27][O:28][CH2:29]Cl>CN(C=O)C>[CH:1]1([C:7]2[C:8]3[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][C:9]=3[N:10]([CH2:27][O:28][CH3:29])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCCl
Reactant: COC(=O)c1cc2[nH]c(-c3ccccc3)c(C3CCCCC3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCn1c(-c2ccccc2)c(C2CCCCC2)c2sc(C(=O)OC)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution (0.25 M) of methyl 6-cyclohexyl-5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in DMF at 0° C. was treated with NaH (1.5 eq., 60% dispersion in mineral oil), and the suspension was stirred at 0° C. for 60 min then it was treated with chloromethyl methyl ether (5 eq.). The mixture was stirred at RT for 2 h then it was quenched with ice/water and extracted with AcOEt. The combined organic phase was washed with brine and dried. Evaporation of the solvent under reduced pressure gave a residue that was purified by flash chromatography on silica gel (1:12 acetone/toluene) to afford the title compound (92%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]2[C:23](=O)[CH2:24][CH2:25][C:3]=12.[O:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1.CC(O)=O.[BH3-]C#N.[Na+]>CCO>[C:17]1([C:14]2[N:13]=[CH:12][C:11]([C:10]3[CH:9]=[N:8][N:7]4[C:2]([NH2:1])=[C:3]5[CH2:25][CH2:24][CH:23]([NH:33][CH:30]6[CH2:31][CH2:32][O:27][CH2:28][CH2:29]6)[C:4]5=[N:5][C:6]=34)=[CH:16][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC1CCOCC1
Reactant: Nc1c2c(nc3c(-c4ccc(-c5ccccc5)nc4)cnn13)C(=O)CC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1c2c(nc3c(-c4ccc(-c5ccccc5)nc4)cnn13)C(NC1CCOCC1)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 8-amino-3-(6-phenylpyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidin-5-one (61.5 mg, 0.18 mmol), tetrahydro-2H-pyran-4-amine (100 uL), HOAc (100 uL) in EtOH (2 mL) was stirred at room temperature for 15 min. NaBH3CN (56.7 mg, 0.90 mmol) was added and the reaction was stirred overnight. Purification with prep-LC provided 3-(6-phenylpyridin-3-yl)-N5-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidine-5,8-diamine: LCMS tR=2.35 Min (10 min run, UV254nm), Mass calculated for, M+426.0, observed LC/MS m/z 427.0 (M+H).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].C(O[C:12]([C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[C:16]([C:21]([O:23]CCCC)=O)[CH:15]=1)=[O:13])CCC>C(O)CCC>[NH2:20][C:18]1[CH:19]=[C:14]([C:12]([NH:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4])=[O:13])[CH:15]=[C:16]([C:21]([NH:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4])=[O:23])[CH:17]=1
Reactant: CCCCOC(=O)c1cc(N)cc(C(=O)OCCCC)c1
Reactant: NC(CO)CO
Solvent: CCCCO
Product: Nc1cc(C(=O)NC(CO)CO)cc(C(=O)NC(CO)CO)c1
Temperature: 70 °C
Yield: 96 %

Procedure:
A mixture of 2-amino-1,3-dihydroxypropane (31 g, 340 mmol) and 5-amino-1,3-benzenedicarboxylic acid di-n-butyl ester (20.0 g, 68.2 mmol) is heated to 125° C. for 3 hours while the n-butyl alcohol which forms is distilled off. After cooling the reaction mixture to about 70° C. the solution is diluted with methanol (0.35 L) and a solid product crystallizes out. After 4 hours at room temperature the mixture is filtered and the solid on filter is washed with methanol (30 mL) and dried yielding the compound of the title (21.4 g, 65.5 mmol, yield: 96%).
Reaction SMILES: C(OC([N:8]1[CH2:14][C:13]2(O)[NH:15][C:16]([CH3:33])=[C:17]([C:27]([O:29][CH2:30][CH2:31][OH:32])=[O:28])[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[Cl:26])[CH:12]2[S:11](=[O:36])(=[O:35])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[Cl:26][C:20]1[C:21]([Cl:25])=[CH:22][CH:23]=[CH:24][C:19]=1[CH:18]1[C:12]2[S:11](=[O:35])(=[O:36])[CH2:10][CH2:9][NH:8][CH2:14][C:13]=2[NH:15][C:16]([CH3:33])=[C:17]1[C:27]([O:29][CH2:30][CH2:31][O:32][C:37](=[O:39])[CH3:38])=[O:28]
Reactant: CC1=C(C(=O)OCCO)C(c2cccc(Cl)c2Cl)C2C(O)(CN(C(=O)OC(C)(C)C)CCS2(=O)=O)N1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCOC(=O)C1=C(C)NC2=C(C1c1cccc(Cl)c1Cl)S(=O)(=O)CCNC2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
2-Hydroxyethyl 4-t-butyloxycarbonyl-9-(2,3-dichlorophenyl)-1,1-dioxo-5a-hydroxy-2,3,4,5,5a,6,9,9a-octahydro-7-methylpyrido[2,3-f][1,4]thiazepine-8-carboxylate (0.500 g, 0.97 mmole) from Example 18, was dissolved in 5 mL of pyridine and 5mL of acetic anhydride, and stirred for 2 hours. The solvents were removed under reduced pressure, and the residue was slurried in 25 mL of ethyl acetate and cooled to 0° C., after which the mixture was saturated with gaseous HCl. After 90 minutes, the reaction was poured into 30 mL of 4N NaOH. The ethyl acetate layer was separated and dried with brine, and the aqueous layer was extracted with 2×30 mL of chloroform. The combined organic extracts were dried with sodium sulfate and evaporated, and the residue was chromatographed (2% methanol, 0.1% ammonia in chloroform, silica gel) to give the product as a white solid (0.351 g, 89% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12]Cl.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC(C)C)=O.ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)CC(C)C
Product: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
0.14 g (0.65 mmol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester were added to a mixture of 0.1 g (0.5 mmol) of 3-piperidin-4-yl-1H-indole, 0.10 g (0.75 mmol) of potassium carbonate and 0.06 g (0.37 mmol) of potassium iodide in 1.5 mL of isobutyl methyl ketone under nitrogen atmosphere and the reaction mixture was refluxed for 18 hours. After cooling at room temperature, 1.5 mL of dichloromethane and 0.08 g (0.1 mmol) of polystyrene methyl isocyanate were added and the mixture was stirred at this temperature for 3 hours. After filtering, the solution was placed directly onto a 500 mg Varian SCX ion exchange column. The columns were washed with 5 mL of methanol and the product was eluted with 5 mL of methanol/ammonia 20:1 affording, after removal of the solvent at reduced pressure, 0.113 g (60% yield) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester as a yellow oil.