Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C([Li])CCC.B(F)(F)F.CCOCC.[CH:21]([C:23]([CH3:25])=[O:24])=[CH2:22]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:22][CH2:21][C:23](=[O:24])[CH3:25]
Reactant: C=CC(C)=O
Reactant: C#CCCCCl
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(=O)CCC#CCCCCl
Reaction time: 0.25 h

Procedure:
14.85 Parts of 5-chloropent-1-yne is dissolved in 250 parts by volume of toluene and the resulting solution is cooled to approximately -40°. To that solution is then added 62.8 parts by volume of 2.31 M ethereal butyl lithium and stirring is continued for approximately 15 minutes. 6.87 Parts of boron trifluoride etherate is added and the reaction mixture is stirred for about 2 hours, then allowed to stand for about 16 hours at -5° to -10°. At the end of that time 10.14 parts of methyl vinyl ketone is added at -40° and the reaction mixture is stirred for about 4 hours, then is quenched with water. 50 Parts by volume of 3 N hydrochloric acid is added and the mixture is kept at room temperature for about 16 hours, at the end of which time the aqueous and organic layers are separated. The aqueous layer is extracted with toluene and the organic layer with water. The organic solutions are combined, washed successively with aqueous sodium hydroxide and water, then dried over anhydrous sodium sulfate and stripped to dryness under reduced pressure, thus affording the crude product. This material is purified by distillation under reduced pressure to afford 9-chloro-5-nonyn-2-one, boiling at about 80°-92° at a pressure of 0.11-0.06 mm.
Reaction SMILES: CS(O[CH:6]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:7]1)(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O>[N:22]([CH:6]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:7]1)=[N+:23]=[N-:24]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(OS(C)(=O)=O)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(N=[N+]=[N-])C2

Procedure:
A solution of 5.90 g (18.47 mmol) of tert-butyl 2-methanesulfonyloxy-7-azaspiro[3.5]nonane-7-carboxylate (WO 2003/084 948) and 3.60 g (55.41 mmol) of sodium azide in 27 mL of N,N-dimethylformamide is refluxed for 12 hours under an inert atmosphere.
Reaction SMILES: [Br:1]C1N(C2N=C(I)N=C(N)C=2N=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.[C:22]([O:25][C@@H:26]1[C@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@@H:29]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[O:28][C@@:27]1(Br)[N:40]1[C:49]2[N:48]=[C:47]([I:50])[N:46]=[C:44]([NH2:45])[C:43]=2[N:42]=[CH:41]1)(=[O:24])[CH3:23]>>[C:22]([O:25][C@@H:26]1[C@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@@H:29]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[O:28][C@H:27]1[N:40]1[C:49]2[N:48]=[C:47]([I:50])[N:46]=[C:44]([NH2:45])[C:43]=2[N:42]=[C:41]1[Br:1])(=[O:24])[CH3:23]
Reactant: Nc1nc(I)nc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CC(=O)OC[C@H]1O[C@@](Br)(n2cnc3c(N)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Br)nc3c(N)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Amination of compound 5 or 6 to obtain the 8-alkylamino-2-iodoadenosines 7–10 was generally as follows: to 8-bromo-2-iodoadenosine (5) or 2′,3′,5′-tri-O-acetyl-2-iodo-bromoadenosine (6) (0.17 mmol) the appropriate alkylamine was added (excess) and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the product was crystallised from water.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)=[C:11]([O:21][CH3:22])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:23]([O-:25])[CH3:24].[Na+].C(O)C>O>[CH2:23]([O:25][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)=[C:11]([O:21][CH3:22])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)[CH3:24]
Reactant: CC[O-]
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cccc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 200 °C
Yield: 39 %

Procedure:
A solution of (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (63 mg, 0.2 mmol) and 21% sodium ethanolate solution in ethanol (112 uL, 0.3 mmol) was heated to 200° C. for 30 minutes in a microwave oven. The same amount of sodium ethanolate solution was added and the reaction was again heated to 200° C. for 30 minutes in a microwave oven. Water was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound as a light brown solid (25 mg, 39%). MS ISP (m/e): 325.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.64 (s, 1H), 7.45 (t, 1H), 7.34 (s, 1H), 7.15 (d, 1H), 6.92 (d, 1H), 6.87 (s, 1H), 6.50 (s, 1H), 6.37 (d, 1H), 6.24 (d, 1H), 4.35 (q, 2H), 3.83 (s, 3H), 2.30 (s, 3H), 1.41 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([NH:30][CH3:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C@H:39]([NH:41][C:42]([NH2:44])=[O:43])[CH3:40])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.O1CCOCC1>[F:32][C:33]1[CH:34]=[CH:35][C:36]([C@H:39]([NH:41][C:42]([NH:44][C:2]2[N:7]=[CH:6][C:5]3[C:8]([NH:30][CH3:31])=[N:9][N:10]([C:11]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:4]=3[CH:3]=2)=[O:43])[CH3:40])=[CH:37][CH:38]=1
Reactant: CNc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Reactant: C[C@@H](NC(N)=O)c1ccc(F)cc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CNc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccc(F)cc3)ncc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
6-Chloro-N-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (332 mg, 0.781 mmol), (R)-1-(1-(4-fluorophenyl)ethyl)urea (Intermediate 20C; 193 mg, 1.059 mmol), BrettPhos pre-catalyst (48.0 mg, 0.060 mmol), and cesium carbonate (759 mg, 2.330 mmol) were taken up in 1,4-dioxane (6 mL) in a 20 mL microwave vial. The vial was evacuated and back-filled with N2 (×3) and the reaction was stirred at 100° C. for 3 h. Room temperature was attained, the reaction mixture was filtered through Celite, eluting with MeOH, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (0-100% EtOAc-DCM) gave (R)-1-(1-(4-fluorophenyl)ethyl)-3-(3-(methylamino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. MS ESI calc'd. For C35H31FN6O [M+1]+ 571. found 571.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C:11]=3[C:12](=[O:30])[CH2:13][C@@H:14]2[C@H:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19])[CH2:6]1)(=[O:3])[CH3:2].CC(C)=[O:33].OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C>CC(C)=O>[C:1]([O:4][C@H:5]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C:11]=3[C:12](=[O:30])[CH2:13][C@@H:14]2[C@H:15]([CH3:20])[CH2:16][CH2:17][C:18]([OH:33])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CCC3=C4C(=O)C[C@H]([C@H](C)CCCO)[C@@]4(C)CC[C@@H]32)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CCC3=C4C(=O)C[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C

Procedure:
To 3β-acetoxy-24-hydroxy-5α-chol-8(14)-en-15-one (1.0 g) in acetone (50 ml) an 8N solution of Jones reagent was added dropwise with stirring at room temperature until the orange color of the reagent persisted. 2-Propanol (1 ml) was added, and the reaction mixture was filtered through a sintered glass filter and evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate, and the organic solution was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to give 3β-acetoxy-15-keto-5α-chol-8(14)-en-24-oic acid (1.0 g) of over 98% purity as judged by 1H NMR. The product showed single component on TLC in three solvent systems (20% methanol in CHCl3, Rf 0.64; isooctaneethyl acetate-acetic acid 5:5:1, Rf 0.56; and CHCl3 -acetonemethanol 7:5:1, Rf 0.18. The structure was confirmed by I.R, N.M.R., and M.S. analyses.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:3]=1.C(OC(=O)N([C@H]1C[C@@H](N2C=NC3C2=NC(Cl)=NC=3Cl)C=C1)C(=O)CC)(C)(C)C.[NH2:57][C@H:58]1[CH2:63][CH2:62][C@H:61]([NH2:64])[CH2:60][CH2:59]1>>[NH2:57][CH:58]1[CH2:63][CH2:62][CH:61]([NH:64][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]3[OH:22])=[C:4]([NH:23][CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:3]=2)[CH2:60][CH2:59]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(CC)CC)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: N[C@H]1CC[C@H](N)CC1
Agent: CCC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(CC)CC)nc(NC4CCC(N)CC4)nc32)[C@H](O)[C@@H]1O

Procedure:
N-{(1S,2R,3S,4R)-4-[2-Chloro-6-(1-ethyl-propylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (the compound of Example 14) is reacted with trans-1,4-diaminocyclohexane to give the title compound using a procedure analogous to that of Example 9. MS (ES+) m/e 489 (MH+).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:17]3[C:28](=[O:32])[NH:29][C:30](=[O:31])[C:16]=3[C:15]=2[C:14]2[CH:13]=[C:12]([OH:33])[CH:11]=[CH:10][C:9]1=2)(=O)=O.[C:34]1([SH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>O>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[C:17]2[C:28](=[O:32])[NH:29][C:30](=[O:31])[C:16]=2[C:15]2[C:14]3[CH:13]=[C:12]([OH:33])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:7][CH2:6][S:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:20]=2[CH:19]=1
Reactant: Sc1ccccc1
Reactant: CS(=O)(=O)OCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1c2c2cc(O)ccc2n1CCSc1ccccc1
Temperature: 110 °C
Yield: 27 %

Procedure:
Mesylate (229) (55 mg, 0.11 mmol) prepared as decribed in example 171 was reacted with excess thiophenol (0.10 mL) according to the procedure described in example 179, except that triethylamine (2.0 mL) was added and the reaction was heated at 110° C. for 4 days. Addition of water was followed by extracted of the compound with with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness followed by chromatography on silica eluting with ethyl acetate/hexane (1:4 to 1:1) to give carbazole (242) (16 mg, 27%) as an orange powder, mp 262–264° C. 1H NMR δ [(CD3)2SO] 11.04 (br s, 1H), 9.37 (br s, 1H), 8.34 (d, J=2.5 Hz, 1H), 7.58 (m, 1H), 7.46 (m, 5H), 7.19 (m, 2H), 7.12 (m, 3H), 7.05 (m, 1H), 4.66 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.4 Hz, 2H). Found: C, 63.64; H, 4.09; N, 4.98. C28H19ClN2O3S.1¾H2O requires: C, 63.39; H, 4.28; N, 5.28.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17].C[S:19]([CH3:21])=O>C(#N)C>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][S:19][C:21]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:10]
Reactant: Sc1ccccc1Cl
Reactant: CS(C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC#N
Product: Clc1ccccc1SSc1ccccc1Cl

Procedure:
Hexamethyldisilazane (4.4 ml) was added to a stirred solution of 2-chlorobenzenethiol (2.0 ml) and DMSO (3.7 ml) in dry acetonitrile at room temperature. After 2 h the white precipitate was filtered and washed (cold acetonitrile) to give the sub-title compound as a white solid (2.27 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH:7](C(OCC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].CS(C)=O.[Cl-].[Na+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C(=O)OCC)c1ncccn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1ncccn1
Temperature: 142.5 °C
Reaction time: 0.33 h
Yield: 63.9 %

Procedure:
4.76 g of diethyl (2-pyrimidinyl)malonate and 20 ml of dimethyl sulfoxide were mixed. To the mixture was added 1.40 g of sodium chloride and 0.72 g of water. The mixture was stirred for about 20 minutes at an inner temperature of 140 to 145° C., and for about 20 minutes at an inner temperature of 145 to 148° C. The mixture was allowed to cool to room temperature, then, to the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure to obtain 2.12 g of ethyl (2-pyrimidinyl)acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=O)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36].[CH3:38][NH:39][CH3:40].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][N:39]([CH3:40])[CH3:38])=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36]
Reactant: CNC
Reactant: CCN(c1cc(-c2ccc(C=O)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(-c2ccc(CN(C)C)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.1 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(6-formylpyridin-3-yl)-2-methylbenzamide (0.102 g, 0.203 mmol) and dimethylamine (0.044 g, 2M 0.507 mL, 1.01 mmol) in dichloroethane (3 mL), acetic acid (0.073 g, 1.021 mmol) was added and reaction stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (0.129 g, 0.609 mmol) was added at 0° C. and reaction stirred for 4 h at room temperature. On completion, solvent was removed under reduced pressure and water was added, extraction was carried out using 10% MeOH/DCM. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure giving crude material which was purified by column chromatography to afford the title compound (0.08 g, 75%). LCMS: 532.30 (M+1)+; HPLC: 97.53% (@254 nm) (Rt; 3.878; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.75 (d, 1H, J=1.2 Hz), 8.20 (t, 1H, J=4.8 Hz), 8.02 (d, 1H, J=6.4 Hz), 7.49 (s, 1H), 7.47 (s, 1H), 7.27 (s, 1H), 5.87 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.81-3.84 (m, 2H), 3.56 (s, 2H), 3.22-3.24 (m, 2H), 3.02-3.12 (m, 3H), 2.25 (s, 3H), 2.21 (s, 6H), 2.20 (s, 3H), 2.10 (s, 3H), 1.65-1.67 (m, 2H), 1.50-1.56 (m, 2H), 0.82 (t, 3H, J=6.8 Hz).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.Cl.[NH2:28][CH:29]([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C(=O)([O-])[O-].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:28][CH:29]([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(N)C(=O)OC(C)(C)C
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(C=O)cc2C)ncn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CNC(C)C(=O)OC(C)(C)C)cc2C)ncn1
Reaction time: 18 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 100 mg; 0.28 mmol) in DCM (5 ml) was treated with tert-butyl 2-aminopropanoate hydrochloride (227.1 mg; 1.24 mmol) and polymer supported carbonate (150 mg) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 18 hours the mixture was filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give tert-butyl 2-(4-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)-3-methylbenzylamino)propanoate which was used directly without any further purification. The residue was taken up into DCM (4.5 ml) and TFA (0.5 ml) added. After stirring at RT for 2 hours the solvent was removed in vacuo. The residue was taken up into dilute HCl and precipitated by basification to pH 3-4. The solid was removed by filtration, washed with water and dried to give the title compound as a white solid (85 mg, 71%).
Reaction SMILES: C[C@@H]1O[C@@H](O[C@H:8]2[C@H:13](O)[C@@H:12](O)[C@H:11](NC(N)=N)[C@@H:10](O)[C@@H:9]2[NH:21][C:22]([NH2:24])=[NH:23])[C@H](O[C@@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2NC)[C@@]1(O)C=O.CC1(C)S[C@@H]2[C@H](N[C:51]([CH2:53][C:54]3C=C[CH:57]=[CH:58][CH:59]=3)=O)C(=O)N2[C@H]1C([O-])=O.[K+]>>[CH3:51][CH2:53][CH2:54][CH2:59][CH2:58][CH2:57][CH2:8][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:21][C:22]([NH2:24])=[NH:23]
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: [K+]
Product: CCCCCCCCCCCCNC(=N)N

Procedure:
1.0 ml/l COMBIOTIC® (tradename for a streptomycin-pennicillin mixture) (Streptomycin, Penicillin Mixture, Pfizer Corp.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH3:15])[C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[N:16]O)[C:7]2=1.[OH2:18]>O1CCOCC1.CO>[F:1][C:2]1[C:14]2[N:13]([CH3:15])[C:12]3[CH2:11][CH2:10][CH2:9][NH:16][C:8](=[O:18])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c2c(c3cccc(F)c31)C(=NO)CCC2
Reactant: O
Solvent: C1COCCO1
Solvent: CO
Product: Cn1c2c(c3cccc(F)c31)C(=O)NCCC2
Reaction time: 1 h

Procedure:
A mixture of 8-fluoro-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one oxime (1.8 g) and polyphosphoric acid (ca. 20 ml) in dioxan (30 ml) was stirred under nitrogen at 100°-110° for 1 h. After cooling, the reaction mixture was poured into iced water (1 l) and the resulting suspension was extracted with dichloromethane. The organic extract was concentrated in vacuo to give a solid which was taken up in methanol and adsorbed onto silica. Purification by FCC eluting with System A (200:8:1) gave the title compound (850 mg), m.p. 233°-235°.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[N:24]1([CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:29][CH2:30][CH2:31][C:32]([O:23][C@@:9]2([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:33])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)CCCN1CCCC1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCCN1CCCC1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-pyrrolidin-1-yl-butyric acid to yield (3aR,4S,7aR)-methyl 4-(4-(pyrrolidin-1-yl)butanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=453; RT=0.96 min; UPLC Method I
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7](=[O:14])[CH2:6][CH2:5]2.[CH:16]([Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[CH3:15][C:3]1[C:2]([O:1][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:16]([CH3:18])[CH3:17])=[C:11]([CH3:12])[C:10]([CH3:13])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:14])[O:8]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(=O)O2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1O[Si](C(C)C)(C(C)C)C(C)C)CCC(=O)O2
Yield: 58.3 %

Procedure:
A solution of 6-hydroxy-5,7,8-trimethyl-chroman-2-one (1.22 g), triisopropylsilyl chloride (1.71 g) and imidazole (806 mg, 11.84 mmol) in anhydrous DMF (2 mL) was stirred at room temperature for two days. The solution was diluted with ethyl acetate, washed with water and brine. Evaporation and chromatography (silica gel, hexane-ethyl acetate) gave 1.25 g of 5,7,8-trimethyl-6-triisopropylsilanyloxy-chroman-2-one.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[CH:13]=[C:12]2[C:14]([C:17]([C:19](Cl)=[O:20])=[O:18])=[CH:15][NH:16][C:11]2=[CH:10][CH:9]=1.[C:22]([NH:30][CH2:31][CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][NH:34]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:22]([NH:30][CH2:31][CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][N:34]1[C:19](=[O:20])[C:17]([C:14]1[C:12]2[C:11](=[CH:10][CH:9]=[CH:8][CH:13]=2)[NH:16][CH:15]=1)=[O:18])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(NCCC1CCCN1)c1ccccc1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCC1CCCN1C(=O)C(=O)c1c[nH]c2ccccc12)c1ccccc1
Reaction time: 10 h

Procedure:
Tri-ethylamine (1 ml) was added into a solution of indole-3-glyoxyloyl chloride, intermediate 9 (50 mg, purchased from Lancaster) and intermediate 10 2-(N-benzoylaminoethyl)-pyrrolidine (49 mg, Wang, et al, Tetrahedron Lett. 1999, 40, 6745-6747) in THF (5 ml). After the reaction was stirred for 10 hours, the solvents were removed under vacuum to afford a residue which was purified using Shimadzu automated preparative HPLC System to give 2-(N-benzoylaminoethyl)-1-[(indol-3-yl)-2-oxoacetyl]-pyrrolidine (20 mg). Start %=0
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][Si](C)(C)C)=[CH:8][N:7]=2)[CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][N:7]=2)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)C#Cc1ccc(NCC2CC2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(NCC2CC2)nc1
Reaction time: 2 h
Yield: 77.5 %

Procedure:
To a 0° C. solution of 855 mg (3.50 mmol) of cyclopropylmethyl-(5-trimethylsilanylethynyl-pyridin-2-yl)-amine in 7 mL of THF, was slowly added 7.0 mL (7.0 mmol) of 1M TBAF in THF. The mixture was stirred for 2 h, then poured into water and extracted with Et2O. The Et2O was washed with brine. The washes were extracted once with Et2O, and the combined extracts were diluted with 10 mL of CH2Cl2 and left to sit for 10 min. The solution was then decanted from the water that had separated, and was dried with Na2SO4, filtered, concentrated, and chromatographed (1-20% EtOAc in hexanes) to provide 467 mg of 2-(cyclopropylmethyl)amino-5-ethynyl pyridine.