Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][CH:12]=[C:11]([C:14]3[CH:25]=[CH:24][C:17]4[C:18]5([CH2:23][NH:22][CH2:21]5)[O:19][CH2:20][C:16]=4[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:39][S:40]([CH2:43][C:44](O)=[O:45])(=[O:42])=[O:41].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:28])([F:27])[F:29])[O:13][CH:12]=[C:11]([C:14]3[CH:25]=[CH:24][C:17]4[C:18]5([CH2:23][N:22]([C:44](=[O:45])[CH2:43][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:21]5)[O:19][CH2:20][C:16]=4[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc3c(c2)COC32CNC2)=CO1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)CC(=O)N1CC2(C1)OCc1cc(C3=COC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
To a stirred solution of hydrochloride salt of 5′-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-3-yl]-3′H-spiro[azetidine-3,1′-[2]benzofuran](Preparation 16, 0.5 g, 1.04 mmol) in THF (6 mL) was added DIPEA (1.82 mL, 10.45 mmol) at room temperature and stirred for 10 minutes at room temperature. Methane sulfonyl acetic acid (0.289 g, 2.09 mmol) and T3P (50% solution in ethyl acetate, 3.1 mL, 5.22 mmol) were added at room temperature. Resulting reaction mixture was stirred for 16 hours at room temperature under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (5×25 mL). Combined organic layer was washed with saturated solution of NaHCO3 (2×100 mL), dried over sodium sulphate and concentrated in vacuo to get pale yellow oil (0.62 g, crude). Crude was purified by column chromatography using 100-200 mesh silica gel. Desired product gets eluted in 0.7% MeOH in DCM to afford white semisolid (0.36 g), which was triturated with DCM: n-pentane (1:10; 2×5 mL) to afford off white solid (0.295 g, 50.18%). 1H NMR (400 MHz, CDCl3) δ: 3.17 (s, 3H), 3.21 (d, J=8.4 Hz, 1H), 3.31 (d, J=17.32 Hz, 1H), 3.84 (s, 2H), 4.31 (d, J=10.96 Hz, 1H), 4.41 (d, J=11.24 Hz, 1H), 4.58-4.64 (m, 2H), 5.08 (s, 2H), 7.15 (s, 1H), 7.33 (d, J=7.76 Hz, 1H), 7.40-7.43 (m, 2H), 7.51 (d, J=1.12 Hz, 2H). LC-MS (m/z): 559.7 (M−H).
Reaction SMILES: CS([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1)=O.[F:28][C:29]([F:33])([F:32])[CH2:30][OH:31].[H-].[Na+].Cl>O1CCCC1>[F:28][C:29]([F:33])([F:32])[CH2:30][O:31][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1
Reactant: CS(=O)c1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(OCC(F)(F)F)nc2[nH]1
Reaction time: 0.17 h

Procedure:
2-(Methylsulfinyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (150 mg) was suspended in tetrahydrofuran (5 ml), 2,2,2-trifluoroethanol (108 μl) was added thereto, and then sodium hydride (60% in oil, 37.6 mg) was added thereto under ice-cooling, and the mixture was stirred for 10 min. To the reaction mixture was added 0.5M hydrochloric acid (4 ml), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained white residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (128 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>>[C:1]([O:5][C:6](=[O:16])[N:7]([C@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][Br:17])[CH2:13][CH2:14]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](O)CC1
Reactant: BrCCCCCCBr
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](OCCCCCCBr)CC1

Procedure:
In analogy to examples 1.4 and 1.5, trans-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid tert-butyl ester was reacted with 1,6-dibromohexane to yield trans-[4-(6-Bromo-hexyloxy)-cyclohexyl]-methyl-carbamic acid tert-butyl ester which was reacted with N-allylmethylamine to yield trans-(4-[6-(Allyl-methyl-amino)-hexyloxy]-cyclohexyl)-methyl-carbamic acid tert-butyl ester as light brown oil, MS: 382 (M).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH3:13][CH:14]([NH:16][CH2:17][CH2:18][CH2:19][N:20]1[C:29]([S:30][C:31]2[CH:36]=[C:35]3[O:37][CH2:38][O:39][C:34]3=[CH:33][C:32]=2I)=[N:28][C:22]2[C:23]([NH2:27])=[N:24][CH:25]=[N:26][C:21]1=2)[CH3:15].C([O-])(O)=O.[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([C:32]2[C:31]([S:30][C:29]3[N:20]([CH2:19][CH2:18][CH2:17][NH:16][CH:14]([CH3:15])[CH3:13])[C:21]4[C:22]([N:28]=3)=[C:23]([NH2:27])[N:24]=[CH:25][N:26]=4)=[CH:36][C:35]3[O:37][CH2:38][O:39][C:34]=3[CH:33]=2)=[CH:5][CH:4]=1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2ccc(N(C)C)cc2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C
Yield: 85.5 %

Procedure:
4-(Dimethylamino)phenylboronic acid (14.5 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 3 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH—NH3 (7N), 4:5:2:1) to give 25.3 mg (85%) of DZ2-392. 1H NMR (500 MHz, CDCl3) δ 8.24 (s, 1H), 7.13 (d, J=8.7 Hz, 2H), 6.93 (s, 1H), 6.83 (s, 1H), 6.67 (d, J=8.7 Hz, 2H), 6.01 (br s, 2H), 5.98 (s, 2H), 4.02 (t, J=6.7 Hz, 2H), 2.97 (s, 6H), 2.78 (septet, J=6.3 Hz, 1H), 2.44 (t, J=6.7 Hz, 2H), 1.87 (m, 2H), 1.10 (d, J=6.3 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 154.4, 152.4, 151.5, 149.9, 148.5, 148.0, 147.1, 139.6, 130.0, 127.8, 120.5, 119.7, 112.8, 111.7, 111.0, 101.7, 49.3, 43.1, 40.9, 40.4, 28.9, 21.9; HRMS (ESI) m/z [M+H]+ calcd. for C26H32N7O2S, 506.2338; found. 506.2330; HPLC: method A Rt=5.72, method B Rt=5.12.
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][C@H:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C@H:9]1[C:10]([OH:12])=[O:11])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]1([C@H:13]2[CH2:14][CH2:15][NH:8][C@@H:9]2[C:10]([OH:12])=[O:11])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C2CCCCC2)[C@H]1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@H]1NCC[C@@H]1C1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of N-BOC-3(R)-cyclohexyl-(L)-proline from step A (1.0 g, 0.28 mmol) in CH2Cl2 (3 mL) at 0° C. was added TFA (6 mL). The reaction was allowed to warm to rt for 4 h. The reaction was then concentrated in vacuo and azeotroped with toluene. The crude product was used in the subsequent reaction.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([C:24](=[O:35])[NH:25][CH:26]([C:31](=[O:34])[NH:32][CH3:33])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:5][P:6]([CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[C:16]([N+:20]([O-])=O)[CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:23])(=[O:8])[OH:7]>CO.[Pd]>[NH2:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:12]2[C:11]([N:10]([CH2:9][P:6]([CH2:5][CH:4]([C:24](=[O:35])[NH:25][C@H:26]([C:31](=[O:34])[NH:32][CH3:33])[CH2:27][CH:28]([CH3:29])[CH3:30])[CH2:3][CH:2]([CH3:36])[CH3:1])(=[O:7])[OH:8])[C:14](=[O:15])[C:13]=12)=[O:23]
Reactant: CNC(=O)C(CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Pd]
Solvent: CO
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CN1C(=O)c2cccc(N)c2C1=O
Reaction time: 3 h
Yield: 99 %

Procedure:
75 mg of [4-methyl-2-[[3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl][(3-nitrophthalimido)methyl]phosphinic acid were dissolved in 2.5 ml of methanol containing 0.01 g of 10% palladium-on-charcoal. The mixture was hydrogenated for 3 hours and then filtered. The filtrate was evaporated to give 70 mg of [(3-aminophthalimido)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid in the form of a yellow foam.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:11])=[N:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>CN(C=O)C>[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:4]1[C:5]2=[N:6][C:7]([CH3:11])=[N:8][CH:9]=[C:10]2[C:2]([I:1])=[N:3]1
Reactant: Fc1cccc(CBr)c1F
Reactant: Cc1ncc2c(I)n[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ncc2c(I)nn(Cc3cccc(F)c3F)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
7.100 g (approx. 10.92 mmol, purity 40%) of 3-iodo-6-methyl-1H-pyrazolo[3,4-d]pyrimidine and 4.626 g (14.20 mmol) of caesium carbonate were initially charged in 100 ml of DMF, and 2.939 g (14.20 mmol) of 2,3-difluorobenzyl bromide dissolved in 50 ml of DMF were added. The reaction mixture was stirred at RT for 3 h, added to 1.5 l of ice-water and extracted with diethyl ether. The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 30:70→95:5). 1.360 g of the target compound were obtained (31% of theory).
Reaction SMILES: [Mg].C(OCC)C.[CH2:7](Br)[CH2:8][CH2:9][CH3:10].Br[C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>ClCCl.O>[CH2:7]([C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCBr
Reactant: BrC12CC3CC(CC(C3)C1)C2
Agent: [Mg]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCC12CC3CC(CC(C3)C1)C2
Yield: 38 %

Procedure:
Into a 1 liter egg plant-shaped flask, 4.9 g (0.2 moles) of magnesium was weighed and placed. Under the stream of nitrogen gas, 80 ml of diethyl ether was added and stirred. Then, a solution prepared by dissolving 27.4 g (0.2 moles) of n-butyl bromide into 20 ml of diethyl ether was added dropwise. After the addition was completed, the resultant mixture was heated under the refluxing condition for 30 minutes. The temperature was adjusted at the room temperature, and diethyl ether was completely removed using a vacuum pump. Then, a solution prepared by dissolving 21.5 g (0.1 mole) of 1-bromoadamantane into 300 ml of dichloromethane was added dropwise. After the addition was completed, the resultant mixture was heated under the refluxing condition for 5 hours. The reaction fluid was poured into 200 ml of ion-exchanged water and treated by extraction with dichloromethane using a separation funnel. The solvent was removed using an evaporator. The residue was dissolved into 20 ml of hexane and purified in accordance with the silica gel column chromatography (the solvent of development: hexane). The solvent was removed using an evaporator, and 7.3 g of 1-(n-butyl)-adamantane was obtained as a colorless transparent liquid substance (the yield: 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]([CH:20]([CH3:22])[CH3:21])[NH:11][C:10]2=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]([CH:20]([CH3:21])[CH3:22])[N:11]([CH3:25])[C:10]2=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)N1NC(=O)C(c2ccc(Cl)c(Cl)c2)C1c1ccncc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)N1C(c2ccncc2)C(c2ccc(Cl)c(Cl)c2)C(=O)N1C
Temperature: 0 °C

Procedure:
In a 100 mL round bottom flask, was added 0.1 g 4-(3,4-Dichloro-phenyl)-1-isopropyl-5-pyridin-4-yl-pyrazolidin-3-one and 10 mL THF, stirred at 0° C. under nitrogen. 0.43 mL 1 M LHMDS in THF was added drop wise. After stirred at 0° C. for 30 min 0.026 mL iodomethane was added drop wise. The resulted mixture was stirred from 0° C. to rt for 2 hours, quenched with 20 mL sat. NH4Cl, extracted with dichloromethane 3×25 mL. The organic phase was dried over anhydrous Na2SO4. After purification by flash chromatography, obtained the title compound 80 mg as light solid. MS (ES+): 364 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].ClCCl.[Br-].[CH3:33][C:34]1[CH:35]=[CH:36][C:37]([Zn+])=[N:38][CH:39]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:15]([NH:14][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:37]3[CH:36]=[CH:35][C:34]([CH3:33])=[CH:39][N:38]=3)=[CH:3][C:4]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:5][C:6]=2[N:7]=1)=[O:13])[CH3:16]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(Br)c2s1
Reactant: Cc1ccc([Zn+])nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3ccc(C)cn3)c2s1
Temperature: 100 °C
Reaction time: 15 h
Yield: 4.3 %

Procedure:
To a solution of 1-(7-bromo-5-pyridin-3-yl-benzothiazol-2-yl)-3-ethyl-urea (0.25 g, 0.66 mmol) in anhydrous DMF (5.0 mL) was added K2CO3 (0.28 g, 1.99 mmol) and the resulting solution was purged with nitrogen for 15 min. [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (0.054 g, 0.066 mmol) was added to the reaction mixture, purged again with nitrogen for another 15 min followed by addition of 5-methyl-2-pyridyl zinc bromide (3.32 mL, 1.66 mmol). The resulting reaction mixture was stirred at 100° C. for 15 h followed by removal of DMF in vacuo. Water was added and extracted with EtOAc (3×20 mL). The combined organics was washed with brine, dried (Na2SO4) and concentrated. The residue was purified through prep-HPLC to get the desired product (0.011 g, 4%) as an off-white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([C:24]([O:26]C)=[O:25])=[CH:11][CH:10]=3)[CH3:2].C(O)C.[OH-].[K+]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([C:24]([OH:26])=[O:25])=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(NCC3CCCCC3)c3cc(C(=O)OC)ccc3nc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(C(=O)O)ccc3nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A mixture of 1-ethyl-6-methoxycarbonyl-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinoline-4-amine (1.4 g), ethanol (90 mL), KOH (2 g) and water (10 mL) was stirred at room temperature overnight. The reaction mixture was evaporated and the residue was partitioned between CH2Cl2 and water. The aqueous layer was separated, acidified with acetic acid and the solid which formed was collected by filtration and dried. The solid was recrystallized from hot acetic acid (50 mL) to afford 1.0 g of 1-ethyl-6-carboxy-N-(cyclohexylmethyl)-1H-pyrazolo[3,4 -b]quinolin-4-amine. HOAc, m.p. 240° C.
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[CH3:40][C:41]([CH3:45])([CH3:44])[CH:42]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:40][C:41]([CH3:45])([CH3:44])[CH2:42][N:13]([CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(N[C@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Reactant: CC(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)CN(C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reaction time: 0.25 h
Yield: 12.7 %

Procedure:
The product from Example 26D (87.5 mg, 0.155 mmol) in 1,2-dichloroethane (3.0 mL) was treated with trimethylacetaldehyde (21 μL, 0.186 mmol) at ambient temperature. After stirring for 15 minutes, the mixture was treated with acetic acid (11 μL, 0.181 mmol) followed by sodium triacetoxyborohydride (53 mg, 0.248 mmol). After stirring at ambient temperature for 24 hours, the mixture was treated with aqueous 10% NaHCO3 (5.0 mL) and extract with ethyl acetate (3×10 mL). The ethyl acetate extracts were combined, wash with brine (20 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified on a silica gel cartridge eluting with chloroform to provide the title compound (12.5 mg, 13%). 1H NMR (CDCl3) δ 8.73 (s, 2H), 7.79 (s, 2H), 7.28-7.05 (m, 10H), 5.20 (s, 4H), 4.88-4.76 (br s, 2H), 3.90-3.66 (m, 2H), 2.87 (dd, 2H), 2.75-2.60 (m, 2H), 2.47 (d, 4H), 2.17 (s, 2H), 0.78 (s, 9H); MS (ESI+) m/z 636 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[C:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=O)[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:55][NH:56][C:57](=[NH:59])[CH3:58]>C(Cl)Cl>[O:23]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([NH:59]/[C:57](=[N:56]\[OH:55])/[CH3:58])=[O:19])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][NH:3]1
Reactant: O=C(O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NCCO3)c1
Reactant: CC(=N)NO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C/C(=N/O)NC(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NCCO3)c1
Reaction time: 0.33 h

Procedure:
To a suspension of the product obtained in Step A above (540 mg, 1.61 mmol) in 10 ml of CH2Cl2 there are added, in succession, 516 mg (1.61 mmol) of TBTU and then 364 μl (2.09 mmol) of DIEA. After stirring for 20 minutes, 120 mg (1.61 mmol) of N-hydroxyacetamidine are added and the reaction mixture is stirred for 1.5 hours at ambient temperature. The reaction mixture is washed with water and then with saturated NaCl solution, dried (MgSO4) and evaporated to dryness. The residue is taken up in CH2Cl2; a white precipitate forms which is filtered off to yield the expected product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2.[CH2:17](I)[CH2:18][CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCCI
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)cc(C(=O)OCC)n2C
Temperature: 100 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
A mixture of ethyl 5-hydroxy-1-methyl-1H-indole-2-carboxylate (103 mg, 0.47 mmol), propyl iodide (141 mg, 0.56 mmol) and cesium carbonate (230 mg, 0.70 mmol) in 1 mL dimethylformamide was stirred vigorously at 100° C. in a sealed vessel for 16 h. After cooling to room temperature, solids were filtered and the liquor concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (20-40% ethyl acetate in hexanes) to give ethyl 1-methyl-5-propoxy-1H-indole-2-carboxylate (96 mg, 55%). Used without further characterization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][CH:10]=[C:9]([C:13]#[N:14])[C:8]2=O.O(Cl)[Cl:17]>CN(C=O)C>[Cl:17][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=[CH:10][C:9]=1[C:13]#[N:14]
Reactant: COc1cccc2c(=O)c(C#N)c[nH]c12
Reactant: ClOCl
Solvent: CN(C)C=O
Product: COc1cccc2c(Cl)c(C#N)cnc12
Yield: 91 %

Procedure:
A mixture of 3.8 g (19 mmol) of 1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarbonitrile and 40 mL of phosphorous oxochloride and 5 drops of DMF was refluxed for 0.5 hours. The mixture was evaporated to dryness and diluted with hexanes. The solid was collected and mixed with cold dilute sodium carbonate solution and extracted several times with ethyl acetate. The organic layer was dried over sodium sulfate and filtered through a pad of silica gel. Removal of the solvent gave 3.8 g of 4-chloro-8-methoxy-3-quinolinecarbonitrile as an off white solid in 91% yield, mass spectrum (electrospray, m/e): M+H 219.1.
Reaction SMILES: [CH3:1][C:2]([NH2:15])([CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(N(CC)CC)C>ClCCl>[CH3:14][C:2]([NH:15][C:16](=[O:18])[CH3:17])([CH3:1])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2c(CC(C)(C)N)c[nH]c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)(C)Cc1c[nH]c2cc(C)ccc12
Temperature: 22 °C
Reaction time: 18 h

Procedure:
A solution of 1,1-dimethyl-2-(6-methyl-1H-indol-3-yl)-ethylamine (2 mmole, prepared according to Lit. 2) and acetic anhydride (2.2 mmole) in dichloromethane (3 ml) was treated with triethylamine (6 mmole) and the mixture was stirred at 22° C. for 18 h. The mixture was washed with aqueous hydrochloric acid (1N), the organic layer was dried and evaporated to give N-[1,1-dimethyl-2-(6-methyl-1H-indol-3-yl)-ethyl]-acetamide as a brownish solid. MS: 243.2 ([M−H]−).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.Br[CH2:17][C:18]1[C:19]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=2[S:21][CH:22]=1>CN(C)C=O>[Cl:27][C:25]1[CH:24]=[CH:23][C:20]2[S:21][CH:22]=[C:18]([CH2:17][N:3]3[C:4](=[O:15])[C:5]4[C@@H:6]5[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]5)[C:10]=4[N:2]3[CH3:1])[C:19]=2[CH:26]=1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: Clc1ccc2scc(CBr)c2c1
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1csc3ccc(Cl)cc13)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 73.8 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 3-(bromomethyl)-5-chlorobenzo[b]thiophene (Maybridge plc, Tintagel, Cornwall, UK; 164 mg, 0.63 mmol) in dimethylformamide (5 mL) was heated at 100° C. for 2 days. The solvent was evaporated and ethyl acetate (50 mL) was added. The solution was washed with water (twice) and brine, dried (magnesium sulfate), filtered, evaporated and purified by chromatography, eluting with 1-3% methanol/dichloromethane to give (4S,7R)-2-(5-chloro-benzo[b]thiophen-3-ylmethyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (140 mg, 74%) as an off-white foam. APCI(+)-MS (M+H) 387.