Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[C:3]([O:7][C:8](=[O:23])[CH2:9][CH2:10][N:11]([CH2:15][C:16]1[S:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=1)[C:12]([NH2:14])=[S:13])([CH3:6])([CH3:5])[CH3:4].CCO[C:27]([CH3:29])=O>>[C:3]([O:7][C:8](=[O:23])[CH2:9][CH2:10][N:11]([C:12]1[S:13][CH:15]=[C:16]([CH:20]2[CH2:19][CH:18]3[CH2:29][CH:27]2[CH2:22][CH2:21]3)[N:14]=1)[CH2:15][C:16]1[S:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=1)([CH3:5])([CH3:6])[CH3:4]
Reactant: CCc1ccc(CN(CCC(=O)OC(C)(C)C)C(N)=S)s1
Reactant: CCOC(C)=O
Solvent: CO
Product: CCc1ccc(CN(CCC(=O)OC(C)(C)C)c2nc(C3CC4CCC3C4)cs2)s1
Temperature: 60 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Following a method analogous to General Procedure C, a portion of the above crude alpha-bromoketone (81 mg, 0.37 mmol) was added to a methanol (about 10 mL) solution of 3-[1-(5-ethyl-thiophen-2-ylmethyl)-thioureido]-propionic acid tert-butyl ester (122 mg, 0.371 mmol) and the reaction was heated at 60° C. and stirred overnight. The solvent was evaporated and ethyl acetate and saturated aq sodium bicarbonate solution were added to the residue. Extraction of the aq layer was performed two times with ethyl acetate. The combined organic portion was dried over sodium sulfate, and the dried solvent was decanted from the drying agent. The solvent was removed under reduced pressure to give the crude material. This was purified using silica gel chromatography (eluent: hexanes→19:1 hexanes:EtOAc→9:1 hexanes:EtOAc to give the purified 3-[(4-bicyclo[2.2.1]hept-2-yl-thiazol-2-yl)-(5-ethyl-thiophen-2-ylmethyl)-amino]-propionic acid tert-butyl ester (139 mg, 0.311 mmol, 84%) after evaporation of the eluent under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:13]1([CH:9]2[NH:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]([F:33])([F:32])[F:21])=[CH:3][CH:4]=3)[CH2:8]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Brc1ccc(CN2CCNC(c3ccccc3)C2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Temperature: 120 °C
Yield: 41.4 %

Procedure:
100 mg of 1-(4-Bromo-benzyl)-3-phenyl-piperazine was combined with 136 mg of 2-(Trifluoromethyl)phenyl boronic acid, 17 mg of tetrakis(triphenylphosphine)palladium(0), 1.01 mL of 2M sodium carbonate solution, 2.7 mL toluene and 1.4 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography eluting in a 0-20% methylene chloride/methanol gradient. The product fractions were pooled and concentrated to afford 49.5 mg of product. ES MS (+) m/z 397
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:17]4[N:18]=[CH:19][C:20]([C:21]([OH:23])=O)=[C:16]4[N:15]=[CH:14][C:13]=3[C:24]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[O:25])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:17]4[N:18]=[CH:19][C:20]([C:21]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:23])=[C:16]4[N:15]=[CH:14][C:13]=3[C:24]([N:26]3[CH2:27][CH2:28][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:30][CH2:31]3)=[O:25])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: CCS(N)(=O)=O
Reactant: Cn1ccc2cc(Nc3c(C(=O)N4CCC(c5ccccc5)CC4)cnc4c(C(=O)O)cnn34)ccc21
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc4c(ccn4C)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 47.8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(1-methyl-5-indolylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.065 g, 0.6 mmol), the title compound (0.028 g, 47%) was obtained.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:20]1[CH:24]=[C:23]([C:25]2[C:26]3[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=3[N:28]=[CH:29][N:30]=2)[CH:22]=[N:21]1)[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)#[N:2].Cl.O1CCOCC1>C(Cl)Cl>[N:6]1([CH2:5][CH:4]([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:39])([CH3:41])[CH3:40])[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:3][C:1]#[N:2])[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCCN(CC(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCCNCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
To a solution of tert-butyl 4-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-1,4-diazepane-1-carboxylate (6.4 g, 11 mmol;) in DCM (10 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (22 mL, 88 mmol). The reaction solution was stirred at room temperature for 90 minutes. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with 1.0 N NaOH solution. The aqueous was extracted with ethyl acetate. The combined extracts were dried over MgSO4, filtered, and concentrated to give the desired product as a brown sticky gum (4.1 g, 77%). LCMS calculated for C24H37N8OSi(M+H)+: m/z=481.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10]2)=[C:5]2[NH:21][CH:22]=[C:23]([C:24](=[O:28])[C:25]([OH:27])=O)[C:4]=12.[Cl-].[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[C:40]([N:41]2[CH2:46][CH2:45][NH2+:44][CH2:43][CH2:42]2)=[N:39][N:38]=[N:37]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([NH:14][C:15](=[O:20])[C:16]([CH3:18])([CH3:19])[CH3:17])=[N:10]2)=[C:5]2[NH:21][CH:22]=[C:23]([C:24](=[O:28])[C:25](=[O:27])[N:44]3[CH2:43][CH2:42][N:41]([C:40]4[N:36]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=5)[N:37]=[N:38][N:39]=4)[CH2:46][CH2:45]3)[C:4]=12
Reactant: COc1cnc(-n2cnc(NC(=O)C(C)(C)C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: c1ccc(-n2nnnc2N2CC[NH2+]CC2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cnc(-n2cnc(NC(=O)C(C)(C)C)n2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
A mixture of 2-(4-methoxy-7-(3-pivalamido-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (15 mg, 0.039 mmol), 4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-ium chloride (11.43 mg, 0.043 mmol), 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (13.71 mg, 0.043 mmol) and N,N-diisopropyl ethylamine (0.022 ml, 0.124 mmol) in DMF (1 ml) was stirred overnight at room temperature. The reaction mixture was filtered through a silica gel pad and concentrated under reduced pressure. The resulting crude was purified by prep HPLC to give N-(1-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)pivalamide (10 mg, 43%) as white solid. LCMS: m/e 600.47 (M+H)+, ret time 2.67 min (method 4). 1H NMR (500 MHz, DMSO-D6) δ ppm 1.22 (s, 9H) 3.23-3.29 (m, 2H) 3.39-3.49 (m, 4H) 3.68-3.74 (m, 2H) 3.99 (s, 3H) 7.64 (dd, J=7.63, 4.88 Hz, 1H) 7.85 (d, J=8.24 Hz, 1H) 7.88 (s, 1H) 8.13-8.18 (m, 1H) 8.21 (s, 1H) 8.23 (d, J=3.66 Hz, 1H) 8.64-8.69 (m, 1H) 11.36 (s, 1H) 12.59 (d, J=3.36 Hz, 1H)
Reaction SMILES: [CH3:1][NH:2][CH3:3].C[O-].[Na+].[C:7]([O:14]CC)(=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].P(=O)(O)(O)O>CO>[CH3:1][N:2]([CH3:3])[C:7](=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CNC
Reactant: CCOC(=O)C(=O)OCC
Agent: C[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(=O)N(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a 1,500 mL reactor, are added at 0° C., 360 g (4 mol) of dimethylamine (DMA) solution at 50% by weight in methanol and 44 g (0.2 mol) of sodium methylate at 25% by weight in methanol. To this mixture are added at 0-5° C. and within 1 hour, 584 g (4 mol) of diethyl oxalate. The mixture is maintained with stirring at 0° C. for 4 hours. The reaction medium is concentrated in vacuo (Pmax=200 mbars) for removing residual DMA and methanol and an 85% orthophosphoric acid solution (23.3 g 0.2 mol) is then added. The salts formed are filtered and the filtrate is then distilled in vacuo (Tbp=77-78° C., P<1 mbar) for recovering the desired product (500 g).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[NH2:30][CH2:31][CH2:32][C:33]#[N:34].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[C:31]([CH2:32][CH2:33][NH:34][C:20]([C:19]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1/[CH:11]=[CH:10]/[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:1])[F:29])[C:5]=1[O:23][CH2:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:21])#[N:30]
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Reactant: N#CCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)NCCC#N)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (80 mg, 0.189 mmol) with 3-aminopropanenitrile (14.56 mg, 0.208 mmol) in the presence of EDCI hydrochloride (72 mg, 0.378 mmol), DMAP (21 mg, 0.189 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 60 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.08 (s, 9H), 2.82-2.86 (m, 2H), 3.52-3.60 (m, 4H), 7.16 (t, J=73.5 Hz, 1H), 7.18-7.30 (m, 2H), 7.37-7.52 (m, 2H), 7.72-7.88 (m, 2H), 8.00-8.06 (m, 1H), 8.59 (br s, 1H); APCI-MS (m/z) 475.28 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCC/C=C\CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCC/C=C\CCCOc1ccc(C(=O)OC)cc1
Yield: 100.1 %

Procedure:
90 mg of 32 (590 μmol) and 81 mg of K2CO3 (590 μmol) are added to 150 mg of 13 (535 μmol) in anhydrous DMF (2 mL). After reaction for 7 hours at 90° C., the reaction medium is concentrated, taken up in DCM and then washed with water. 163 mg of a yellow oil are obtained, and are chromatographed on silica gel in pentane/ethyl acetate (80/1). 129 mg of the expected coupling product are isolated in the form of a yellow oil, i.e. a yield of 79%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].B(O)(O)[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(B(O)O)c2ccccc12
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NN(C)C(=O)OC(C)(C)C)c2ccccc12
Temperature: 50 °C
Yield: 9.2 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 450 mg, 3.1 mmol), (4-methyl-1-naphthalene)boronic acid (Aldrich; 561 mg, 3.0 mmol), copper(II) acetate (559 mg, 3.1 mmol) and triethylamine (430 μL, 3.1 mmol) in 1,2-dichloroethane (4 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 5% ethyl acetate/hexanes, to give N-methyl-N′-(4-methyl-naphthalen-1-yl)-hydrazinecarboxylic acid tert-butyl ester (79 mg, 9%) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH:17]([C:19]1[NH:23][CH:22]=[C:21]([C:24]([OH:26])=[O:25])[C:20]=1[CH2:27][CH2:28][OH:29])=O>>[OH:29][CH2:28][CH2:27][C:20]1[C:21]([C:24]([OH:26])=[O:25])=[CH:22][NH:23][C:19]=1[CH:17]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: O=Cc1[nH]cc(C(=O)O)c1CCO
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: O=C1Nc2cccc(-c3ccncc3)c2C1=Cc1[nH]cc(C(=O)O)c1CCO

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 5-formyl-4-(2-hydroxyethyl)-1H-pyrrole-3-carboxylic acid to give the title compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Si]([O:32][CH2:33][CH2:34][C:35]1[C:36]([F:53])=[C:37]([CH:50]=[CH:51][CH:52]=1)[CH2:38][N:39]1[CH2:49][CH2:48][C:42]2([O:47][CH2:46][CH2:45][NH:44][CH2:43]2)[CH2:41][CH2:40]1)(C(C)(C)C)(C)C.[CH:54]([C:57]1[N:62]=[C:61]([C:63](O)=[O:64])[CH:60]=[CH:59][CH:58]=1)([CH3:56])[CH3:55].C(N(CC)CC)C>CN(C=O)C>[F:53][C:36]1[C:35]([CH2:34][CH2:33][OH:32])=[CH:52][CH:51]=[CH:50][C:37]=1[CH2:38][N:39]1[CH2:40][CH2:41][C:42]2([O:47][CH2:46][CH2:45][N:44]([C:63]([C:61]3[CH:60]=[CH:59][CH:58]=[C:57]([CH:54]([CH3:56])[CH3:55])[N:62]=3)=[O:64])[CH2:43]2)[CH2:48][CH2:49]1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: CC(C)c1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.20 g) was added to a solution of 9-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecane (example 78, step d) (0.17 g), 6-isopropylpicolinic acid (example 85, step d) (0.07 g) and triethylamine (0.22 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL). The organic phase was separated, washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The residue was dissolved in THF (10 mL) and a solution of TBAF in THF (1M, 0.8 mL) was added. The resulting mixture was stirred for 2 h and the solvent evaporated. Purification was by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (50 mL) was added and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.2 g.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1C(O)=O>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([OH:1])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccc2c(O)c(C(=O)O)cnc2c1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc2c(O)ccnc2c1
Temperature: 25 °C
Yield: 97 %

Procedure:
A suspension of 4-hydroxy-7-methoxyquinoline-3-carboxylic acid (4.0 g) in Dowtherm A (75 mL) was heated at reflux for 2 hrs. The resulting brown solution was allowed to slowly cool to ambient temperature. The resulting precipitate was isolated by filtration and then dried in a vacuum oven at 80° C. for 2.5 days to provide 3.1 g of 7-methoxyquinolin-4-ol as a light tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH:10]([F:12])[F:11].ClC1C=CC=C(C(OO)=[O:21])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:21])=[C:4]([CH3:8])[C:3]=1[O:9][CH:10]([F:11])[F:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nccc(Cl)c1OC(F)F
Solvent: ClCCl
Product: Cc1c(OC(F)F)c(Cl)cc[n+]1[O-]
Temperature: 5 °C
Reaction time: 12 h
Yield: 94.3 %

Procedure:
76.38 g of 4-chloro-3-difluoromethoxy-2-methylpyridine (XIX) was dissolved in 2500 ml of anhydrous dichloromethane, to which 93.62 g of 3-chloro-perbenzoic acid was added under cooling with ice, and the resulting mixture was stirred at 5° C. for 12 hours. The resulting organic layer was washed with 5% sodium carbonate solution, and thereafter, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 77.97 g of 4-chloro-3-difloromethoxy-2-methylpyridine N-oxide (VI).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[C:7]([NH:11]N)([CH3:10])([CH3:9])[CH3:8]>C(O)CCCC.C(OC(C)C)(C)C>[NH2:5][C:4]1[N:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:1]=[C:2]([CH3:6])[CH:3]=1
Reactant: C/C(N)=C/C#N
Reactant: CC(C)(C)NN
Solvent: CC(C)OC(C)C
Solvent: CCCCCO
Product: Cc1cc(N)n(C(C)(C)C)n1
Yield: 58.7 %

Procedure:
To a solution of 16.4 g (0.2 mol) of 3-aminocrotononitrile in 100 cm3 of n-pentanol were added 19.4 g (0.22 mol) of tert-butylhydrazine. This solution was heated at reflux for 20 hours. The n-pentanol was subsequently distilled off under reduced pressure. A pale yellow solid was obtained, which was taken up in 100 cm3 of isopropyl ether at room temperature and filtered on a sinter funnel. After drying under vacuum at 40° C., 18 g of the expected product were obtained in the form of a pale yellow solid, the melting point of which was from 172 to 175° C.
Reaction SMILES: C(O[C@H:5]1[C@H:10]2[C@H:11]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@:7]([CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:8][O:9]2)[O:6]1)(=O)C.[C:29]([NH:37][C:38]1[N:46]=[CH:45][N:44]=[C:43]2[C:39]=1[NH:40][CH:41]=[N:42]2)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>C(#N)C>[C:29]([NH:37][C:38]1[N:46]=[CH:45][N:44]=[C:43]2[C:39]=1[N:40]=[CH:41][N:42]2[C@@H:5]1[C@H:10]2[C@H:11]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@:7]([CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:8][O:9]2)[O:6]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(=O)O[C@@H]1O[C@@]2(COCc3ccccc3)CO[C@@H]1[C@@H]2OCc1ccccc1
Reactant: O=C(Nc1ncnc2nc[nH]c12)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: O=C(Nc1ncnc2c1ncn2[C@H]1O[C@@]2(COCc3ccccc3)CO[C@@H]1[C@@H]2OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
A solution of furanose 207 (167 mg, 0.434 mmol) and 6-N-benzoyladenine (194 mg, 0.813 mmol) in anhydrous acetonitrile (5.3 mL) was added BSA (0.43 mL, 1.76 mmol) and stirred at room temperature for 1 h. The solution was cooled to 0° C. and trimethylsilyl triflate (0.16 mL, 0.86 mmol) was added dropwise. After stiffing at 65° C. for 2 h, the reaction was quenched with a saturated aqueous solution of sodium hydrogen carbonate (40 mL) and the mixture was extracted with dichloromethane (2×50 mL). The combined extract was dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by chromatography over silica gel with dichloromethane:methanol (98:2) as eluent to give the product 208 as a solid (111 mg, 45%); 1H NMR (CDCl3): δ 8.82 (1H, s, H-8), 8.14 (1H, s, H-2), 7.59-7.26 (15H, m, Bz, Bn), 6.74 (1H, s, H-1′), 4.92 (1H, s, H-2′), 4.74-4.39 (4H, m, Bn), 4.42 (1H, s, H-3′), 4.19-4.10 (2H, m, H-5″), 3.92 (1H, d, J 11.8 Hz, H-5′), 3.88 (1H, d, J 11.5 Hz, H-5′); MS FAB: 564 (M+H, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=O)[NH:10][N:9]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:23])=O>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([Cl:23])=[N:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Cc2n[nH]c(=O)c3ccccc23)cc1
Product: COc1ccc(Cc2nnc(Cl)c3ccccc23)cc1

Procedure:
To 4-(4-methoxybenzyl)phthalazin-1(2H)-one (1.18 g, 4.43 mmol) was added phosphorus oxychloride (4.13 ml, 44.3 mmol). A water condenser was attached and the mixture was heated to reflux under a nitrogen atmosphere for 15 hours. The reaction was concentrated in vacuo, diluted with methylene chloride and ice water, then quenched with solid sodium bicarbonate until pH was basic and gas evolution ceased. The layers were separated and the organic layers were dried over sodium sulfate, filtered through a pad of silica gel using EtOAc and concentrated to yield 1-(4-methoxybenzyl)-4-chlorophthalazine as a light orange solid. MS m/z=285 [M+1]+. Calc'd for C16H13ClN2O: 284.75.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].[Cl:13]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([Cl:13])=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(=O)c1cc(Br)ccc1N
Solvent: ClCCl
Product: CCC(=O)c1cc(Br)cc(Cl)c1N
Temperature: 45 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
1-(2-Amino-5-bromo-phenyl)-propan-1-one (144.0 mg, 0.63 mmol) was dissolved in CH2Cl2 (10.0 mL), and N-chlorosuccinimide (168.0 mg, 1.26 mmol) was added to this solution. The resulting mixture was stirred at 45° C. overnight. The reaction was cooled to room temperature and concentrated. The residue was purified through column chromatography to afford 1-(2-amino-5-bromo-3-chloro-phenyl)-propan-1-one as a solid (130.0 mg, 76.1%).
Reaction SMILES: Br.[NH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([CH2:13][CH2:14][CH3:15])[CH2:8]2.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH2:5][CH2:6][N:7]([CH2:13][CH2:14][CH3:15])[CH2:8]3)=[O:23])=[CH:20][CH:19]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCCN1CCc2c(N)cccc2C1
Agent: Br
Product: CCCN1CCc2c(cccc2NC(=O)c2ccc(OC)cc2)C1

Procedure:
5-Amino-2-n-propyl-1,2,3,4-tetrahydroisoquinoline hydrobromide was reacted with 4-methoxybenzoyl chloride according to the procedure of Example 14 to produce 5-(4-methoxybenzamido)-2-n-propyl-1,2,3,4-tetrahydroisoquinoline; m.p. 162.5°-163.5° C. after purification with ethanol.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([NH2:17])[C:8]=1[O:18][CH:19]([CH3:21])[CH3:20].N1C=CC=CC=1>ClCCl>[NH2:6][C:7]1[C:8]([O:18][CH:19]([CH3:21])[CH3:20])=[C:9]([NH:17][S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:14])[CH3:15])[CH:12]=1
Reactant: CC(C)Oc1c(N)cc(C(C)(C)C)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)Oc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At ambient temperature 0.20 ml methanesulphonic acid chloride are added dropwise to a solution of 0.48 g 1,3-diamino-5-tert-butyl-2-isopropoxy-benzene and 0.35 ml of pyridine in 5 ml dichloromethane. The solution is stirred for 2 h at ambient temperature and then evaporated down. The residue is chromatographed on silica gel with cyclohexane/ethyl acetate (90:10→40:60) as eluant.