Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:10]=1[Cl:11])=[O:5])C.O.[OH-].[Li+]>CO>[Cl:11][C:10]1[N:9]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(C2CCCC2)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn(C2CCCC2)c1Cl
Temperature: 80 °C
Yield: 92.2 %

Procedure:
5-Chloro-1-cyclopentyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.710 g, 2.93 mmol) was dissolved in methanol (4.3 mL). Water (4.3 mL) and lithium hydroxide (0.097 g, 4.05 mmol) were added and the mixture was heated at 80° C. for 2 hours. After cooling to room temperature, methanol was removed in vacuo. Tetrahydrofuran was added to the residue and then removed in vacuo to ensure complete removal of the methanol. The residue was diluted with water and treated with 6N HCl to pH 2-3, resulting in precipitation of a milky solid. The solid was collected, washed with water and dried under house vacuum at 45° C., yielding 5-chloro-1-cyclopentyl-1H-pyrazole-4-carboxylic acid (0.580 g, 91%). This material was used as is without any further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH:17]([CH:18]=[CH:19][C:20](=[O:27])[CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][CH2:15][C:10]21[O:14][CH2:13][CH2:12][O:11]2.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+].[BH4-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Cl-].[Na+]>CO.CC(C)=O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH:17]([CH:18]=[CH:19][CH:20]([OH:27])[CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][CH2:15][C:10]21[O:14][CH2:13][CH2:12][O:11]2
Reactant: CCCCC(C)C(=O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [BH4-]
Solvent: CC(C)=O
Solvent: CO
Product: CCCCC(C)C(O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Reaction time: 1.5 h
Yield: 59.7 %

Procedure:
6-(7-Hydroxyheptyl)-7-(4-methyl-3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane [1.0 g; prepared as hereinbefore described in Example 1 (v)] was dissolved in methanol (50 ml.) and added to aqueous sodium citrate solution (130 ml; 2% w/v). To this stirred solution, at -5° to 0° C., solid potassium borohydride (2.24 g.) was added portionwise at such a rate as to avoid undue effervescence and the reaction mixture was maintained at pH 8 by the occasional addition of aqueous citric acid solution (10% w/v). After the final addition of the potassium borohydride the reaction mixture was stirred at -5° to 0° C. and pH 8 for 90 minutes. Acetone (50 ml.) was then added, the solution was saturated with sodium chloride, and extracted with diethyl ether. The combined ether extracts were washed with a saturated solution of sodium chloride in hydrochloric acid (2 N) and saturated sodium chloride solution respectively, then dried over sodium sulphate. Removal of the solvent under reduced pressure gave crude 6-(7-hydroxyheptyl)-7-(3-hydroxy-4-methyloct-1-enyl)-1,4-dioxaspiro[4,4]nonane (0.6 g.), νmax 3400 cm-1, 1040 cm-1 , 970 cm-1, which was used in the next stage without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]([NH2:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:13]([NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[NH:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: CCCCCCC(N)c1nc(-c2ccc(F)cc2)c[nH]1
Product: CCCCCCC(NC1CCCCC1)c1nc(-c2ccc(F)cc2)c[nH]1
Yield: 15 %

Procedure:
This compound was obtained according to a protocol analogous to that of stage 13777.4 of example 13777, using 1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-heptanamine (0.5 g; 0.0014 mol) as starting amine and cyclohexanone (0.17 ml; 0.0014 mol) as starting ketone. A white powder was obtained with a yield of 15%. Melting point: 190-192° C. MH+=358.2.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=1[O:13][CH3:14].[F:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:22][O:23][C:19]=2[CH:18]=1>C(O)(C)C>[F:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([CH:24]3[CH2:25][CH2:26][N:27]([CH2:15][CH:2]([OH:1])[CH2:3][O:4][C:5]4[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=4[O:13][CH3:14])[CH2:28][CH2:29]3)=[N:22][O:23][C:19]=2[CH:18]=1
Reactant: COc1cc(C=O)ccc1OCC1CO1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC(C)O
Product: COc1cc(C=O)ccc1OCC(O)CN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 55 °C
Yield: 89.2 %

Procedure:
A stirred mixture of 4-(2,3-epoxypropoxy)-3-methoxyphenyl methanone (4.5 g, 22.5 mmol) and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5.36 g, 24.3 mmol) in isopropyl alcohol (150 ml) was heated at 55° C. for 16 hours. The mixture was cooled and the solvent was removed on a rotary evaporator. The residue was purified by flash chromatography over a silica gel column (SiO2, 80 g; eluted with dichloromethane, DCM, and 1% CH3OH in DCM). The oil thus obtained solidified quickly, weight: 9.47 g. Recrystallization from ethanol and isopropyl ether, then toluene provided 8.6 g (86%) of white crystals, m.p.=107°-108° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=1)[O:7][C@@H:8]1[CH2:12][O:11][C@@H:10]2[C:13](=[O:16])[CH2:14][O:15][C@H:9]12.[CH3:21][Li].[NH4+].[Cl-]>C1COCC1.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=1)[O:7][C@@H:8]1[CH2:12][O:11][C@@H:10]2[C@:13]([CH3:21])([OH:16])[CH2:14][O:15][C@H:9]12
Reactant: O=C1CO[C@H]2[C@@H]1OC[C@H]2Oc1cc(F)ccc1[N+](=O)[O-]
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@]1(O)CO[C@@H]2[C@H](Oc3cc(F)ccc3[N+](=O)[O-])CO[C@@H]21
Reaction time: 2.5 h

Procedure:
1.6 g (5.7 mmol) (3R,3aR,6aS)-3-(5-fluoro-2-nitro-phenoxy)-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one (III.7) in THF are cooled to −70° C. 3.5 ml (5.7 mmol) 1.6 mol/l methyl lithium in diethyl ether are added dropwise and the reaction mixture is allowed to reach RT and stirred for 2.5 h. Aqueous NH4Cl solution and diethyl ether are added and the organic layer is separated, dried and evaporated. The residue is purified by FC (Al2O3).
Reaction SMILES: C[CH2:2][N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C.[Cl:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)C=C(NC)[N:12]=1.C(=O)C.C([BH3-])#N>CO.C(O)(=O)C>[Cl:10][C:11]1[C:20]2[C:19](=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2)[CH:9]=[C:7]([N:3]([CH2:4][CH3:6])[CH3:2])[N:12]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNc1cc2cc(OC)ccc2c(Cl)n1
Agent: CC=O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: CCN(C)c1cc2cc(OC)ccc2c(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
Hunig's base (0.235 mL, 1.347 mmol) was added to a solution of 1-chloro-6-methoxy-N-methylisoquinolin-3-amine (150 mg, 0.674 mmol) and acetaldehyde (0.042 mL, 0.741 mmol) in MeOH (5 mL) and stirred for 30 min Acetic Acid (1 mL) and Cyanoborohydride, polymer supported (2 mmol/gram) (50 mg, 0.674 mmol) were then added and the reaction stirred at r.t. for 2 hrs. Reaction filtered through nylon frit filter and evaporated on rotovap to give the crude product with no purification. The material was taken up in EtOAc and washed with sat. sodium bicarbonate. The organic layer was collected, dried over MgSO4, filtered and evaporated to give the expected product 1-chloro-N-ethyl-6-methoxy-N-methylisoquinolin-3-amine (140 mg, 83% yield) as a dark orange solid. MS: MS m/z 251.15(M++1).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:58]1[CH2:63][CH2:62][CH:61]([N:64]2[CH2:70][CH2:69][C:68]3[CH:71]=[CH:72][CH:73]=[CH:74][C:67]=3[NH:66][C:65]2=[O:75])[CH2:60][CH2:59]1>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:19])[N:58]4[CH2:59][CH2:60][CH:61]([N:64]5[CH2:70][CH2:69][C:68]6[CH:71]=[CH:72][CH:73]=[CH:74][C:67]=6[NH:66][C:65]5=[O:75])[CH2:62][CH2:63]4)[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
(S)-2-(1,4-Dibromo-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino [3,4-e]indazol-7-yl)acetic acid (52 mg, 0.104 mmol) was dissolved in N,N-dimethylformamide (1.5 mL). N,N-Diisopropylethylamine (70 μl, 0.402 mmol) was added to the mixture followed by TBTU (34.8 mg, 0.108 mmol). 3-(Piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one (35.4 mg, 0.144 mmol) was then added to the mixture. Reaction stirred at room temperature for 1 hour. Reaction was quenched with 50% acetonitrile-water. Material was purified by reverse phase prep HPLC (acetonitrile-water-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 67% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.92 (s, 1H) 8.51 (s, 1H) 7.48 (s, 1H) 6.98-7.08 (m, 3H) 6.76-6.86 (m, 1H) 5.58 (d, J=17.40 Hz, 1H) 5.39 (d, J=17.09 Hz, 1H) 4.49 (d, J=13.12 Hz, 1H) 4.26-4.42 (m, 2H) 4.10-4.24 (m, 1H) 3.90-4.09 (m, 2H) 3.33-3.41 (m, 2H) 3.19 (d, J=16.79 Hz, 1H) 3.05-3.15 (m, 1 H) 2.95-3.02 (m, 1H) 2.83-2.94 (m, 3H) 2.53-2.65 (m, 1H) 2.33-2.46 (m, 1H) 1.58-1.85 (m, 3H) 1.40-1.57 (m, 1H). High resolution MS m/e (M+H)+=725.0720.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:14][S:13][CH:12](OCC)[S:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:18]([O:20][P:21]([O:25]CC)[O:22][CH2:23][CH3:24])[CH3:19].P(Cl)(Cl)Cl>ClCCl.[Cl-].[Zn+2].[Cl-]>[Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][S:13][C@@H:12]([P:21]([O:22][CH2:23][CH3:24])([O:20][CH2:18][CH3:19])=[O:25])[S:11]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCOP(OCC)OCC
Reactant: CCOC1SCC(CO[Si](C)(C)C(C)(C)C)S1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: CCOP(=O)(OCC)[C@@H]1SC[C@@H](CO[Si](C)(C)C(C)(C)C)S1
Temperature: 0 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
To a solution of 4-(t-butyldimethylsilyloxymethyl)-2-ethoxy-1,3-dithiolane (example 48) (37.1 g, 126 mmol) and triethylphosphite (14.3 mL, 83.0 mmol, 0.66 eq) in dichloromethane (100 mL) were added phosphorus trichloride (3.6 mL, 42.0 mmol, 0.33 eq) and zinc chloride (catalytic) at 0° c. The solution was stirred at 0° C. for 2 hr and at room temperature for 18 hr. The solvent was evaporated and the crude material was purified by flash chromatography with a mixture of hexane and ethyl acetate (80:20 to 60:40) to give 3.64 g of the cis isomer, 8.62 g of the trans isomer and 9.95 g of the mixture (2:1 trans:cis) for a total yield of 46%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[C:16]3=[CH:17][C:18]4[O:19][CH2:20][CH2:21][O:22][C:23]=4[CH:24]=[C:15]3[N:14]=[CH:13]1)[CH:8]=[CH:7]2.[C:25]([O:29][C:30](=[O:38])[NH:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26].C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C(O)(C(F)(F)F)=O.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:25]([O:29][C:30](=[O:38])[NH:31][CH:32]1[CH2:37][CH2:36][N:35]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([N:12]2[C:16]4=[CH:17][C:18]5[O:19][CH2:20][CH2:21][O:22][C:23]=5[CH:24]=[C:15]4[N:14]=[CH:13]2)[CH:8]=[CH:7]3)[CH2:34][CH2:33]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Brc1cccc2ccc(-n3cnc4cc5c(cc43)OCCO5)nc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(c2cccc3ccc(-n4cnc5cc6c(cc54)OCCO6)nc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
1-(8-Bromo-quinolin-2-yl)-6,7-dihydro-1H-5,8-dioxa-1,3-diaza-cyclopenta[b]naphthalene 81C (700 mg, 1.83 mMol) and piperidin-4-yl-carbamic acid tert-butyl ester (733 mg, 3.66 mMol) were dissolved in 6.0 mL of dioxane under an atmosphere of dry N2. To this solution was added Cs2CO3 (835 mg, 2.56 mMol), racemic-BINAP (68 mg, 0.109 mMol) and tris(dibenzylideneacetone)dipalladium (0) (34 mg, 0.037 mMol) and the reaction mixture was heated to reflux and reacted at this temperature overnight. The mixture was then cooled to ambient temperature, filtered; and concentrated under vacuum to give 1.12 g of an orange film. The film was dissolved in a solution of 5 mL of TFA and 5 mL of DCM under an atmosphere of dry N2. The reaction mixture was stirred at ambient temperature for 30 minutes after which time it was concentrated under vacuum to give a yellow oil. The oil was partitioned between ethyl ether and 0.1 N aqueous HCl. The aqueous layer was then washed with DCM. The aqueous layer was basified to pH˜11 with NaOH. The resulting solution was washed three times with DCM. The DCM extracts were combined, dried over Na2SO4, filtered and concentrated to give 500 mg of a yellow solid. The solid was chromatographed on flash silica gel eluting with MeOH/DCM (1090) to give 127 mg of the title compound 81 as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9]C2C=CC(Cl)=C(NC(=O)C3C=CC=C(Cl)C=3)C=2)=[O:8])=[CH:5][N:4]=1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1>>[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([NH:36][CH2:2][C:3]2[CH:28]=[CH:27][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][N:4]=2)[CH2:32][CH2:31]1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2cccc(Cl)c2)c1)c1ccc(CBr)nc1
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NCc2ccc(C(N)=O)cn2)CC1

Procedure:
6-(bromomethyl)-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide (0.2 mmol) was used in general procedure 5 with 1-methylpiperidin-4-amine (0.4 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(3-chlorobenzamido)phenyl))-6-((1-methylpiperidin-4-ylamino)-methyl)nicotinamide. MS (Q1) 512.3 (M)+
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=O.P(Cl)(Cl)(Cl)=O>>[C:8]([C:7]1[O:12][C:3]([CH2:2][Cl:1])=[N:5][CH:6]=1)([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)C(=O)CNC(=O)CCl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1cnc(CCl)o1
Temperature: 105 °C
Yield: 95.5 %

Procedure:
N-Chloroacetyl-1-amino-3,3-dimethyl-2-butanone (180.13 g, 0.9398 mol, 1 eq) was combined with phosphorus oxychloride (262 mL, 2.8109 mol, 3 eq) under N2. The reaction mixture was heated at 105° C. for 1 h. The mixture was cooled to rt and then quenched with 1.3 kg of ice. The aqueous phase was extracted with ethyl acetate (1 L, then 2×500 mL). The organic extracts were washed with saturated aqueous NaHCO3 (4×1 L) which was back-extracted several times with ethyl acetate. The organic phases were combined, washed with saturated aqueous NaHCO3 (500 mL) followed by saturated aqueous NaCl (300 mL), dried over MgSO4, and concentrated in vacuo to give a brown oil. The crude material was distilled under high vacuum at 100° C. to provide 155.92 g (96%) of 5-t-butyl-2-chloromethyloxazole. HPLC R.T.=3.62 min (Phenomenex 5 μm C18 column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[Si](C=[N+]=[N-])(C)(C)C.[Cl:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.O>C1COCC1>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([O:20][CH2:19][CH2:18][CH2:17][Cl:16])=[CH:22][CH:23]=1)#[CH:2]
Reactant: O=Cc1ccc(OCCCCl)cc1
Reactant: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(OCCCCl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To LDA (2M in THF, 15 mL) in THF (100 mL) at −78° C., TMSCHN2 (2M in hexanes, 15 mL) was added dropwisely. Ten minutes later, 4-(3-chloropropoxy)benzaldehyde (0.025 mol, 4.97 g) in THF (60 mL) was added. After 1 h stirring at −78° C., the mixture was warmed up and refluxed for 3 h. Water (250 mL) was added and extracted by EtOAc (2×200 mL). After being dried over Na2SO4 and concentration, the title compound (4.8 g) was obtained.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5](=O)[CH3:6].O.[NH2:16][NH2:17].CCCCCC>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5](=[N:16][NH2:17])[CH3:6]
Reactant: CON=C(C(C)=O)c1ccc(Cl)cc1
Reactant: NN
Solvent: CCO
Solvent: CCCCCC
Solvent: O
Product: CON=C(C(C)=NN)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of 6.12 g of 1-(4-chlorophenyl)-propane-1,2-dione-1-(O-methyloxime) in 20 ml of ethanol is mixed with 4 ml of hydrazine hydrate. After stirring for 21 hours at room temperature, 80 ml of hexane are added. The precipitated crystals are filtered off, washed with a little hexane and dried. In this way, 4.5 g of 1-(4-chlorophenyl)-2-hydrazono-propan-1-one O-methyloxime are obtained as white crystals having a melting point of 118-119° C. A solution of 3.06 g of the above substance and 3.0 g of (2-formylphenyl)-methoxyimino-acetic acid methyl ester (EP 621277) in 30 ml of pyridine is stirred for 18 hours at 90° C. After cooling, the reaction solution is poured onto ice water and the precipitated oil is extracted with ethyl acetate. Purification takes place with ethyl acetate/hexane (1:9) on silica gel, and the title compound is obtained as a viscous, yellow oil, which crystallises after some time. (melting point 104-105° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[S:20](Cl)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:20]([C:11]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=1)(=[O:22])=[O:21]
Reactant: COc1ccccc1N
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: COc1ccccc1NS(=O)(=O)c1ccc2ccccc2c1

Procedure:
prepared by reaction of o-anisidine with naphthalene-2-sulfonyl chloride
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([C:19](O)=[O:20])=[C:9]1[CH:22]([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:33][NH2:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([C:19]([NH:34][CH2:33][C:32]2[CH:35]=[CH:36][C:37]([F:38])=[C:30]([F:29])[CH:31]=2)=[O:20])=[C:9]1[CH:22]([CH3:23])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: COc1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccc3)c2c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-benzyl-2-isopropyl-6-methoxy-1H-indole-3-carboxylic acid (Compound 6, 226 mg, 0.70 mmol) in CH2Cl2 (7.0 ml) was added EDC (202 mg, 1.05 mmol) and DMAP (128 mg, 1.05 mmol) followed by 3,4-difluorobenzylamine (0.25 ml, 2.1 mmol). The reaction was stirred at room temperature for 18 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]Br>C(O)(=O)C>[CH2:1]([N:8]1[C:16]([Br:18])=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: Nc1ncnc2c1ncn2Cc1ccccc1
Solvent: CC(=O)O
Product: Nc1ncnc2c1nc(Br)n2Cc1ccccc1

Procedure:
A solution of N9-benzyladenine (1 mmol) in acetic acid buffer (pH=4) was treated with bromine (1 mmol) at room temperature for 12 h. The reaction was quenched with 10% sodium sulfite solution and extracted with dichloromethane. The combined extracts were dried (Na2SO4) and evaporated to dryness. Chromatography afforded N9-benzyl-8-bromoadenine.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[O:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(Cl)Cl.CCOC(C)=O>[CH:8]([C:5]1[O:6][CH:7]=[C:3]([CH2:2][N:30]2[CH2:29][CH2:28][N:27]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:32][CH2:31]2)[N:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)c1nc(CCl)co1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)c1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)co1
Temperature: 35 °C
Reaction time: 17 h
Yield: 98.9 %

Procedure:
4-(Chloromethyl)-2-isopropyloxazole (0.920 g, 5.75 mmol, 1 eq) was suspended in DCM (9 mL). DIPEA (2.5 mL, 14.4 mmol, 2.5 eq) was added dropwise, followed by N-Boc-piperazine (2.350 g, 12.6 mmol, 2.2 eq). The reaction mixture was stirred at 35° C. for 17 h, then diluted with EtOAc, washed with H2O, and brine. The organic layer was separated, dried (MgSO4) and the solvent removed in vacuo. The crude product was purified by column chromatography on a Biotage SP1 system (DCM/EtOAc; v/v 1:1) to give the title compound (1.760 g, 99%); 1H-NMR (500 MHz, CDCl3): δ 1.33 (d, J=5.5 Hz, 6H, iPr—CH3), 1.45 (s, 9H, C(CH3)3), 2.45 (br t, J=4.8 Hz, 4H, piperazine N(CH2)2), 3.07 (m, 1H, iPr—CH), 3.41-3.50 (m, 6H, piperazine N(CH2)2 and NCH2), 7.41 (s, 1H, oxazole 5-H); LC (Method B)-MS (ESI, m/z): Rt=2.51 min—310 [(M+H)+, 100%].
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])=[O:5].[OH-].[Na+]>O>[N+:18]([C:15]1[CH:16]=[CH:17][C:2]2[O:13][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[NH:6][C:4](=[O:5])[C:3]=2[CH:14]=1)([O-:20])=[O:19]
Reactant: O=C(Nc1ccccc1O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1Nc2ccccc2Oc2ccc([N+](=O)[O-])cc21

Procedure:
2-Chloro-N-(2-hydroxy-phenyl)-5-nitrobenzamide (10 g, 34.1 mmol) was added to a solution of sodium hydroxide (1.5 g, 37.6 mmol) in water (300 mL) and the resultant solution heated at 90° C. for 6 hr. The precipitate was filtered and washed with 4×100 mL of water. Yield 8.4 g (96%).