Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:23][CH2:24][CH3:25])[C:5]1S[C:7]([Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=1)[CH3:2].C([O:28]C(OCC)C1OC=CC=1)C>>[CH2:1]([O:3][CH:4]([O:23][CH2:24][CH3:25])[C:5]1[O:28][C:7]([Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(OCC)OCC)s1
Reactant: CCOC(OCC)c1ccco1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C(OCC)OCC)o1
Yield: 82 %

Procedure:
Following the procedure for preparing 2-(diethoxymethyl)-5-(tributylstannyl)-thiophene as described in step (1) of Example 1, 17 g (10 mmol) of 2-(diethoxymethyl)furan was converted to 32.6 g (82% yield) of 2-(diethoxymethyl)-5-(tributylstannyl) furan (bp 110° C., 1 torr).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH3:49])[CH2:43][C@H:44]1[CH2:48][CH2:47][CH2:46][O:45]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]([CH3:49])[CH2:43][C@H:44]2[CH2:48][CH2:47][CH2:46][O:45]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C[C@H]1CCCO1)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)C[C@H]2CCCO2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 73.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N—[(R)-tetrahydrofuran-2-ylmethyl]acetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (12 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:18])[S:17][C:13]=2[C:12]([C@@H:19]([OH:22])[CH2:20][Br:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:40]1[CH:45]=[CH:44][CH2:43][CH2:42][CH2:41]1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:18])[S:17][C:13]=2[C:12]([C@@H:19]([O:22][CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45][O:40]2)[CH2:20][Br:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: O=c1[nH]c2c(OCc3ccccc3)ccc([C@@H](O)CBr)c2s1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=c1[nH]c2c(OCc3ccccc3)ccc([C@H](CBr)OC3CCCCO3)c2s1

Procedure:
To a stirred solution of 4-(benzyloxy)-7-[(1R)-2-bromo-1-hydroxyethyl]-1,3-benzothiazol-2(3H)-one (31 mg) in dry DCM (5 ml) under nitrogen, was added pyridinium p-toluenesulphonate (5 mg), followed by 3,4-dihydro-2H-pyran (30 μl). The mixture was evaporated in vacuo after 18 h and purified on a 2 g silica SPE cartridge, eluting with a stepped gradient 10% to 100% DCM-cyclohexane mixtures, to give the title compound (42 mg). LCMS RT=3.72 and 3.78 min.
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:8][C:9]1[C:10]2[C:15]([C:16]3[C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=[CH:20][C:21]=3[CH:22]=1)=[CH:14][C:13]([CH3:27])=[CH:12][CH:11]=2)[CH3:7].S([O-])([O-])(=O)=O.[Na+].[Na+].[C:35](=O)=[O:36]>CCCCCC.O1CCCC1>[CH2:6]([N:8]1[C:9]2[CH:22]=[C:21]3[CH:20]=[CH:19][C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[C:16]3=[C:15]3[CH:14]=[C:13]([CH3:27])[CH:12]=[C:11]([C:10]=23)[C:35]1=[O:36])[CH3:7]
Reactant: CCNc1cc2ccc(OC)c(OC)c2c2cc(C)ccc12
Reactant: O=C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN1C(=O)c2cc(C)cc3c2c1cc1ccc(OC)c(OC)c13
Reaction time: 0.5 h

Procedure:
661.4 ml (1.084M) of a 15% solution of n-butyl-lithium in hexane are added at 0°, over a period of 20 minutes and under a nitrogen atmosphere, to a solution of 97 g (0.328M) of 9-ethylamino-3,4-dimethoxy-6-methyl-phenanthrene in 1000 ml anhydrous tetrahydrofuran; the reaction mixture becomes dark red. After stirring for 30 minutes at 0°, the mixture is transferred in portions with a teflon tube with nitrogen pressure at -50° onto a mixture of 500 g sodium sulfate and 500 g dry ice in 1500 ml tetrahydrofuran. After the temperature of the mixture has reached room temperature, the mixture is poured onto water/ice, extracted three times with methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated to give the title compound. M.pt. 158°-160° (decomp.) after crystallisation from ether/petroleum ether.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([CH3:21])=[C:18](Br)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:22](C([SnH3])=C(CCCC)CCCC)[CH2:23]CC>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:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([CH3:21])=[C:18]([CH:22]=[CH2:23])[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Cc1ncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cc1Br
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1C
Yield: 56.4 %

Procedure:
The product of 196e (1.0 g, 2.8 mmol) and tributylvinyl tin hydride (0.98 mL, 3.4 mmol) and tetrakis(triphenylphosphine)palladium (161 mg, 0.14 mmol) were as in Example 191a to provide the title compound (0.48 g, 1.58 mmol, 56%) after chromatography (silica gel; hexanes/EtOAc, 4:1): MS (CI/NH3) 305 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH2:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])[CH2:25][CH2:24]2)=[O:22])=[CH:16][C:15]([CH3:37])=[CH:14][CH:13]=3)=[CH:6][CH:5]=1.I[CH3:39].O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH3:39])[C:12]3[C:17]([C:18]=2[CH2:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])[CH2:25][CH2:24]2)=[O:22])=[CH:16][C:15]([CH3:37])=[CH:14][CH:13]=3)=[CH:6][CH:5]=1
Reactant: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)[nH]c3ccc(C)cc23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)n(C)c3ccc(C)cc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.5 mg, 0.062 mmol) was added to a solution of 1-{3-[2-(4-chlorophenyl)-5-methyl-1H-indol-3-yl]-1-oxopropyl}-4-(2-methoxyphenyl)piperazine (Example 119, 20 mg, 0.041 mmol) in N,N-dimethylformamide (1 mL) and the mixture was stirred at room temperature for 10 min. Iodomethane (5 μl, 0.12 mmol) was added and the mixture was stirred at room temperature for 10 min. Water (25 mL) was added and the mixture was extracted with ethyl acetate. The combined organic fractions were dried (MgSO4), the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexane/ether (35:65) to give the title compound as a pale yellow foam (20 mg, 97%). 1H NMR (360 MHz, CDCl3) δ7.48-7.43 (3H, m), 7.33-7.31 (2H, m), 7.24-7.21 (1H, m), 7.11-7.02 (2H, m), 6.91-6.84 (3H, m), 3.86 (3H, s), 3.76 (2H, m), 3.53 (3H, s), 3.38 (2H, m), 3.04 (2H, m), 2.94 (2H, m), 2.77 (2H, m), 2.57 (2H, m), and 2.49 (3H, s). m/z (ES+) 502, 504 (M+1).
Reaction SMILES: [CH3:1][C:2]1(C)[CH2:6][CH2:5][O:4][C:3]1=[O:7].[OH-].[K+].[CH2:11]([OH:13])[CH3:12]>>[OH:13][CH2:11][CH2:12][C:2]([CH3:6])([CH3:1])[C:3]([O:4][CH3:5])=[O:7]
Reactant: CC1(C)CCOC1=O
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: COC(=O)C(C)(C)CCO
Temperature: -15 °C
Reaction time: 8 h

Procedure:
To a solution of 3,3-dimethyldihydrofuran-2(3H)-one (1 eq.) in ethanol (1 M) was added 8 N KOH (17 eq.). The mixture was stirred overnight, and the ethanolic solvent was concentrated in vacuo. To the remaining aqueous solution was added ethyl acetate and cooled to −15° C. Concentrated HCl was added dropwise until pH<1, taking care the internal temperature does not exceed 10° C. The aqueous layer was extracted with ethyl acetate three times. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and cooled in an ice water bath. A solution of diazomethane in ether was added until a yellow color persisted. The reaction was stirred for an additional 10 min at rt and then concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 10 to 60% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([CH2:11]O)=[N:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:13])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>C(Cl)Cl>[Br:34][CH2:11][C:8]1[C:7]2[C:2]([CH3:1])=[CH:3][C:4]([CH3:13])=[CH:5][C:6]=2[S:10][N:9]=1
Reactant: Cc1cc(C)c2c(CO)nsc2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(C)c2c(CBr)nsc2c1
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of (4,6-dimethyl-benzo[d]isothiazol-3-yl)-methanol (100 mg, 0.5 mmol) in CH2Cl2 (15 mL) were added triphenylphosphine (PPh3) (200 mg, 0.78 mmol) and carbon tetrabromide (CBr4) (340 mg, 1 mmol) at room temperature. The solution was stirred at the same temperature for 1 hour. The solution was concentrated and the residue was purified by silica gel flash column chromatography with 10% EtOAc in Hexane as the eluent to afford the title compound (90 mg, 68%) as a white solid.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2[N:14]=[CH:15][S:16][CH:17]=2)=[O:12])=[N:8][CH:9]=1)=[C:2]=[S:3].[CH3:18][C@@H:19]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[NH2:20]>C(#N)C>[F:28][C:27]([F:29])([F:30])[C:25]1[CH:26]=[C:21]([C@@H:19]([NH:20][C:2]([NH:1][C:4]2[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]3[N:14]=[CH:15][S:16][CH:17]=3)=[O:12])=[N:8][CH:9]=2)=[S:3])[CH3:18])[CH:22]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:24]=1
Reactant: C[C@H](N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Nc1ccc(N=C=S)cn1)c1cscn1
Solvent: CC#N
Product: C[C@H](NC(=S)Nc1ccc(NC(=O)c2cscn2)nc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
A mixture of N-(5-isothiocyanato-2-pyridinyl)-1,3-thiazole-4-carboxamide (0.36 g) and (S)-alpha-methyl-3,5-bis(trifluoromethyl)-benzenemethanamine (0.36 g) is heated with acetonitrile (10 mL) until all solids are dissolved. The solution is allowed to stand for 12 hours. A white solid forms and is collected by filtration (0.40 g). ]M+H] 520.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH:8]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:19])[CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]1.[CH3:30][C:31]1[CH:39]=[C:38]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[CH:37]=[C:36]([CH3:46])[C:32]=1[C:33](O)=[O:34]>>[CH3:46][C:36]1[CH:37]=[C:38]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[CH:39]=[C:31]([CH3:30])[C:32]=1[C:33]([NH:18][CH2:17][CH2:16][CH:15]([N:12]1[CH2:11][CH2:10][CH:9]([CH:8]([O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)[CH3:19])=[O:34]
Reactant: CC(CCN)N1CCC(C(Oc2ccccn2)c2ccc(C(F)(F)F)cc2)CC1
Reactant: Cc1cc(-c2ccncc2)cc(C)c1C(=O)O
Product: Cc1cc(-c2ccncc2)cc(C)c1C(=O)NCCC(C)N1CCC(C(Oc2ccccn2)c2ccc(C(F)(F)F)cc2)CC1
Yield: 50.4 %

Procedure:
Using general procedure E, 3-{4-[(pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butylamine (75 mg, 0.18 mmol) (see EXAMPLE 22) and 2,6-dimethyl-4-pyridin-4-yl-benzoic acid (46 mg, 0.20 mmol) gave COMPOUND 49 as a white solid (56 mg, 50%). 1H NMR (CDCl3) δ 0.46-1.09 (m, 2H), 0.94 (dd, 3H, J=6.6, 3.6 Hz), 1.44-2.05 (m, 5H), 2.24-2.46 (m, 1H), 2.40 (s, 3H), 2.41 (s, 3H), 2.54-2.89 (m, 4H), 3.23-3.40 (m, 1H), 3.77-3.94 (m, 1H), 5.23-5.31 (m, 1H), 6.60 (dd, 1H, J=8.4, 3.6 Hz), 6.54 (dd, 1H, J=11.7, 4.8 Hz), 7.17 (d, 2H, J=8.1 Hz), 7.36-7.44 (m, 5H), 5.54-5.57 (m, 2H), 7.84, 7.79 (dd, 1H, J=4.8, 1.2 Hz), 8.57, 8.73 (d, 1H, J=5.7 Hz), 8.61, 8.63 (s, 2H). 13C NMR (CDCl3) δ 13.22, 13.39, 19.40 (2 carbons), 28.23, 28.80, 29.09, 29.77, 30.52, 31.09, 39.72, 39.85, 42.21, 43.98, 51.97, 52.14, 60.25, 60.55, 79.55, 79.63, 111.01, 116.96, 121.67, 124.05 (q, J=272 Hz), 124.91, 124.95, 126.05, 126.07, 127.25, 129.46 (q, J=32 Hz), 135.18, 138.06, 138.16, 138.54, 139.39, 144.59, 144.67, 146.64, 147.88, 150.27, 162.79, 162.82, 169.26, 169.52. ES-MS m/z 617 (M+H). Anal. Calcd. for C36H39F3N4O2: C, 68.76; H, 6.36; N, 8.88; F, 9.04. Found. C, 68.54; H, 6.31; N, 8.75; F, 9.26.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].[CH:7]1([CH3:24])[CH2:12][CH2:11][CH:10]([CH:13]([CH3:15])[CH3:14])[CH:9]([O:16][CH:17]([CH2:19]S([O-])(=O)=O)C)[CH2:8]1.C(OC(C)C)(C)C>CN(C)C=O>[CH:7]1([CH3:24])[CH2:12][CH2:11][CH:10]([CH:13]([CH3:14])[CH3:15])[CH:9]([O:16][CH2:17][CH2:19][O:3][CH2:2][CH2:1][OH:4])[CH2:8]1
Reactant: OCCO
Reactant: CC1CCC(C(C)C)C(OC(C)CS(=O)(=O)[O-])C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: CC1CCC(C(C)C)C(OCCOCCO)C1
Temperature: 72 °C
Yield: 10997.7 %

Procedure:
Under the ice-cooling and stirring conditions, a mixture solution of 50 ml of dimethyl formamide (DMF) and 49.6 g (0.8 mmol) of ethylene glycol was dropwise added to a mixture of 4.4 g (0.11 mol) of 60% NaH and 50 ml of DMF under stirring and then the resulting mixture was stirred at a room temperature for 1 hour. Thereafter the mixture was heated to 70 to 74° C., and 50 ml of DMF solution containing 27.8 g (0.1 mole) of the l-menthyloxyethylmethane sulfonate obtained as described in (2) was dropwise added to the mixture in 50 minutes. After being stirred for 3 hours at this temperature, the reaction mixture was cooled to a room temperature, mixed with 100 ml of diisopropyl ether, and then washed with 50 ml of water three times, and the separated organic layer was concentrated under reduced pressure and then distilled to obtain 21.5 g of diethylene glycol monomenthyl ether (bp: 102-105° C./40 Pa, chemical purity (GC): 98.5%) in form of a colorless and transparent oily substance. Yield: 88.0%.
Reaction SMILES: I[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[NH:16][C:15](=[O:22])/[C:14]/2=[CH:23]\[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([OH:33])[CH:27]=1>CN(C)C=O>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[NH:16][C:15](=[O:22])/[C:14]/2=[CH:23]\[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:2][CH3:3])=[C:28]([OH:33])[CH:27]=1
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccc(O)c(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Temperature: 25 °C
Yield: 24 %

Procedure:
To a solution of 1-iodoethane (43.3 μl, 0.28 mmol) in anhydrous N,N-dimethylformamide (2 ML) is added potassium carbonate (207 mg, 1.5 mmol). The mixture stirred at room temperature and (4Z)-6-bromo-4-{[(3,4-dihydroxybenzyl)amino]methylene} isoquinoline-1,3(2H,4H)-dione (100 mg, 0.26 mmol) is added. After the mixture is stirred at 65° C. for 30 min, the resulting mixture is concentrated and the residue is then partitioned between water (50 ml) and ethyl acetate (50 ml). The organic layer is then dried and purified by high performance liquid chromatography to give 26 mg of a white solid. MS (ESI) m/z 416.7 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@:11]([CH3:25])([C:20](OCC)=[O:21])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@@:11]([CH2:20][OH:21])([CH3:25])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)[C@]1(C)CC[C@H](c2cncc(F)c2)N1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](c2cncc(F)c2)CC[C@@]1(C)CO
Temperature: 0 °C
Yield: 94.6 %

Procedure:
A solution of (2S,5R)-1-tert-butyl 2-ethyl 5-(5-fluoropyridin-3-yl)-2-methylpyrrolidine-1,2-dicarboxylate (240 mg, 0.681 mmol) in THF (10 mL) was cooled to −78° C. and 1M LiAlH4 in THF (1.50 mL, 1.50 mmol) was added dropwise. The reaction was allowed to warm to 0° C. and was quenched with small portions of Na2SO4-10H2O (967 mg, 6.81 mmol). The mixture was filtered and concentrated to afford (2S,5R)-tert-butyl 5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate (200 mg, 95% yield). MS (apci) m/z=311.1 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH3:20])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:27]([CH2:29][NH2:30])[OH:28]>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH:30][CH2:29][CH2:27][OH:28])=[N:3][C:4]([CH3:20])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc2c(Cl)nc(C)c(-c3ccccc3)c2c1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc2c(NCCO)nc(C)c(-c3ccccc3)c2c1
Temperature: 25 °C

Procedure:
1-chloro-6-methoxy-3-methyl-4-phenylisoquinoline (0.29 g) was combined with 10 mL of ethanolamine and heated at 120 C for 5 h, then cooled to room temp. The reaction was poured into saturated aqueous sodium carbonate and extracted with EtOAc (3×). The combined organic solutions were washed with water (1×), then dried (Na2SO4) and concentrated. Flash chromatography (10% MeOH/CHCl2) gave a solid which was recrystallized from ether/hexanes to give the titled compound.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[C:21]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=4)=[N:20]3)[CH2:15][CH2:14]2)=[O:12])[CH:6]=1)(=O)C.[OH-].[Na+].Cl>C1COCC1.CC(C)=O.CO>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([C:21]2[C:22]([CH3:26])([CH3:25])[C:23](=[O:24])[N:19]([CH:16]3[CH2:17][CH2:18][N:13]([C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([OH:4])[CH:6]=4)=[O:12])[CH2:14][CH2:15]3)[N:20]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH3:34]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(OC(C)=O)c4)CC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(O)c4)CC3)C(=O)C2(C)C)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g 3-({4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}carbonyl)phenyl acetate (compound described in example 12) are dissolved in a mixture of 200 ml THF, 100 ml acetone and 200 ml of methanol. To this mixture 200 ml of 2 M methanolic sodium hydroxide solution are added, and the reaction mixture is stirred at RT for 1 h until the reaction is completed according to TLC analysis. The reaction mixture is acidified with concentrated aqueous hydrochloric acid, and the solvents are largely removed under reduced pressure, while the crude product is precipitating. The solids are collected and washed with water to yield the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]([NH:27][CH:28]1[C:54](=[O:55])[N:30]2[C:31]([C:51]([OH:53])=[O:52])=[C:32]([CH2:35][S:36][C:37]3[CH:38]=[CH:39][C:40]4[N:41]([C:43](=[O:50])[N:44]([CH2:46][C:47]([OH:49])=[O:48])[N:45]=4)[N:42]=3)[CH2:33][S:34][C@H:29]12)=[O:26])C)=O)CCC>CCOCC>[CH3:13][NH:15][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]([NH:27][CH:28]1[C:54](=[O:55])[N:30]2[C:31]([C:51]([OH:53])=[O:52])=[C:32]([CH2:35][S:36][C:37]3[CH:38]=[CH:39][C:40]4[N:41]([C:43](=[O:50])[N:44]([CH2:46][C:47]([OH:49])=[O:48])[N:45]=4)[N:42]=3)[CH2:33][S:34][C@H:29]12)=[O:26]
Reactant: CCCCOC(=O)N(C)Cc1ccccc1CC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3ccc4nn(CC(=O)O)c(=O)n4n3)CS[C@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CNCc1ccccc1CC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3ccc4nn(CC(=O)O)c(=O)n4n3)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Trifluoroacetic acid (7 ml.) was added to the t-BOC-derivative 7b (3.8 g., 5.5 m.mole) at 0° C., and the mixture was stirred for 20 minutes at room temperature. Dry ether (100 ml.) was added to the mixture. The resulting precipitate was collected by filtration and washed with dry ether (3×100 ml.). The precipitate was dissolved in a mixture of CH3CN (120 ml.) and water (18 ml.) and the solution was adjusted to pH 5-6 with concentrated NH4OH to give an oily precipitate which was triturated with CH3CN to form solid material. The product 8b was collected by filtration, washed with CH3CN and dried. Yield 2.55 g. (77%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C.C(Cl)Cl.CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: Nc1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 16 %

Procedure:
To a solution of 6-amino-2-pyridinecarboxylic acid (120 mg, 0.89 mmol, available from Apollo Scientific) in DMF (2 ml) was added HATU (340 mg, 0.89 mmol) and DIPEA (0.464 ml, 2.67 mmol). The mixture was stirred at room temperature for 20 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (110 mg, 0.44 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was applied to the top of a 50 g aminopropyl cartridge that had been preconditioned with DCM/MeOH (1:1). The reaction mixture remained on the cartridges for 2 h before being eluted with DCM/MeOH (1:1). The solvent was removed in vacuo to give a brown oil that was purified by chromatography using silica gel (50 g cartridge, FlashMaster II) eluting with 0-100% ethyl acetate in cyclohexane over 30 mins followed by 0-20% MeOH in ethyl acetate over 10 mins to afford the title compound (26 mg) as a pale yellow gum.