Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[CH2:7][N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)(=[O:31])=[O:30])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[N:10]=1)(C)([CH3:3])[CH3:2].Cl.C(=O)([O-])O.[Na+]>C(O)(C)C>[CH:1]([O:5][C:6](=[O:45])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)(=[O:31])=[O:30])[NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[N:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(NCc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccccn2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)OC(=O)CNc1cccc(C(NCc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccccn2)n1
Temperature: 40 °C
Reaction time: 9 h
Yield: 80 %

Procedure:
To a solution of tert-butyl[tert-butoxycarbonyl(6-{(pyridin-2-ylsulfonyl)[4-(thiazol-2-yl)benzyl]aminomethyl}pyridin-2-yl)amino]acetate (200 mg, 0.307 mmol) obtained in Example 3-(a) in isopropanol (1.5 ml) was added a 4N hydrogen chloride/-1,4-dioxane solution (1.5 ml), followed by stirring at 40° C. for 9 hours. After completion of the reaction, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=1:2 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (132 mg) (pure content: 118 mg) as a colorless oil. (Yield: 80%)
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3](O)[CH:2]=1.[O-2].[O-2].[O-2].[Al+3].[Al+3].C(O)(=O)C=CC1C=CC=CC=1>[Pt].C(O)(=O)C>[O:10]1[C:5]2[C:6](=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:7]=[CH:8][C:9]1=[O:11]
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Agent: [Pt]
Agent: O=C(O)C=Cc1ccccc1
Agent: [Al+3]
Solvent: CC(=O)O
Product: O=c1ccc2ccccc2o1
Temperature: 100 °C

Procedure:
To a stirred glass reactor is added 10 mmoles of coumaric acid, 0.5 mmoles of platinum composited on a gamma-alumina support and 60 grams of acetic acid. The reactor is heated to a temperature of 100° C. by means of an oil bath while effecting the reaction in a nitrogen atmosphere. At the end of 4 hours, it will be found that a major portion of the cinnamic acid is cyclized to form coumarin.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[B-](F)(F)(F)[F:17].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O>C1COCC1>[F:17][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1
Reactant: COC(=O)c1cc(-c2ccnn2C)cs1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(-c2c(F)cnn2C)cs1
Reaction time: 1 h
Yield: 33 %

Procedure:
A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (330 mg, 1.49 mmol) and Selectfluor® (793 mg, 2.23 mmol) in THF (7 mL) and H2O (500 uL) was stirred in a sealed tube at 70° C. After 1 h, additional selectfluor (793 mg, 2.23 mmol) was added and the solution stirred an additional 12 h. The reaction mixture was then partitioned between H2O-DCM, the aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 20% EtOAc in hexanes) affording the title compound (126 mg, 33%) as a white solid: LCMS (ES) m/z=241 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[C:13]([CH:21]=[O:22])=[CH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(=O)([O-])[O-].[K+].[K+].CCCCCC>CO>[CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[C:13]([CH2:21][OH:22])=[CH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cn(C(=O)OCc2ccccc2)c2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCC
Product: O=C(OCc1ccccc1)n1cc(CO)c2cc(Cl)ccc21
Temperature: 0 °C
Yield: 89.4 %

Procedure:
To a solution of 1-benzyloxycarbonyl-5-chloro-3-formylindol (2.00 g) in methanol (13 ml) was added sodium borohydride (241 mg) at 0° C. After the mixture was stirred for 15 minutes at the same temperature, ice water was added to the mixture. Potassium carbonate was added to make the mixture saturate. The whole was extracted with ether and the extract was dried over magnesium sulfate. Concentration of the mixture gave a residue, to which hexane was added. 1-benzyloxycarbonyl-5-chloro-3-hydroxymethylindol (1.80 g) was obtained as a crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:12][C:11]3([N:16]([CH3:17])[CH2:15][CH2:14][CH2:13]3)[CH2:10]2)[C:6]([N+:18]([O-])=O)=[CH:5][C:4]=1[NH:21][C:22]1[N:27]=[C:26]([C:28]2[CH:29]=[N:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=23)[CH:25]=[CH:24][N:23]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:10][C:11]3([N:16]([CH3:17])[CH2:15][CH2:14][CH2:13]3)[CH2:12]2)[C:6]([NH2:18])=[CH:5][C:4]=1[NH:21][C:22]1[N:27]=[C:26]([C:28]2[CH:29]=[N:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=23)[CH:25]=[CH:24][N:23]=1
Reactant: COc1cc(N2CC3(CCCN3C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC3(CCCN3C)C2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Yield: 83.8 %

Procedure:
N-[2-Methoxy-4-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 142, 320 mg, 0.65 mmol), iron (219 mg, 3.91 mmol) and NH4Cl (26.2 mg, 0.49 mmol) were heated at reflux in ethanol (18 mL) and water (6 mL) for 4 h. The mixture was then cooled, filtered and concentrated in vacuo. The resulting residue was triturated in 10% CH3OH in CH2Cl2 (15 mL) for 15 minutes and the mixture was then filtered. The residues were re-triturated with 10% CH3OH in CH2Cl2 (15 mL) and the mixture was then filtered. The combined filtrates were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave the title compound (251 mg, 84%) as a brown gum which crystallised on standing; 1H NMR: 1.64-1.76 (2H, m), 1.75-1.87 (2H, m), 1.91-2.03 (2H, m), 2.08 (2H, dd), 2.39 (3H, s), 2.63 (2H, t), 3.06 (2H, t), 3.56 (2H, d), 3.72 (3H, s), 3.82 (2H, d), 4.01 (2H, s), 4.10 (2H, t), 6.25 (1H, s), 6.91 (1H, d), 7.21 (1H, s), 7.67 (1H, s), 8.04 (1H, s), 8.23 (1H, d); m/z: ES+ MH+ 461.37.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:18]([CH2:19][OH:20])[O:17][C@@H:12]([O:13][CH2:14][CH2:15]Cl)[C@H:11]([F:21])[C@H:10]1[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:18]([CH2:19][OH:20])[O:17][C@@H:12]([O:13][CH2:14][CH2:15][N:23]=[N+:24]=[N-:25])[C@H:11]([F:21])[C@H:10]1[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@H]1O[C@@H](OCCCl)[C@H](F)[C@@H](O)[C@@H]1OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCO[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](O)[C@H]1F
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloroethyl 4-O-benzyl-2-deoxy-2-fluoro-β-D-glucopyranoside (1.53 g, 4.57 mmol) in DMF (45 mL) at rt was added sodium azide (360 mg, 5.54 mmol). After stirring at 70° C. for 16 hr, the reaction mixture was cooled down to rt and poured onto ice water (200 mL) and extracted with CH2Cl2 (3×100 mL). The organic layers were combined and washed with brine (2×100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (120 g), eluting with 0-100% EtOAc in hexanes to give the title compound. TLC: silica gel, hexane/EtOAc: 1/1, Rf=0.55. 1H NMR (CDCl3) δ 7.37-7.28 (5 H, m), 4.84-4.71 (2H, m), 4.55-4.52 (1 H, m), 4.22-4.07 (1H, m), 4.03-3.98 (1H, m), 3.94-3.86 (2H, m), 3.79-3.71 (2H, m), 3.56-3.51 (1H, m), 3.48-3.36 (3H, m).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][N:4]1[C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[N:24]=[CH:23][CH:22]=[N:21]1)=[O:12].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[CH2:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][N:4]2[C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)=[O:12])=[N:27][CH:28]=1
Reactant: Clc1ccc(Br)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC(F)(F)CC2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC(F)(F)C[C@H]2CNc2ccc(Cl)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using (2-(aminomethyl)-4,4-difluoropiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 447 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[OH:20])#[N:2].I[CH3:22].[H-].[Na+].Cl>CN(C)C=O.O>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[O:20][CH3:22])#[N:2]
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 5-(4-cyano-3-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (100 mg, 0.375 mmol) and iodomethane (0.070 mL. 1.1 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% oil dispersion, 45 mg, 1.1 mmol) at 0° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 2 h. Water and 1 M HCl were added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with hexane/diisopropyl ether to give 5-(4-cyano-3-methoxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (92 mg, 87%).
Reaction SMILES: CO[C:3]1C=C(C=C(OC)[C:10]=1OC)C=O.[CH3:15][C:16]1[CH:35]=[CH:34][C:19]([N:20]=[CH:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=2)=[CH:18][CH:17]=1>>[CH2:15]([C:16]1[CH:17]=[CH:18][C:19]([N:20]=[CH:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=2)=[CH:34][CH:35]=1)[CH2:3][CH3:10]
Reactant: COc1cc(C=Nc2ccc(C)cc2)cc(OC)c1OC
Reactant: COc1cc(C=O)cc(OC)c1OC
Product: CCCc1ccc(N=Cc2cc(OC)c(OC)c(OC)c2)cc1
Yield: 87.6 %

Procedure:
From compounds 107g (4.2 g, 99%, 31.0 mmol) and 106 (6.0 g, 98%, 31.0 mmol), a similar procedure as described for 108a gave 108g (8.5 g, 87.6%) as a thick oil. 1H NMR (200 MHz, CDCl3) δ8.36 (s, 1H), 7.20 (d, J=8 Hz, 2H), 7.16 (s, 2H), 7.14 (d, J=8 Hz, 2H), 3.93 (s, 6H), 3.91 (s, 3H), 2.60 (t, J=8 Hz, 2H), 1.64 (sextet, J=8 Hz, 2H), 0.95 (t, J=8 Hz, 3H). EIMS (M+ 100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.B([C:48]1[CH:53]=[CH:52][C:51]([S:54]([N:57]2[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]2)(=[O:56])=[O:55])=[CH:50][CH:49]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:48]2[CH:53]=[CH:52][C:51]([S:54]([N:57]3[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62]3)(=[O:56])=[O:55])=[CH:50][CH:49]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Reactant: O=S(=O)(c1ccc(B(O)O)cc1)N1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)N3CCCCC3)cc2)c1C
Temperature: 25 °C

Procedure:
A stirred solution of (6-fluoro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (0.20 g, 0.52 mmol) in dimethoxyethane (10 mL) was purged with argon for 5 minutes at room temperature. Triphenylphosphine (0.031 g, 0.12 mmol), palladium (II) acetate (0.013 g, 0.06 mmol), 1-(4-boronophenylsulfonyl)piperidine (0.191 g, 0.71 mmol) and a 2 M aqueous solution of sodium carbonate (1.0 mL, 2.0 mmol) were added simultaneously to the reaction mixture at room temperature under argon. The reaction mixture was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The collected organic extracts were washed with water and then brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (Biotage, 5-10% ethyl acetate-hexane) to {6-fluoro-3-methyl-4-[4-(piperidine-1-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.195 g, 84%) as a solid. MS calcd. for C25H25FNO4S [(M−H)−] 454, obsd. 454.2 (low intensity).
Reaction SMILES: ClC1C=C2C(=C(C(OCC3(C4C=CC(F)=CC=4)CCN(C(OC(C)(C)C)=O)CC3)C(OC)=O)C=1)NN=C2.[Cl:38][C:39]1[CH:47]=[C:46]([CH:48]([C:71]#[N:72])[O:49][CH2:50][C:51]2([C:64]3[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=3)[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:53][CH2:52]2)[C:45]2[C:41](=[CH:42][N:43](COCC[Si](C)(C)C)[N:44]=2)[CH:40]=1>>[Cl:38][C:39]1[CH:40]=[C:41]2[C:45](=[C:46]([CH:48]([C:71]#[N:72])[O:49][CH2:50][C:51]3([C:64]4[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=4)[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:53][CH2:52]3)[CH:47]=1)[NH:44][N:43]=[CH:42]2
Reactant: CC(C)(C)OC(=O)N1CCC(COC(C#N)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Agent: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn[nH]c12
Product: CC(C)(C)OC(=O)N1CCC(COC(C#N)c2cc(Cl)cc3cn[nH]c23)(c2ccc(F)cc2)CC1

Procedure:
Prepared according to the procedure used to prepare tert-butyl 4-((1-(5-chloro-1H-indazol-7-yl)-2-methoxy-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate using tert-butyl 4-(((5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)(cyano)methoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate as the starting material. 1H-NMR (CDCl3, 500 MHz) δ 9.66 (bs, 1H), 7.98 (s, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.31 (m, 3H), 7.13 (dd, J=8.6, 8.6 Hz, 2H), 5.46 (s, 1H), 3.60-3.90 (m, 4H), 3.07 (m, 2H), 2.18 (m, 2H), 1.82 (m, 2H), 1.43 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 171.2, 161.9 (d, J=248 Hz), 154.9, 137.4, 135.6, 134.4, 128.6 (d, J=7.7 Hz), 126.3, 125.5, 125.4, 122.0, 116.2 (d, J=21 Hz), 79.9, 78.9, 69.5, 41.1, 39.9 (br), 32.5, 32.3, 28.5.
Reaction SMILES: CC(OC(C)=O)=O.NC1C=CC2OC([C:17]3[O:22][C:21](=[O:23])[C:20]([CH3:24])=[C:19]([O:25][CH2:26][O:27][CH3:28])[C:18]=3[CH3:29])=CC=2C=1.[NH4+].[Cl-]>N1C=CC=CC=1>[CH3:24][C:20]1[C:21](=[O:23])[O:22][CH:17]=[C:18]([CH3:29])[C:19]=1[O:25][CH2:26][O:27][CH3:28]
Reactant: COCOc1c(C)c(-c2cc3cc(N)ccc3o2)oc(=O)c1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COCOc1c(C)coc(=O)c1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Pyridine (400 μl) and Ac2O (15 μl) were added to 6-(5-aminobenzofuran-2-yl)-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one (45 mg), and after stirring the mixture at room temperature for 6 hours, an NH4Cl aqueous solution was added and extraction was performed with CH2Cl2. The organic layer was dried, filtered and concentrated, and the residue was purified by silica gel thin-layer chromatography (CH2Cl2) to obtain 6-(5-acetylamino)benzofuran-2-yl)-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:11]([CH:12]3[CH:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:10][C:9]([O:27][CH3:28])=[CH:8][CH:7]=2)=[O:4].C(O)(=O)C.CO.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([O:27][CH3:28])[CH:10]=2)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C1=C(c2ccc(OC)cc2)C2CCCCC2c2cc(OC)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1c2ccc(OC)cc2C2CCCCC2C1c1ccc(OC)cc1
Reaction time: 18 h
Yield: 98.5 %

Procedure:
Combine 6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,10a-hexahydro-phenanthren-9-carboxylic acid methyl ester (10.06 g, 26.6 mmol), 10% Pd—C (1.014 g), acetic acid (100 mL), methanol (150 mL), and ethyl acetate (150 mL), and stir under 100 psi of hydrogen atmosphere at 50° C. After 18 hours, filter reaction through Celite using ethyl acetate and concentrate to yield the titled compound (9.97 g, 99%) as a white solid. TLC Rf=0.25 in 6:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.28 (m, 1H), 7.22 (d, 2H, J=8.8 Hz), 6.98 (d, 1H, J=2.2 Hz), 6.84 (d, 2H, J=8.8 Hz), 6.80 (d, 1H, J=2.6 Hz), 4.33 (d, 1H, J=7.9 Hz), 3.86 (s, 3H), 3.82 (s, 3H), 3.55 (m, 1H), 3.51 (s, 3H), 3.06 (m, 1H), 2.36 (m, 2H), 1.78 (m, 3H), 1.38 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH2:16]([O:15][C:13]([NH:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Reaction time: 2 h

Procedure:
To (trans)-4-(aminomethyl)cyclohexanecarboxylic acid (10 g, 44.5 mmol) in 1,4-dioxane (75 ml) and water (75 ml) was added dropwise benzyl chloroformate (6.99 ml, 49.0 mmol). The pH was kept between 7 and 8 by adding saturated aqueous sodium carbonate. After stirring for two hours the reaction mixture was concentrated in vacuo till half volume, 1M sodium hydroxide (aq) was added till pH=9 and the mixture was extracted with diethylether. 2M Hydrochloric acid was added till pH=1 was the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to yield (trans)-4-((benzyloxycarbonylamino)methyl)cyclohexanecarboxylic acid (12.03 g)
Reaction SMILES: Cl[C:2]1[N:3]([CH3:19])[C:4](=[O:18])[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9][NH:8][C:6]=2[N:7]=1.Cl.[NH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[OH:27].CCN(C(C)C)C(C)C>CN(C=O)C>[OH:27][C@@H:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[NH:21][C:2]1[N:3]([CH3:19])[C:4](=[O:18])[C:5]2[C:6](=[N:8][NH:9][C:10]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: Cn1c(Cl)nc2[nH]nc(Nc3ccccc3)c2c1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(N[C@@H]2CCC[C@H]2O)nc2n[nH]c(Nc3ccccc3)c2c1=O
Yield: 85.7 %

Procedure:
A solution of 6-chloro-5-methyl-3-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (3.3 g, 12 mmol), (1R,2R)-2-aminocyclopentanol hydrochloride (2 g, 14.4 mmol) and DIPEA (4.6 mL, 27 mmol) in DMF (25 mL) is heated at 120° C. for 5 hours. Solvent is removed under reduced pressure. The residue is dissolved in CH2Cl2 and MeOH (10:1, v/v), and then washed with water three times. The solution is dried over MgSO4 and evaporated to dryness to give 3.5 g of crude product MS (ESI) m/z 341.2 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.C(N(CC)C(C)C)(C)C.[C:37](O)(=[O:39])[CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[OH-].[Na+]>CN(C=O)C>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37](=[O:39])[CH3:38])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) in DMF (1.8 ml) was added N,N-diisopropylethylamine (210 mg, 278 μl, 1.63 mmol), acetic acid (18.0 mg, 17.2 μl, 300 μmol) and TBTU (128 mg, 400 μmol). The mixture was allowed to stir at room temperature for 4 h. The mixture was added to ice/water (5 ml) and 1N NaOH (5 ml) and extracted with dichloromethane/MeOH (9:1, 20 ml). The organic phase was washed with brine (20 ml), dried (MgSO4) and evaporated. The crude material (0.15 g) was triturated with dichloromethane (2 ml) and diethyl ether (5 ml) for ½ h, the precipitate was collected by filtration, washed with diethyl ether and dried to yield the title compound as off-white solid (92 mg, 99%), MS (ISP) m/z=373.2 [(M+H)+], mp 260° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[CH:7]=[CH:8][C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1.[CH3:19][NH:20][CH3:21].Cl>>[CH3:19][N:20]([CH3:21])[CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[CH:7]=[CH:8][C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1
Reactant: CNC
Reactant: ClCCOc1ccccc1C=Cc1cnccn1
Agent: Cl
Product: CN(C)CCOc1ccccc1C=Cc1cnccn1

Procedure:
2-[o-(β-Dimethylamino-ethoxy)-styryl]-pyrazine was prepared from 2-[o-(β-chloro-ethoxy)styryl]-pyrazine and dimethylamine, and the free base was converted into its monohydrochloride, yielding 54% of theory of the compound of the formula ##STR13## which had a melting point of 194°-195° C.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[S:13][C:14]([C:16]([O:18]C)=[O:17])=[CH:15][C:4]=2[NH:3]1.[OH-].[Na+]>C(O)C.C1COCC1>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[S:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:4]=2[NH:3]1
Reactant: COC(=O)c1cc2c(s1)Oc1ccccc1C(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(s1)Oc1ccccc1C(=O)N2
Temperature: 55 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a stirring solution of compound 119 (0.856 g, 3.11 mmol) in ethanol (16 mL) and THF (8 mL) was added an aqueous solution of sodium hydroxide (5 mL, 31.3 mmol) and the resulting mixture was stirred at 55° C. for 2 h. The reaction mixture was solvent evaporated to one third volume, acidified with 3N HCl to pH 2 and the resulting white precipitate was filtered to afford 120 (0.801 g, 99%) as a beige solid. LRMS (ESI): (calc) 261.01 (found) 262.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C1C(=O)N([I:34])C(=O)C1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[N:6]([C:8]([I:34])=[CH:9][N:10]=2)[N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3ccnc23)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(I)cnc23)cc1

Procedure:
To 6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (940 mg, 2.57 mmol) from Example X, step (1a) in chloroform (10 mL) at room temperature was added NIS in one portion and the resulting mixture was refluxed for 5 h. Concentration and purification by flash chromatography provided 6-chloro-3-iodo-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine as a foamy, yellow solid (960 mg, 76%). LCMS [M+H]+ 490.