Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][N:17]=[C:18](I)[C:11]=12)[NH2:5].[CH3:20][N:21]1[CH2:26]CNC[CH2:22]1.[CH3:27][N:28]([CH:30]=[O:31])[CH3:29]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:16][N:17]=[C:18]([C:30]([N:28]4[CH2:29][CH2:22][N:21]([CH3:26])[CH2:20][CH2:27]4)=[O:31])[C:11]=23)=[C:2]([F:1])[CH:3]=1
Reactant: Nc1ccc(Oc2ccnc3[nH]nc(I)c23)c(F)c1
Reactant: CN(C)C=O
Reactant: CN1CCNCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CN1CCN(C(=O)c2n[nH]c3nccc(Oc4ccc(N)cc4F)c23)CC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
3-Fluoro-4-(3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline (30 mg, 0.0811 mmol) was dissolved in DMF (1 mL), and 1-methylpiperazine (0.045 ml, 0.405 mmol) and 1,1′-bis(diphenylphosphino) ferrocenedichloropalladium(II) (6.67 mg, 0.0081 mmol) were added. The reaction mixture was purged with N2(g) followed by CO(g) and then held under balloon pressure of CO(g). The mixture was stirred at 70° C. for 18 hours. The crude mixture was partitioned between ethyl acetate and water. The organic layer washed with brine, dried over Na2SO4 and evaporated to afford crude product. The residue was purified by silica gel column chromatography (Biotage 12M) eluting with 5% MeOH/CHCl3 to afford the desired product. Yield: 14 mg at 80% purity, 37%. LRMS (APCI pos) m/e 371.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:21]([NH2:29])(=[NH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CCO.C1CCCCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[C:4]1[N:28]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:29][C:11](=[O:13])[C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=Cc1ccc(Cl)cc1Cl)C(=O)OCC
Reactant: N=C(N)c1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2Cl)nc(-c2ccccc2)[nH]c1=O
Reaction time: 1 h
Yield: 105 %

Procedure:
A solution of diethyl 2-(2,4-dichlorobenzylidene)malonate (300 mg, 0.91 mmol) and benzamidine (134 mg, 0.91 mmol) in EtOH (3 mL) was heated to 60° C. for 2 hrs. The reaction was concentrated under reduced pressure. The resulting residue was dissolved in CH2Cl2 (4 mL) and DDQ (238 mg, 1.05 mmol) was added. After 1 hr, The reaction was diluted with cyclohexane/EtOAc solution (4:1, 100 mL) and the organic layer was extracted with saturated NaHCO3 solution (2×60 mL), brine (50 mL). The organic layer dried (MgSO4), filtered and concentrated under reduced pressure to give ethyl 4-(2,4-dichlorophenyl)-6-oxo-2-phenyl-1,6-dihydropyrimidine-5-carboxylate (372 mg, 100%) as a yellow solid. This product was moved onto next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6](Br)([F:12])[CH2:5]2.[NH2:14][C:15]([NH2:17])=[S:16].C(N(CC)CC)C>CS(C)=O>[NH2:17][C:15]1[S:16][C:6]2([F:12])[CH2:5][C:4]3[CH:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:8]=3[C:7]2([OH:11])[N:14]=1
Reactant: NC(N)=S
Reactant: O=C1c2ccc(Cl)cc2CC1(F)Br
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: NC1=NC2(O)c3ccc(Cl)cc3CC2(F)S1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
263 mg of 5-chloro-2-bromo-2-fluoroindan-1-one and 152 mg of thiourea are dissolved in 2.5 ml of dry dimethyl sulfoxide and stirred at 50° C. for 8 h. Excess triethylamine is added to the reaction mixture, which is then concentrated in vacuo. The residue is purified by chromatography on silica gel with ethyl acetate as eluent. 2-Amino-6-chloro-8a-fluoro-8 ,8a-dihydroindeno[1,2-d]thiazol-3a-ol is obtained with a melting point of 159° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10](OS(C1C=CC(C)=CC=1)(=O)=O)[C:9]=2[N+:28]([O-:30])=[O:29])=[O:5])[CH3:2].[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClC1C=CC=CC=1Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([NH:38][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]=2[N+:28]([O-:30])=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(=O)c2ccc(OS(=O)(=O)c3ccc(C)cc3)c([N+](=O)[O-])c2o1
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(=O)c2ccc(NCc3ccccc3)c([N+](=O)[O-])c2o1
Temperature: 170 °C
Yield: 66.8 %

Procedure:
To a solution of 8-nitro-4-oxo-7-(toluene-4-sulfonyloxy)-4H-chromene-2-carboxylic acid ethyl ester (433 mg, 1 mmol) in o-dichlorobenzene was added benzylamine (214 mg, 2 mmol). The reaction mixture was heated at 170° C. for 1 hour, and the solvent was removed in vacuo to give a residue. The residue was dissolved in ethyl acetate and washed sequentially with aqueous HCl (2N 50 ml), NaOH (2N, 50 mL) and water, dried over anhydrous Na2SO4, and filtered. The solvent was evaporated in vacuo to give a solid residue. Recrystallization of the residue from ethyl acetate-hexane (2:1) provided 246 mg (67%) of the title compound: mp 168° C.; 1H NMR (400 MHz, CDCl3): 1.43 (t, J=7 Hz, 3H), 4.45 (q, J =7.0 Hz, 2H), 4.61 (d, J=5.0 Hz, 2H), 6.90 (d, J=9.2 Hz), 7.09 (s, 1H), 7.42-7.32 (m, 5H), 8.04 (t, J=5 Hz, 1H), 8.10 (d, J=9.2 Hz, 1H); IR: 3350, 2980, 1730,1660, 1600,1420,1250 cm−1; MS 369 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]4[CH:30]=[C:29]([CH3:31])[N:28]=[N:27]4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.ClC(OC(Cl)=O)C.Cl.FC1C=C(N2C[C@H](CN3C=C(C)N=N3)OC2=O)C=C(F)C=1C1CCNCC=1>>[F:33][C:15]1[CH:16]=[C:17]([N:20]2[CH2:24][C@H:23]([CH2:25][N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[N:27]3)[O:22][C:21]2=[O:32])[CH:18]=[CH:19][C:14]=1[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1
Reactant: Cc1cn(C[C@H]2CN(c3ccc(C4=CCN(Cc5ccccc5)CC4)c(F)c3)C(=O)O2)nn1
Agent: CC(Cl)OC(=O)Cl
Agent: Cc1cn(C[C@H]2CN(c3cc(F)c(C4=CCNCC4)c(F)c3)C(=O)O2)nn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(C[C@H]2CN(c3ccc(C4=CCNCC4)c(F)c3)C(=O)O2)nn1
Yield: 107.4 %

Procedure:
(5R)-3-[4-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl]-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (Example 43) (5.13 g, 11.46 mmol) was reacted with diisopropylethylamine (0.40 ml, 2.29 mmol) and 1-chloroethylchloroformate (1.50 ml, 13.76 mmol) as described for Intermediate 53 to give the crude title compound (4.4 g).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH:5]([NH2:7])=[O:6].CN([CH:11]=[O:12])C.[CH3:13][C:14](N(C)C)=[O:15]>ClCCCl.C(Cl)Cl>[CH:5]([NH2:7])=[O:6].[C:1]([O:4][C:14](=[O:15])[CH3:13])(=[O:3])[CH3:2].[C:1]([O:4][C:11](=[O:12])[CH2:13][CH3:14])(=[O:3])[CH2:2][CH3:5]
Reactant: CN(C)C=O
Reactant: CC(=O)O
Reactant: CC(=O)N(C)C
Solvent: ClCCl
Solvent: ClCCCl
Solvent: NC=O
Product: CC(=O)OC(C)=O
Product: CCC(=O)OC(=O)CC

Procedure:
The compounds of formula types A-C may be produced in various ways, for example preferably from the known compounds having general formula types 2, 4 or 8 (see below), in which the letters X and R have the same meaning as above, by heating them with the ammonium salt of a preferably organic acid, such as formic or acetic acid, in a dipolar solvent (Solv) with high boiling point, such as a primary or secondary alkanol having a boiling point above 150° C., an aliphatic carboxylic acid amide, such as formamide, DMF or dimethyl acetamide, or also in a polyvalent alkanol of the 1,2-, 1,3-diol or 1,2,3-triol type, leading to the formation, in a mostly gradual reaction, as described for exemplary purposes by V. F. Donyagina, S. Shimizu, N. Kobayashi and E. A. Lukyanets in Tetrahedron Lett. 2008, 49, 6152, initially of the compounds having general formula type A, recognizable by their deep colours, which are then, following their isolation, reacted as necessary by heating with a compound having general formula ML1L2L3, in which L1 and L2 have the same meaning as above and L3 is a ligand identical to or different from L1 and L2, and like L1 and L2 is able to form a stable coordination sphere with atom M, in a polar solvent, such as a low or higher alkanol, an aliphatic carboxylic acid amide, such as formamide, DMF or dimethyl acetamide, a carboxylic acid anhydride such as acetic acid anhydride or propionic acid anhydride, methylene chloride or 1,2-dichloroethane, to form the target compounds of formula type B or C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([OH:14])[C:11]2[C:6](=[C:7](C)[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[Br:18]C1C(OC)=CC=CC=1N>>[Br:18][C:7]1[C:8]([O:15][CH3:16])=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=[C:12]2[OH:14]
Reactant: COc1cccc(N)c1Br
Reactant: CCOc1cc(O)c2ccc(OC)c(C)c2n1
Product: CCOc1cc(O)c2ccc(OC)c(Br)c2n1

Procedure:
8-Bromo-2-ethoxy-7-methoxy-quinolin-4-ol was synthesized according to the method presented in the synthesis of 2-ethoxy-7-methoxy-8-methyl-quinolin-4-ol in example 132 with the exception of utilizing 2-bromo-3-methoxy-aniline.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]=O)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C([N:54]1[CH2:59][CH2:58][NH:57][C@@H:56]([CH3:60])[CH2:55]1)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:57]5[CH2:58][CH2:59][NH:54][CH2:55][C@H:56]5[CH3:60])[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(C=O)c2)c1)C(=O)C1(C(N)=O)CC1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(CN3CCNC[C@H]3C)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
A mixture of N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide (55 mg, 0.088 mmol), (S)-4-N-Boc-2-methyl piperazine (17.69 mg, 0.088 mmol), sodium triacetoxyborohydride (37.4 mg, 0.177 mmol) and acetic acid (6.07 μL, 0.106 mmol) in DCM (2 mL) was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were concentrated under vacuum to give the crude residue. It was re-dissolved in 25% TFA in DCM (2 mL) and stirred at room temperature for 2 h. Solvent was evaporated under a stream of nitrogen and then purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents) with eluting with 10 to 60% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(6-methyl-3′-{[(2R)-2-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide as a solid (26 mg, 41.6%). LC-MS m/z 707 (M+H)+, 0.77 min (ret time).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.[CH3:14][O:15][C:16](=[O:23])[C@@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18]>>[CH3:21][CH:20]([CH3:22])[CH2:19][C@@H:17]([NH:18][C:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:13][C:6]=2[CH:7]=1)=[O:12])[C:16]([O:15][CH3:14])=[O:23]
Reactant: Cc1ccc2oc(C(=O)O)cc2c1
Reactant: COC(=O)[C@H](N)CC(C)C
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1cc2cc(C)ccc2o1

Procedure:
Prepared in a similar manner to example 4 using 5-methylbenzofuran-2-carboxylic acid (example 26a) and D-leucine methyl ester. 1H NMR (500 MHz, CDCl3): 0.98 (d, 3H, J=6.26 Hz), 1.00 (d, 3H, J=6.17 Hz), 1.56 (s, 3H), 1.76 (m, 3H), 2.48 (s, 3H), 3.78 (s, 3H), 4.86 (m, 1H), 6.95 (m, 1H), 7.23 (dd, 1H, J=8.54 Hz, J=1.55 Hz), 7.40 (m, 2H). 7.44 (dd, 1H, J=1.72, J=0.9 Hz). MS 304 (M+H, 304)
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]1[S:7][C:8](Br)=[CH:9][N:10]=1.[C:12]([C:15]1[CH:16]=[C:17]([SH:21])[CH:18]=[CH:19][CH:20]=1)([OH:14])=[O:13].Cl.O1CCOC[CH2:24]1>CO>[CH3:24][O:13][C:12](=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([S:21][C:8]2[S:7][C:6]([NH2:5])=[N:10][CH:9]=2)[CH:16]=1
Reactant: O=C(O)c1cccc(S)c1
Reactant: C1COCCO1
Reactant: Nc1ncc(Br)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(Sc2cnc(N)s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A 4.37 M solution of sodium methoxide in methanol (10 mL, 43.7 mmol) was added dropwise to a stirred suspension of 2-amino-5-bromothiazole hydrochloride (2.16 g, 10 mmol) and 3-carboxythiophenol (1.85 g, 12 mmol) in methanol (75 mL) at 0-5° C. The solution was allowed to warm to rt. for 2 h and a 4 M solution of hydrogen chloride in dioxane (15 mL, 60 mmol) was added. The suspension was stirred at rt. overnight and concentrated. The crude residue was diluted with satd. aqueous sodium bicarbonate solution (50 mL). The precipitated solid was filtered and washed with water (20 mL, 5×) and ether (20 mL, 5×). The solid was filtered and dried in vacuo at 60° C. to obtain the titled compound (1.97 g, 75%). B. 3-[[2-[[(1,1-Dimethylethoxy)carbonyl]amino]thiazol-5-yl]thio]benzoic acid methyl ester
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].[Cl:17][C:18]1[N:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=1>C1COCC1>[Cl:17][C:18]1[N:19]=[N:20][C:21]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:22][CH:23]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (5.0 g, 26.4 mmol) in THF (50 mL) was added sodium hydride (55% dispersion in mineral oil, 1.27 g, 29.1 mmol). The mixture was stirred at room temperature for 30 min. After addition of 3,6-dichloropyridazine (4.33 g, 29.1 mmol) the mixture was stirred at room temperature for another 5 h. Then the mixture was evaporated, extracted (ethyl acetate/water) and the organic phase was dried with sodium sulfate and concentrated. Chromatography (SiO2, heptane:ethyl acetate=100:0 to 70:30) afforded the title compound (6.62 g, 83%) as a white solid. MS: m/e=302.0 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[H-].[Na+].[CH2:17]([OH:22])[CH2:18][CH2:19][CH:20]=[CH2:21].Cl>CN(C=O)C>[CH2:17]([O:22][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6])[CH2:18][CH2:19][CH:20]=[CH2:21]
Reactant: C=CCCCO
Reactant: O=C(O)c1cc(F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCOc1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 60 °C
Yield: 55.1 %

Procedure:
A solution of 3-fluoro-5-trifluoromethyl-benzoic acid (400 mg, 1.92 mmol) in DMF (2 ml) was added dropwise to a suspension of sodium hydride (60% oily, 235 mg, 5.88 mmol) and pent-4-en-1-ol (506 mg, 5.88 mmol) in DMF (12 ml), and the mixture was stirred at 60° C. Further, this mixture was irradiated in a microwave apparatus (150° C., 20 min). The reaction solution was poured into 0.2 N aqueous hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3-pent-4-enyloxy-5-trifluoromethyl-benzoic acid (290 mg, 55%).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[CH:4]=[C:5]([F:30])[C:6]2[N:7](C(OC(C)(C)C)=O)[C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][C:11]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[CH:10][CH:9]=3.[Cl:32]CCl>>[Cl-:32].[CH3:1][N:2]([CH3:31])[C:3]1[CH:4]=[C:5]([F:30])[C:6]2[C:15]([CH:16]=1)=[S+:14][C:13]1[C:8](=[CH:9][CH:10]=[C:11]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=1)[N:7]=2
Reactant: CN(C)c1cc(F)c2c(c1)Sc1cc(N3CCOCC3)ccc1N2C(=O)OC(C)(C)C
Reactant: ClCCl
Product: CN(C)c1cc(F)c2nc3ccc(N4CCOCC4)cc3[s+]c2c1
Product: [Cl-]
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution 3-dimethylamino-7-morpholino-1-fluoro-10-Boc-phenothiazine (15) (100 mg) in dichloromethane (10 mL) HCl (1 mL, 4 M solution in 1,4-dioxane)) was added. The reaction mixture was stirred at 40° C. for 3 h. Solvent was removed under vacuum. Product was purified by flash chromatography.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[OH-].[Na+].C(O)(C(F)(F)F)=O>CO>[O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COC(=O)c1cccn(-c2ccccn2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cccn(-c2ccccn2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
A mixture of methyl 2-oxo-1-(pyridin-2-yl)-1,2-dihydropyridine-3-carboxylate (500 mg, 2.17 mmol) and 3 N NaOH (1 mL) and methanol (10 mL) was stirred at rt overnight. To the reaction was added TFA (0.5 mL) and the mixture was concentrated in vacuo. The residue was dissolved in water (3 ML) and i-PrOH (10 mL). The solid which formed was filtered, washed with a small amount of water and i-PrOH, and dried to obtain the acid (260 mg, 55%) as a white solid. 1H NMR (DMF-d7) δ 14.14 (br s, 1H), 8.72 (d, 1H, J=4.9 Hz), 8.62 (dd, 1H, J=7.7, 2.2 Hz), 8.47 (dd, 1H, J=6.6, 2.2 Hz ), 8.18-7.98 (m, 2H), 7.67 (dd, 1H, J=7.2, 5.3 Hz), 6.97 (t, 1H, J=6.6 Hz); MS(ESI+) m/z 217.2 (M+H)+.
Reaction SMILES: O1C=C(CN)N=C1.[CH3:8][C:9]1[N:10]=[CH:11][C:12]([CH2:15][NH2:16])=[N:13][CH:14]=1.[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=3)[C:31](O)=[O:32])[C:24]2=[O:37])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=3)[C:31]([NH:16][CH2:15][C:12]3[CH:11]=[N:10][C:9]([CH3:8])=[CH:14][N:13]=3)=[O:32])[C:24]2=[O:37])=[CH:38][CH:39]=1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: Cc1cnc(CN)cn1
Agent: NCc1cocn1
Product: Cc1cnc(CNC(=O)c2ccnc(N3CCN(Cc4ccc(F)cc4)C3=O)c2)cn1
Yield: 39 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (5-methylpyrazin-2-yl)methanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((5-methylpyrazin-2-yl)methyl)isonicotinamide was obtained as a colorless solid in 39% yield: mp 169-171° C.; 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 8.52 (d, J=0.9 Hz, 1H), 8.39-8.35 (m, 2H), 7.46 (br s, 1H), 7.39-7.37 (m, 1H), 7.29-7.24 (m, 2H), 7.05-6.99 (m, 2H), 4.74 (d, J=5.1 Hz, 2H), 4.44 (s, 2H), 4.04 (t, J=8.1 Hz, 2H), 3.37 (t, J=8.1 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 421.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]CCCC.CCCCCC.[C:25]1([CH:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:33](=O)[O:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O1CCCC1>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:33]1[O:32][C:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:40]2[C:35]=1[CH:36]=[CH:37][CH:38]=[CH:39]2
Reactant: O=C1OC(c2ccccc2)c2ccccc21
Reactant: Brc1ccccc1-c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc(-c2ccccc2-c2oc(-c3ccccc3)c3ccccc23)cc1
Temperature: -50 °C
Reaction time: 2 h

Procedure:
In Ar, 3.9 g (1.68E-2 mol) of o-bromobiphenyl was dissolved in 30 cm3 of tetrahydrofuran (THF) at −50° C. To the solution was added 10 cM3 of a nBuLi hexane solution (1.5 mol/l). After 2 hours, 3 g (1.4E-2 mol) of 3-phenylphthalide was added to the solution while it was kept cooled at −50° C. After 2 hours, the reaction solution was allowed to resume room temperature, and 10 cm3 of a 35% aqueous hydrochloric acid was added thereto. After 1 hour, toluene extraction was carried out using a separatory funnel, followed by thorough washing with distilled water. After the toluene solution was concentrated, the end product was isolated by silica gel chromatography (developer, toluene:hexane=1:4). There was obtained 4 g (80%) of a yellow viscous substance emitting bluish green fluorescence.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]12[O:22][CH2:21][CH2:20][CH2:19][O:18]1.Cl[CH2:24][C:25]([CH3:29])([CH3:28])[C:26]#[N:27].O>CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:24][C:25]([CH3:29])([CH3:28])[C:26]#[N:27])[C:12](=[O:17])[C:11]12[O:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: CC(C)(C#N)CCl
Reactant: O=C1Nc2ccc(Cl)cc2C12OCCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C#N)CN1C(=O)C2(OCCCO2)c2cc(Cl)ccc21
Temperature: 125 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a stirred solution of potassium t-butoxide (0.561 g, 5.00 mmol, 1.2 eq) in anhydrous DMSO (16 mL) was added 5′-chlorospiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (1.00 g, 4.17 mmol) all in one portion. After stirring 10 min. 3-chloro-2,2-dimethylpropionitrile (0.981 g, 8.34 mmol, 2 eq) was added in one portion at room temperature under a dry N2 atmosphere. The reaction was heated at 125° C. for 22 hr, cooled to room temperature, poured into H2O (180 mL) and extracted with Et2O (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was purified on Biotage KP silica gel eluting with 100% CH2Cl2 to give the title compound as a white solid (0.91 g, 68% yield). Anal. Calc'd for C16H17ClN2O3: C, 59.91; H, 5.34; N, 8.73. Found: C, 59.79; H, 5.26; N, 8.57. NMR (300 Mz, DMSO-d6): consistent. IR: consistent. MS: (ES+) m/z 321 [M+H]; one Cl pattern observed. m.p.: 114-115.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[CH3:16][O:17][C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19]>ClCCl.N1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:16][O:17][C:18](=[O:19])[C:20]1[CH:25]=[CH:24][C:23]([N:3]2[C:4](=[O:15])[C:5]3[C@@H:6]4[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]4)[C:10]=3[N:2]2[CH3:1])=[CH:22][CH:21]=1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 29.5 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.48 mmol), 4-methoxycarbonyl-phenyl-boronic acid (180 mg, 0.97 mmol), and copper(II) acetate (133 mg, 0.73 mmol) in dichloromethane (1 mL) and pyridine (0.8 mL) was stirred at room temperature for 2 days. The reaction mixture was evaporated and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an Isco 12 g column, eluting with 10-60% ethyl acetate/hexanes to give 4-((4S,7R)-1,7,8,8-tetramethyl-3-oxo-1,3,4,5,6,7-hexahydro-4,7-methano-indazol-2-yl)-benzoic acid methyl ester (48.2 mg, 29%) as an off-white solid. ES(+)-MS (M+H) 341.