Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH2:26][NH:27][CH2:28][CH2:29][CH:30]=1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:27]1[CH2:28][CH2:29][CH:30]=[C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[CH2:26]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: C1=C(c2ccccn2)CNCC1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@H](N1CCC=C(c2ccccn2)C1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 61.9 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.83 g, 3.3 mmol) and 1′,2′,5′,6′-tetrahydro-2,3′-bipyridine (3.51 g, 21.9 mmol) were dissolved in acetonitrile (50 ml), and lithiumperchlorate trihydrate (1.50 g, 9.3 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.87 g of the intended substance (yield 61.9%).
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15](O)([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Yield: 97.8 %

Procedure:
A suspension of 4-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (Intermediate 73-2, 300 mg, 0.864 mmol) in DCM (2 mL) was treated with triethylsilane (1.380 mL, 8.64 mmol) and then slowly with TFA (0.666 mL, 8.64 mmol) and the mixture was stirred at rt for 40 min. The resulting suspension was diluted with DCM and the resulting solution was washed with NaHCO3 (aq). The organic phase was washed with water and brine, and dried and concentrated to give 4-bromo-7-isopropyl-9H-carbazole-1-carboxamide as a white solid (280 mg, 98%). 1H NMR (400 MHz, chloroform-d) δ 10.50 (1 H, br. s.), 8.63 (1 H, d, J=8.1 Hz), 7.32-7.40 (3 H, m), 7.22 (1 H, dd, J=8.4, 1.3 Hz), 5.97 (2 H, br. s.), 3.02-3.18 (1 H, m), 1.35 (6 H, d, J=6.8 Hz). Mass spectrum m/z 331, 333 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[CH:11]=[CH2:12])=[O:2]>C(O)C.[Pd]>[CH2:11]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH:1]=[O:2])[C:7]#[N:8])[CH3:12]
Reactant: C=Cc1cc(C#N)ccc1C=O
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(C#N)ccc1C=O
Reaction time: 2 h

Procedure:
A solution of 1.3 g (8.27 mmol) of 4-formyl-3-vinylbenzonitrile in 35 ml of ethanol is mixed with 880 mg of 10% palladium on carbon and vigorously stirred under a hydrogen atmosphere for 2 h. The suspension is filtered through a layer of kieselguhr, the residue is washed with ethanol, and the filtrate is concentrated. The residue (890 mg) is employed without further purification in the following stage.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=O)[CH2:11][CH2:10]3)[CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[S:27])[CH2:11][CH2:10]3)[CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCc2cc(-c3cccnc3)ccc2N1
Solvent: Cc1ccccc1
Product: S=C1CCc2cc(-c3cccnc3)ccc2N1

Procedure:
A mixture of 6-Pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one (395 mg, 1.76 mmol) and Lawessons reagent (356 mg, 0.88 mmol) was refluxed in 30 ml toluene for 2 h. After evaporation of the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel (hexanes/ethyl acetate, 3/7, Rf=0.31) which gave 6-Pyridin-3-yl-3,4-dihydro-1H-quinoline-2-thione as yellow plates (63 mg, 0.26 mmol, 15%), mp (hexanes/ethyl acetate) 267° C. 1H-NMR (500 MHz, DMSO-d6): δ=2.87 (m, 2H), 2.97 (m, 2H), 7.20 (d, 3J=8.2 Hz, 1H), 7.46 (dd, 3J=7.9 Hz, 3J=4.6 Hz, 1H), 7.59 (dd, 3J=8.2 Hz, 4J=1.9 Hz, 1H), 7.62 (d, 4J=1.9 Hz, 1H), 8.04 (m, 1H), 8.53 (dd, 3J=4.7 Hz, 4J=1.6 Hz, 1H), 8.87 (d, 4J=2.2 Hz, 1H), 12.30 (s, 1H). MS m/z=241.05 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[C:22]([C:25]2[N:29]4[CH:30]=[CH:31][C:32]([CH:34]=[O:35])=[CH:33][C:28]4=[N:27][N:26]=2)[CH:21]=[CH:20]3)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].N.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CO.CC(O)C.CC(O)=O>[C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[C:22]([C:25]2[N:29]4[CH:30]=[CH:31][C:32]([CH2:34][OH:35])=[CH:33][C:28]4=[N:27][N:26]=2)[CH:21]=[CH:20]3)[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(-c4nnc5cc(C=O)ccn45)nc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(-c4nnc5cc(CO)ccn45)nc23)CC1
Reaction time: 5 h
Yield: 29.2 %

Procedure:
To tert-butyl(1-(2-(7-formyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl)piperidin-4-yl)methylcarbamate (10 mg, 0.021 mmol) in DCM/MeOH (1 mL/1 mL) was added NH3 in IPA (0.1 mL, 2M) and HOAc (0.2 mL), followed by NaB(OAc)3H (13 mg, 0.062 mmol). The reaction was stirred for 5 hours and then concentrated. The crude material was purified by silica gel chromatography (DCM/MeOH/NH4OH 20:1:0.1) to provide the desired product (3 mg). MS ESI (+) m/z 489 (M+1) detected.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[CH3:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.C(O)C.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>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:31]1[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2c(C#N)nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2N)cc1

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.45 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 4-methylphenylboronic acid (0.3 g) in ethanol (1 ml). The mixture was heated under reflux for 2 hours. After cooling the organic layer was separated, dried (MgSO4) and evaporated. The residue was taken up the minimum amount of ethyl acetate and purified by column chromatography on silica gel (50 g) eluted with dichloromethane. Combination and evaporation of suitable fractions followed by trituration with hexane gave the title compound as an off-white crystalline solid, m.p.243-4° C.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13](=[O:15])[O:12][N:11]=2)=[CH:6][CH:5]=1.Cl[CH2:17][O:18][CH3:19]>C1COCC1>[I:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:14]=[C:13]([O:15][CH2:17][O:18][CH3:19])[O:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: O=C1CC(c2ccc(I)cc2)=NO1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cc(-c2ccc(I)cc2)no1
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
Sodium hydride (360 mg, 9.0 mmol, 60% in mineral oil) was added into a solution of 3-(4-iodophenyl)isoxazol-5(4H)-one (2.0 g, 6.97 mmol) in anhydrous THF (20 mL) at 0° C. The mixture was stirred at 0° C. for 2 h. Chloro(methoxy)methane (1.12 g, 14 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 h, poured into ice-water, and extracted with EtOAc (3×60 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on a silica gel column using EtOAc in petroleum ether (1:20) to afford the title compound as pale solid (960 mg, 42%). 1H NMR (DMSO-d6, 400 MHz): δ 7.96 (d, 2H), 7.45 (d, 2H), 5.99 (s, 1H), 4.95 (s, 2H), 3.27 (s, 3H). LCMS: 332 (M+H)+.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[CH:12]=[CH:11][O:10][N:9]=1)=O.OC[C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[O:10]1[CH:11]=[CH:12][C:8]([NH:7][CH2:5][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[C:25]([F:35])[CH:24]=3)[CH2:18]2)=[N:9]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CCOCC2)c(F)c1
Reactant: O=C(Nc1ccon1)OCC(Cl)(Cl)Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C1O[C@@H](CNc2ccon2)CN1c1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 331.2 %

Procedure:
To a stirred solution of 3-(2,2,2-trichloroethyloxycarbonylamino)isoxazole (260 mg, 1.0 mmol), 5(R)-hydroxymethyl-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (see WO 95/07271; 293 mg, 1 mmol) and tributylphosphine (303 mg, 1.5 mmol) in dry tetrahydrofuran (10 ml) at 0° C. under a nitrogen atmosphere, was added 1,1′-(azodicarbonyl)dipiperidine (378.5 mg, 1.5 mmol) in dry tetrahydrofuran (3 ml). The reaction allowed to warm to room temperature and was stirred for 4 days by which time a white suspension had formed. The reaction mixture was filtered and the residue washed with tetrahydrofuran. The filtrate was reconcentrated by rotary evaporation to give a yellow oil (1.2 g) which was purified by MPLC (30% ethyl acetate/hexane, ICN Alumina N 32-63) and further MPLC (100% CH2Cl2, ICN Alumina N 32-63). Concentration of the fractions by rotary evaporation gave the title compound as a crisp white foam (296 mg, 55%). NMR: 2.97 (t, 4H), 3.73 (t, 4H), 3.88 (m, 1H), 4.17 (m, 2H), 4.38 (m, 1H), 5.04 (m, 3H), 6.90 (s, 1H), 7.06 (t, 1H), 7.18(dd, 1H), 7.46 (dd, 1H), 8.91 (d, 1H); m/z ES+ (M+H)=537.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:13][CH:12]=2)=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1ccc(C2CCCCC2)cc1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1ccc(C2CCCCC2)cc1

Procedure:
Using the same method as in Example 1-(ii), 4-cyclohexylaniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-[((2-[(4-cyclohexylphenyl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 89%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=1[OH:32]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([CH3:31])[C:25]=2[CH3:24])=[N:3][CH:4]=1
Reactant: Cc1cccc(O)c1C
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 2,3-dimethylphenol: 1H-NMR (CDCl3) δ 8.56 (1H, d, J=3.0 Hz), 8.32 (1H, d, J=7.4 Hz), 8.11 (1H, d, J=2.8 Hz), 8.02–7.99 (2H, m), 7.43 (2H, d, J=8.4 Hz), 7.23–7.13 (2H, m), 6.95 (1H, d, J=7.7 Hz), 5.46–5.36 (1H, m), 3.90 (3H, s), 2.35 (3H, s), 2.05 (3H, s), 1.59 (3H, d, J=6.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:24][CH:23]([C:25]#[N:26])[CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:27][NH:28][C:29](=[O:45])[C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O1CCOCC1.O.Cl[Pd]Cl>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:24][CH:23]([C:25]#[N:26])[CH2:22]2)[C:5]2[C:10]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([NH:28][CH3:27])=[O:45])=[CH:31][CH:32]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CC(C#N)C3)nc(Cl)nc21
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CC(C#N)C4)c23)cc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
3-((2-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)cyclobutanecarbonitrile (1 equiv), N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1.15 equiv), sodium carbonate (3 equiv) and [1,1′-bisdiphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (0.1 equiv) suspended in 1,4-dioxane/water, and flushed with nitrogen, were stirred at 85° C. for 2 h. The reaction mixture was purified using silica gel chromatography (0 to 100% ethyl acetate in hexane) to give the title compound (50% yield). MS (ESI) m/z 512.3 [M+H]+.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[S:15])[NH:13][NH2:14])=[CH:7][CH:6]=1)([OH:4])=[O:3].[Cl:16][C:17]1[C:18]([OH:26])=[C:19]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[CH:20]=O.O>CN(C)C=O>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[S:15])[NH:13][N:14]=[CH:20][C:19]2[CH:22]=[C:23]([Cl:25])[CH:24]=[C:17]([Cl:16])[C:18]=2[OH:26])=[CH:9][CH:10]=1)([OH:4])=[O:3]
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(NC(=S)NN=Cc2cc(Cl)cc(Cl)c2O)cc1
Reaction time: 18 h
Yield: 55.2 %

Procedure:
Concentrated aqueous hydrochloric acid (1 mL) was added to a stirred solution of 4-(4-carboxyphenyl)-3-thiosemicarbazide (213 mg, 1.00 mmol) and 3,5-dichloro-2-hydroxybenzaldehyde (198 mg, 1.04 mmol) in dimethylformamide (20 mL). The mixture was stirred for 18 h, water was added and the precipitate filtered, washed (water) and dried to give the title compound (212 mg, 55%) as a solid. MS (ES−) m/e 382, 384 [M−H]-.
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[C:9]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:6]=1[CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])(=O)=O>C(O)(=O)C.[Zn]>[SH:2][C:5]1[CH:10]=[C:9]([C:11]([OH:20])([C:12]([F:13])([F:14])[F:15])[C:16]([F:19])([F:18])[F:17])[CH:8]=[CH:7][C:6]=1[CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CCc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1S(=O)(=O)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)CCc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1S

Procedure:
To excess chlorosulfonic acid cooled with an ice-acetone bath can be added methyl 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoate with stirring. The solution should be stirred for several hours. Addition of the reaction mixture to ice and isolation of the product will give 2-chlorosulfonyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoic acid, methyl ester. Reduction of 2-chlorosulfonyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoic acid, methyl ester with zinc in acetic acid followed by isolation of the product will give 2-mercapto-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoic acid, methyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:19])=[N:8][N:9]2[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=2)=[CH:5][CH:4]=1)#[CH:2].[Li+].CC([N-]C(C)C)C.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34](=[O:36])[CH3:35]>C1COCC1>[NH2:18][C:14]1[N:13]=[C:12]([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[C:2][C:34]([C:30]4[N:29]([CH3:28])[CH:33]=[CH:32][N:31]=4)([OH:36])[CH3:35])[CH:11]=3)[C:7]([CH3:19])=[N:8]2)[CH:17]=[CH:16][N:15]=1
Reactant: CC(=O)c1nccn1C
Reactant: C#Cc1ccc2c(C)nn(-c3ccnc(N)n3)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3nccn3C)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-(6-ethynyl-3-methylindazol-1-yl)pyrimidin-2-amine (150 mg, 0.6 mmol) in THF (2 mL) at −78° C. under nitrogen was added 2M LDA in THF (0.75 mL, 1.50 mmol). After 5 minutes, 1-(1-methyl-1H-imidazol-2-yl)ethanone (225 mg, 1.81 mmol) in THF (1.0 mL) was added, and after a further 20 minutes the mixture was allowed to warm to RT and stirred for 1.5 hours. The reaction mixture was then cooled to −78° C. and treated with additional 2M LDA in THF (0.3 mL, 0.6 mmol) and 1-(1-methyl-1H-imidazol-2-yl)ethanone (90 mg, 0.6 mmol). After stirring at RT for 4 hr, the reaction mixture was quenched by addition of saturated aqueous NH4Cl (2 mL). The volatiles were removed in vacuo and the mixture was diluted with DCM (10 ml) and washed with water (2 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage, 3-12% methanol gradient in DCM) to give the title compound: 1H NMR (500 MHz, DMSO) delta 2.00 (3H, s), 2.57 (3H, s), 3.92 (3H, s), 6.32 (1H, s), 6.77 (1H, s), 6.98 (2 H, s), 7.03 (1H, d, J=5.5 Hz), 7.15 (1H, s), 7.36 (1H, d, J=8.2), 7.84 (1H, d, J=8.2 Hz), 8.25 (1H, d, J=5.5 Hz), 8.84 (1H, s); LC-MS: m/z=+374.05 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.[N:35]1([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)CC>[O:17]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:38]3[CH2:37][CH2:36][N:35]([C:41]4[CH:42]=[CH:43][C:44]([C:45]#[N:46])=[CH:47][CH:48]=4)[CH2:40][CH2:39]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:8]12
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (86.0 mg, 0.369 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (108.0 mg, 0.442 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (193 ul, 1.1 mmol). To the stirred mixture was then added 4-(piperazin-1-yl)benzonitrile (76 mg, 0.406 mmol). The reaction was heated to 90° C. with stirring for 16 h. The crude reaction was cooled to room temperature and concentrated to a residue, then taken up in 3 mL DMSO and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (29.7 mg, 20.0%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.48 (s, 1H), 7.65 (s, 1H), 7.57 (d, J=8.8 Hz, 2H), 6.94-7.04 (m, 3H), 4.44-4.55 (m, 1H), 3.79-3.88 (m, 1H), 3.35 (br. s., 2H), 3.30 (br. s., 4H), 2.54-2.69 (m, 1H), 2.45 (br. s., 4H), 1.97-2.09 (m, 1H), 1.80-1.90 (m, 1H), 1.57-1.69 (m, 1H), 1.32-1.56 (m, 3H). [M+H] calc'd for C, 23; H, 26; N, 6; O, , 403; found, 403. MP: 212.2° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=4)[CH2:16][CH2:15]3)=[O:13])[CH2:8][CH2:9]2)=[CH:4][CH:3]=1.C(OCC)(=O)C.CN(C)C.[C:43](Cl)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(O)C>[C:43]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=4)[CH2:16][CH2:15]3)=[O:13])[CH2:8][CH2:9]2)=[CH:4][CH:3]=1)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(CN2CCN(C(=O)C3=Cc4ccc(O)cc4CC3)CC2)cc(OC)c1OC
Agent: CN(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(CN2CCN(C(=O)C3=Cc4ccc(OC(=O)c5ccccc5)cc4CC3)CC2)cc(OC)c1OC
Reaction time: 7 h
Yield: 60.6 %

Procedure:
A mixture of 1-(7-hydroxy-1,2-dihydro-3-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine (0.2 g), ethyl acetate (20 ml), trimethylamine (0.5 g) and benzoyl chloride (0.5 g) is left standing for 7 hours at room temperature. To the mixture is added ethanol (2 ml), and the mixture is left standing overnight. The solvent is distilled off under reduced pressure. To the residue is added ethyl acetate (50 ml), and insolubles are filtered off. The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:acetone=1:1-1:2) and crystallized from ethyl ether to afford 1-(7-benzoyloxy-1,2-dihydro-3-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine (0.15 g) as colorless prisms, m.p. 117°-119° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:14][CH2:15][C:16]([OH:18])=O.S(Cl)([Cl:21])=O>C1C=CC=CC=1>[O:1]=[C:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:14][CH2:15][C:16]([Cl:21])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCC1CCCCCCCCCCC1=O
Solvent: c1ccccc1
Product: O=C(Cl)CCC1CCCCCCCCCCC1=O
Reaction time: 8 h

Procedure:
Ten parts of β-(2-oxocyclododecyl)propionic acid, 6 parts of thionyl chloride, and 35 parts of anhydrous benzene were placed into a reactor and allowed to stand at 0° C for 3 hours and further at room temperature overnight. Then, the excess amount of thionyl chloride and the benzene were distilled off under reduced pressure to give β-(2-oxocyclododecyl)propionic acid chloride. The acid chloride was dissolved in 25 parts of benzene. Into the resulting solution was added dropwise 35 parts of benzene solution containing 30 wt.% pyridine and the mixture was stirred for 6 hours. The produced crystals were filtered off. The filtrate was washed with dilute hydrochloric acid to remove excess pyridine, the organic layer was washed to remove the hydrochloric acid, and then dried with Glauber's salt. Thereafter the resulting solution was treated by the same method as in Example 1 to give 6.3 parts of 13-oxabicyclo(10.4.0)-hexadec-1(12)-en-14-one in 68.4% yield.
Reaction SMILES: O[NH:2][C@H:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]>C(O)C>[NH2:2]/[C:3](=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6])/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C[C@H](NO)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)/C=C(/N)C(=O)OCC
Yield: 34.5 %

Procedure:
A solution (10 ml) of diethyl N-hydroxyaspartate (9.4% solution, 7.8 g, 3.6 mmol) in ethanol was fed in a quartz column (1 inch ID) containing glass beads (3 inches long) at 200° C. at the rate of 0.2 ml per minute along with nitrogen at a rate of 1000 ml per minute. The vaporized material escaping at the end of quartz column was collected using a dry-ice trap. The condensate (0.35 g) was analyzed by GLC. The analysis found that the reaction gave diethyl 2-aminomaleate in about 34.5% yield.