Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:54][NH:53]1>C(OCC)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]([N:53]3[CH2:54][C:55]4[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=4)[CH2:52]3)=[O:25])[CH2:22][CH2:23]2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: c1ccc2c(c1)CNC2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cc2ccccc2n1Cc1ccc(Cl)cc1)N1CCC(C(=O)N2Cc3ccccc3C2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The following was added sequentially to DCM (2 mL): 1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (50 mg, 0.126 mmol), DIPEA (0.07 mL, 0.378 mmol), EDC (30 mg, 0.151 mmol), HOBT (24 mg, 0.151 mmol), and isoindoline (0.018 mL, 0.151 mmol). The mixture was stirred for 18 h at rt, at which time the solution diluted with a 1:1 solution of ethyl acetate:diethyl ether and washed with 1M HCl (1×), 10% aq. sodium carbonate (1×) and brine (1×). The organic phase was dried with magnesium sulfate and concentrated in vacuo. The resulting residue was dissolved in EtOAc and precipitated out hexanes, and then collected over a filter and washed with a 10:1 solution of hexanes:ethyl acetate. (Yield: 22 mg, 0.044 mmol, 35%) 1H NMR (400 MHz, CDCl3) 7.65, 7.35-7.21, 7.15, 7.05, 6.68, 5.47, 4.77-4.17, 2.97, 2.76-2.64, 1.78, 1.47-1.34, 1.37-1.24, 0.95-0.83
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:21])=[C:10]([N:14]3[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:22])[C:5]([C:23]([OH:25])=[O:24])=[CH:4]1)[CH3:2].[CH2:26]=O>C(O)=O>[CH3:20][CH:16]1[N:17]([CH3:26])[CH2:18][CH2:19][N:14]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:22])[C:5]([C:23]([OH:25])=[O:24])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:21])[CH2:15]1
Reactant: C=O
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(C)C3)c(F)c21
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(C)C3)c(F)c21

Procedure:
A mixture of 1.40 g of 1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid, 2.8 ml of 90% formic acid and 2.2 ml of 37% formalin was heated for 4 hours under reflux. The reaction mixture was evaporated and the residue was dissolved in water. The solution was neutralized with aqueous sodium bicarbonate. The precipitate was filtered and recrystallized from ethanol to give 0.32 g of the title compound as colorless needles, M.p. 211.5°-212° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C@H:16]3[CH2:18][C@H:17]3[CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]2)=[N:8][CH:9]=1.Cl[C:23]1[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([C:30]#[N:31])[CH:24]=1>CN(C=O)C.CCOC(C)=O.O>[CH3:29][C:27]1[N:26]=[C:25]([C:30]#[N:31])[CH:24]=[C:23]([O:21][CH2:20][CH2:19][C@@H:17]2[CH2:18][C@@H:16]2[CH:13]2[CH2:12][CH2:11][N:10]([C:7]3[N:8]=[CH:9][C:4]([CH3:3])=[CH:5][N:6]=3)[CH2:15][CH2:14]2)[N:28]=1
Reactant: Cc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Reactant: Cc1nc(Cl)cc(C#N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(C#N)nc(C)n3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
NaH (60%, 18 mg, 0.45 mmol, 1.2 eq) was placed in a 1 dram vial and DMF (1.2 mL) added. A solution of 2-{(1S,2R)-2-[1-(5-methylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (100 mg, 0.375 mmol) was added dropwise (0.5 mL) to the slurry, and the mixture stirred at RT for 10 min. The solution was cooled to −20° C., and a solution of 6-chloro-2-methylpyrimidine-4-carbonitrile (115 mg, 0.75 mmol) in DMF (0.5 mL) was added drop-wise. The red mixture was stirred for 40 minutes. A solution of ice-cold saturated NH4Cl (aq., 1 mL) was added, and the mixture diluted with EtOAc (100 mL) and water (50 mL). The mixture was transferred to a separatory funnel, the mixture shaken, and the layers separated. The organic fraction was washed with water (20 mL), dried over MgSO4, filtered, and concentrated in vac. The red oil was purified by chromatography on silica gel 1:7 EtOAc:Hexanes to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:16][CH2:15][C:14](=[N:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13][NH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[BH4-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]([C@@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13][NH:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCC(=NOCc2ccccc2)CN1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Temperature: -10 °C
Reaction time: 22 h
Yield: 79.9 %

Procedure:
Under nitrogen atmosphere, tetrahydrofuran (2 ml) was added to (2S)-5-benzyloxyimino-piperidine-2-carboxylic acid benzyl ester (0.168 g, 0.50 mmol), and the mixture was cooled down to −10° C. Sulfuric acid (0.302 g, 3.06 mmol) was added to the mixture, and then sodium borohydride (0.0567 g, 1.50 mmol) was added. After 22 hours of stirring, the reaction mixture was analyzed with high performance liquid chromatography to find that the mixture contained 0.136 g of the title compound, and the reduction reaction proceeded with the yield of 80%. The diastereo selectivity was (2S,5R)/(2S,5S)=80.4/19.6 (60.8% de).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[CH:18][C:16]=1[NH2:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:17][C:16]1[CH:18]=[CH:19][C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:21][C:15]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1
Reactant: CC(C)(C)c1ccc(N)c(Br)c1
Reactant: CC(C)(C)c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)(C)c1cccc(-c2cc(C(C)(C)C)ccc2N)c1
Temperature: 25 °C
Yield: 57 %

Procedure:
Added together were 3-t-butylphenylboronic acid (4.0 g, 22.4 mmol), 2-bromo-4-t-butyl aniline (4.3 g, 18.7 mmol), palladium(II)acetate (0.11 g, 0.468 mmol), triphenyl phosphine (0.5 g, 1.8 mmol), and 25 mL of a 2 M solution of potassium carbonate in 36 mL of ethylene glycol dimethyl ether. The reaction mixture was heated at reflux for 18 hours. The reaction was cooled to room temperature and the aqueous phase was separated from the organic phase. The aqueous phase was extracted with ethyl acetate. The organic extractions were combined, dried over magnesium sulfate filtered and concentrated. The crude product was purified by column chromatography using 20% ethyl acetate and hexanes as the eluants. The pure product 2-amino-3′,5-di-tert-butyl biphenyl (3.0 g, 57% yield) was collected as a white solid whose NMR was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[S:27]1(=[O:34])(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1.N1C=CC=CC=1C1C=CC=CN=1.O.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>CN(C=O)C.O.[Cu-]=O>[O:33]=[S:27]1(=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COC(=O)c1nc(Br)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Reactant: O=S1(=O)CCCCN1
Agent: O=[Cu-]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: c1ccc(-c2ccccn2)nc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 118 °C

Procedure:
To a slurry of methyl 5-bromo-8-{[(4-methylphenyl)sulfonyl]oxy}-1,6-naphthyridine-7-carboxylate (7.55 g, 17.27 mmol) in degassed DMF (20 mL) in a pressure tube was added 1,2-thiazinane-1,1-dioxide (2.8 g, 20.7 mmol, prepared as in White et al, J. Org Chem. 1987, 52: 2162) followed by 2,2′-bipyridine (3.24 g, 20.7 mmol) and copper (I) oxide powder (2.96 g, 20.7 mmol). The pressure tube was closed and heated to 118 degrees C. overnight. Celite (0.5 g) was added to the resulting slurry and this was filtered through a plug of DMF wetted celite. The solids were washed with more DMF (10 mL) and the filtrate transferred to a large Erlenmeyer flask (1L) fitted with a 2 inch stirring bar. The volume was brought up to 200 mL with chloroform and a solution of ethylenediaminetetraacetic acid monohydrate (13.3 g, 35.7 mmol) in 140 mL of water was added. The biphasic mixture was vigorously stirred, open to the air, for 3 hours. The organic phase was separated and retreated with another solution of ethylenediaminetetraacetic acid monohydrate (13.3 g, 35.7 mmol) in 140 mL of water overnight (16 hrs). The organic was separated and washed with water and dried over Na2SO4, filtered, and reduced to a small volume in vacuo. The product solidified during solvent reduction. The solid was broken up and dried to afford the desired product.
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.Cl[CH2:14][Cl:15].OC[C@@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1.[Cl-].[Li+]>O.CN(C)C=O>[Cl:15][CH2:14][C@@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(I)cc1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCl)Cc1ccc(I)cc1
Reaction time: 0.5 h

Procedure:
0.27 ml (1.92 mmol) of triethylamine and 165 mg (1.44 mmol) of methanesulfonyl chloride were added to 5 ml of dichloromethane containing 360 mg (0.96 mmol) of t-butyl [(1S)-2-hydroxy-1-(4-iodobenzyl)ethyl]carbamate under cooling with ice. After stirring for 30 minutes, the temperature was elevated to room temperature, and the mixture was stirred for 15 hours. The reaction liquid was diluted with water. After the extraction with dichloromethane, the organic layer was successively washed with 1 N hydrochloric acid, 1 N sodium hydroxide and saturated aqueous NaCl solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. 10 ml of dimethylformamide and 203 mg (4.8 mmol) of lithium chloride were added to the residue, and they were stirred at 50° C. for 19 hours. The reaction liquid was diluted with water. After the extraction with ethyl acetate, the organic layer was successively washed with water and saturated aqueous NaCl solution. The solvent was evaporated, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[N:8]([CH:11]([CH3:26])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]2[CH2:18][C:19]3[C:24]([C:14]1=2)=CC(O)=[CH:21][CH:20]=3)=[N+:9]=[N-:10].N1C=CC=CC=1.O>ClCCl>[N:8]([CH:11]([CH3:26])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]2[CH2:18][C:19]3[C:24]([C:14]1=2)=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:21][CH:20]=3)=[N+:9]=[N-:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC(Cn1ccc2c1-c1cc(O)ccc1C2)N=[N+]=[N-]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)-c1c(ccn1CC(C)N=[N+]=[N-])C2
Reaction time: 16 h
Yield: 85 %

Procedure:
0.7 ml of acetic anhydride was added while stirring to a solution of 1.05 g of (RS)-1-(2-azido-propyl)-7-hydroxy-1,4-dihydro-indeno[1,2-b]pyrrol and 0.6 ml of pyridine in 30 ml of dichloromethane and the mixture was stirred for an additional 16 hours. Subsequently, the reaction mixture was treated with 50 ml of dichloromethane and 40 ml of water. The organic phase was separated and this was washed once with 50 ml of saturated sodium chloride solution. After drying over magnesium sulfate, the solution was concentrated in a vacuum and the crude product was purified by column chromatography on silica gel (ethyl acetate/hexane 1:2). 0.9 g (85%) of (RS)-1-(2-azido-propyl)-7-acetoxy-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as a light orange oil.
Reaction SMILES: O[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5]([S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:6]2.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5]([S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:6]2
Reactant: Oc1ncnc2nc(SCc3ccccc3)[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Clc1ncnc2nc(SCc3ccccc3)[nH]c12
Reaction time: 0.25 h

Procedure:
6-Hydroxy-8-benzylthiopurine (7.33 g) is added to a mixture of phosphorous oxychloride (70 ml) and N,N-diethylaniline (7.5 ml), and the mixture refluxed for 2 hours to give a dark-red product. The mixture is concentrated under vacuum and the resulting syrup poured slowly with stirring onto ice (400 g). The mixture is allowed to stand for 15 min., then made strongly alkaline with cold concentrated KOH. The mixture is triturated thoroughly to dissolve most of the syrup and acidified to pH 1 by the slow addition of cold concentrated HCl, with excess ice still present.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27]>CCO>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:26]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[NH:27])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: CSC(=N)c1cccs1
Reactant: CN1CCCCC1CCn1ccc2cc(N)ccc21
Agent: I
Solvent: CCO
Product: CN1CCCCC1CCn1ccc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
A solution of compound 61 (235 mg, 0.91 mmol) in EtOH (10 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (520 mg, 1.83 mmol) and stirred overnight at room temperature. Argon was bubbled through the mixture for 20 minutes then it was concentrated to give brownish oil. This residue was partitioned between CH2Cl2 (50 mL) with 10% MeOH and saturated sodium bicarbonate (20 mL). The aqueous layer was extracted with an additional CH2Cl2 (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give a brown residue which was subjected to flash chromatography on silica gel (MeOH:CH2Cl2, 5:95 to 2M NH3 in MeOH:CH2Cl2, 1:9) to give compound 62 (154 mg, 46.1%) as a yellow solid. 1H NMR (DMSO-d6) δ 7.71 (d, J=2.9 Hz, 1H), 7.58 (d, J=5.1 Hz, 1H), 7.37-7.30 (m, 2H), 7.10-7.08 (m, 1H), 6.98 (s, 1H), 6.70 (dd, J=1.5, 6.9 Hz, 1H), 6.31 (d, J=3.0 Hz, 1H), 6.25 (brs, 2H), 4.15 (t, J=7.5 Hz, 2H), 2.79-2.75 (m, 1H), 2.19 (s, 3H), 2.05-1.15 (m, 10H); ESI-MS (m/z, %): 367 (M+1,50), 184 (M+2, 100); ESI-HRMS calculated for C21H27N4S (MH+): 367.1966, observed: 367.1937.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:19])OCC)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][CH:22]([O:26][CH3:27])[CH2:23][NH:24][CH3:25]>C1(C)C=CC=CC=1>[C:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([N:24]([CH2:23][CH:22]([O:26][CH3:27])[O:21][CH3:20])[CH3:25])=[O:19])=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCC(OC)OC
Reactant: CCOC(=O)Nc1ccc(Cc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(CN(C)C(=O)Nc1ccc(Cc2ccccc2)cc1)OC

Procedure:
Ethyl [4-(phenylmethyl)phenyl]carbamate (0.1 mole) and toluene (100 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. N-(2,2-dimethoxyethyl)methanamine (0.15 mole) is added to the vessel and the mixture is refluxed for 16 hours. Solvent is then removed by mild warming under reduced pressure to yield the desired product N-[4-(phenylmethyl)phenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]([C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)#[N:41].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@H:7]([O:9][C:45]2[CH:46]=[CH:47][C:42]([C:40]#[N:41])=[CH:43][CH:44]=2)[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: N#Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc(C#N)cc2)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 88.9 %

Procedure:
To a solution of N-carbobenzyloxy-trans-4-hydroxy-L-proline methyl ester (10.0 g, 35.8 mmol) in 200 mL of anhydrous THF under N2 was added triphenylphosphine (10.6 g, 39.4 mmol) and 4-cyanophenol (4.7 g, 39.4 mmol). This solution was cooled to 0° C. and then treated with diethylazodicarboxylate (6.3 mL, 39.4 mmol), added dropwise over 30 minutes. The reaction was warmed to room temperature and stirred for 2 days. The solvent was removed in vacuo, and the residue chromatographed (SiO2, 30% ethyl acetate/hexanes) to provide 12.1 g (89%) of N-carbobenzyloxy-4-(cis)-(4-cyanophenoxy)-L-proline methyl ester as a colorless oil. (MS).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:30]3[CH2:35][CH2:34][CH:33]([O:36][C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=4[F:44])[CH2:32][CH2:31]3)=[C:20]([NH:25][CH2:26][CH:27]([F:29])[F:28])[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:29][CH:27]([F:28])[CH2:26][NH:25][C:20]1[N:21]=[C:22]2[CH2:23][CH2:24][NH:15][CH2:16][C:17]2=[N:18][C:19]=1[N:30]1[CH2:31][CH2:32][CH:33]([O:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[F:44])[CH2:34][CH2:35]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CCN(Cc3ccccc3)C4)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CCNC4)CC2)c(F)c1
Reaction time: 2 h

Procedure:
A solution of 6-benzyl-N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (152 mg, 0.241 mmol) and Pd(OH)2 on carbon (33.9 mg, 0.048 mmol) in THF (2.41 mL) was purged with and placed under hydrogen (balloon) atmosphere at room temperature for 2 h. The mixture was then filtered through Celite™ and concentrated to give the title compound as a TFA salt (115 mg, 0.213 mmol).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=[C:3](/[C:9](/Cl)=[N:10]\[OH:11])[CH:2]=1.CO[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C.O>ClCCl>[Cl:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][O:11][N:10]=2)=[CH:2][CH:1]=1
Reactant: O/N=C(/Cl)c1ccc(CCl)cc1
Reactant: COC=CC(=O)OC
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1conc1-c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
N-Hydroxy-4-chloromethylbenzenecarboxyimidoyl chloride (15.27 g, 74.82 mmol) was dissolved in dichloromethane (300 ml), methyl 3-methoxyacrylate (10.43 g, 89.82 mmol) was added, and triethylamine (21 ml, 151 mmol) was slowly added dropwise. The mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give the title compound (9.67 g, 51%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>[Pt].C(#N)C>[Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCc1cccnc1
Agent: [Pt]
Solvent: CC#N
Product: Nc1c(Cl)nc2ccccc2c1NCc1cccnc1
Yield: 87.8 %

Procedure:
2-Chloro-3-nitro-N-(pyridin-3-ylmethyl)quinolin-4-amine (13.0 g, 41.0 mmol), 5% platinum on carbon (1.3 g), and acetonitrile (60 mL) were added to a hydrogenation vessel and placed under hydrogen pressure (50 psi, 3.4×105 Pa) overnight. The mixture was filtered through a layer of CELITE filter agent, and the filter cake was washed with acetonitrile and methanol. The filtrate was concentrated under reduced pressure to provide 10.25 g of 2-chloro-N4-(pyridin-3-ylmethyl)quinoline-3,4-diamine, which was used without purification.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([OH:17])=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:18][C@H:19]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20]1>>[C:26]1([CH2:25][CH2:24][N:21]2[CH2:22][CH2:23][C@H:19]([NH:18][C:15]([CH:13]3[C:14]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:6][C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)=[O:17])[CH2:20]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)C1c2ccccc2Sc2ccccc21
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C1c2ccccc2Sc2ccccc21

Procedure:
9-Thioxanthenylcarboxylic acid and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-9-thioxanthenylcarboxamide.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[F:29][C:30]([F:39])([F:38])[CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([N:35]5[CH2:34][CH2:33][N:32]([CH2:31][C:30]([F:38])([F:39])[F:29])[CH2:37][CH2:36]5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: FC(F)(F)CN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(N4CCN(CC(F)(F)F)CC4)ccc2OCC3)c(F)c1
Temperature: 125 °C
Reaction time: 0.15 h
Yield: 27.9 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (20 mg, 0.1 mmol), 1-(2,2,2-Trifluoro-ethyl)-piperazine (175 mg, 1.44 mmol), X-phos (70 mg, 0.144 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 125° C. for 9 min under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 110 mg of 309. (yield=28%). 1H NMR (CDCl3, 400 MHz): δ8.08 (s, 1H), 7.57-7.51 (m, 1H), 7.16-7.06 (m, 4H), 6.52 (d, J=8.8 Hz, 1H), 4.25-4.23 (m, 2H), 3.47-3.44 (m, 4H), 3.12-3.02 (m, 4H), 2.80-2.77 (m, 4H). LC-MS (ESI): m/z=549 [M+H]+