Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.C1COCC1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[C:29]([CH3:41])=[N:28]1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:26][N:27]1[CH:31]=[C:30]([C:2]2[N:7]=[CH:6][C:5]([CH2:8][C:9]3[C:10]([CH3:20])=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=3)[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=2)[C:29]([CH3:41])=[N:28]1
Reactant: Cc1nn(C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Cc2ccc(Cl)nc2)c(C)cc1O
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: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cc2ccc(-c3cn(C)nc3C)nc2)c(C)cc1O
Temperature: 85 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of methyl 5-((6-chloropyridin-3-yl)methyl)-2-hydroxy-4-methylbenzoate (0.09 g) in a mixed solvent of THF (2.40 mL)-water (0.80 mL) were added 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.14 g), potassium carbonate (0.17 g) and tetrakis(triphenylphosphine)palladium(0) (0.03 g), and the mixture was stirred overnight at 85° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.09 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1.C(N(CC)CC)C.O>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([C:20](=[O:21])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2
Reactant: c1cc2c(cn1)NCCO2
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC(=O)N2CCOc3ccncc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 10 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (100 mg, 0.73 mmol) and (4-methoxy-phenyl)-acetyl chloride (163 mg, 0.88 mmol) were dissolved in dichloromethane. Triethylamine (0.21 ml, 1.46 mmol) was added thereto and then stirred at room temperature for 2 hours. After completion of the reaction by adding water, the reaction mixture was extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=9:1. The fractions containing the product were collected and evaporated to obtain the target compound, i.e., 1-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-2-(4-methoxy-phenyl)-ethanone, as yellow liquid (198 mg, 95%).
Reaction SMILES: N[CH:2]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]1=[O:20].C(O)(=[O:23])C.N(OC(C)(C)C)=O.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[CH2:18]([O:17][C:15]([CH2:14][N:4]1[C:5]2=[CH:13][CH:12]=[CH:11][CH2:10][CH:6]2[CH2:7][CH2:8][CH2:9][C:2](=[O:23])[C:3]1=[O:20])=[O:16])[CH3:19]
Reactant: CCOC(=O)CN1C(=O)C(N)CCCc2ccccc21
Reactant: CC(=O)O
Agent: CC(C)(C)ON=O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN1C(=O)C(=O)CCCC2CC=CC=C21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-amino-1-ethoxycarbonylmethyl-3,4,5,6-tetrahydro-1-benzazocin-2-(1H)-one (8.0 g), acetic acid (0.4 ml), and t-butyl nitrite (4.2 ml) is dissolved in chloroform (150 ml) and the solution is refluxed for 2 hours then cooled to room temperature. m-Chloroperbenzoic acid (5.7 g) is added in portions, and the resulting solution stirred at room temperature for 30 minutes. The solution is washed with saturated aqueous sodium bicarbonate (120 ml), water (75 ml), 2N hydrochloric acid (50 ml), water (50 ml), 2N hydrochloric acid (50 ml), and water (50 ml). The solution is dried over magnesium sulfate and the solvent removed under reduced pressure to give 1-ethoxycarbonylmethyl-tetrahydro-1-benzazocin-2,3(1H)-dione.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=O)=[CH:15][CH:14]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([NH:27][CH:24]([CH3:26])[CH3:25])=[O:23])=[CH:17][CH:18]=1
Reactant: CC(C)N
Reactant: CC1=C(C)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC1=C(C)C(=O)C(Cc2ccc(CCC(=O)NC(C)C)cc2)=C(C)C1=O
Yield: 63.7 %

Procedure:
3-[4-(3,5,6-trimethyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (25 mg, 0.08 mmol), isopropylamine (0.010 ml, 0.12 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28 mg, 0.12 mmol) in dry methylene chloride (1 ml) were stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and was purified by a silica gel column chromatography (methylene chloride:ethyl acetate=4:1) to obtain the title compound (18 mg, 0.051 mmol, yield 64%).
Reaction SMILES: [C:1]([C@H:5]1[O:9][C:8](=[O:10])[C@@:7]([C@@H:17]2[CH2:21]CC(=O)[CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)([CH3:4])([CH3:3])[CH3:2].F[C:24]([F:35])([F:34])[CH2:25]N(OS(=O)(=O)O)CC>C(Cl)(Cl)Cl>[C:1]([C@H:5]1[O:9][C:8](=[O:10])[C@@:7]([C@@H:17]2[CH2:21][CH2:25][C:24]([F:34])([F:35])[CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@@H]2CCC(=O)C2)O1
Reactant: CCN(CC(F)(F)F)OS(=O)(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@@H]2CCC(F)(F)C2)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2.8 g of (2R, 5R)-2-(t-butyl)-5-((1R)-3-oxocyclopentyl)-5-phenyl-1,3-dioxolan-4-one in 30 ml of chloroform, 4.89 ml of trifluorodiethylaminosulfuric acid was added under cooling with ice, followed by 20 hours' stirring at room temperature. The reaction liquid was diluted with chloroform, washed successively with water and with saturated brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified on silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to provide 2.4 g of the title compound.
Reaction SMILES: C(C1C=C(C=CC=1OC(C)C)C(O)=O)#N.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.ONC(=N)C1C=CN=CC=1C.[C:41]([C:43]1[CH:44]=[C:45]([CH:59]=[CH:60][C:61]=1[O:62][CH:63]([CH3:65])[CH3:64])[C:46]([O:48][NH:49][C:50](=[NH:58])[C:51]1[CH:56]=[CH:55][N:54]=[CH:53][C:52]=1[CH3:57])=O)#[N:42].Cl>CN(C=O)C.CCOCC>[CH:63]([O:62][C:61]1[CH:60]=[CH:59][C:45]([C:46]2[O:48][N:49]=[C:50]([C:51]3[CH:56]=[CH:55][N:54]=[CH:53][C:52]=3[CH3:57])[N:58]=2)=[CH:44][C:43]=1[C:41]#[N:42])([CH3:65])[CH3:64]
Reactant: Cc1cnccc1C(=N)NOC(=O)c1ccc(OC(C)C)c(C#N)c1
Agent: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: Cc1cnccc1C(=N)NO
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: ClCCCl
Product: Cc1cnccc1-c1noc(-c2ccc(OC(C)C)c(C#N)c2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Prepared using General Procedure 2. To a solution of 3-cyano-4-isopropoxybenzoic acid (0.122 g, 0.60 mmol) in DMF (1.5 mL) was added HOBt (0.132 g, 0.86 mmol) and EDC (0.165 g, 0.86 mmol) at room temperature. The reaction was stirred for 0.5 h until the complete formation of the HOBt-acid complex. N-hydroxy-3-methylisonicotinimidamide INT-69 (0.100 g, 0.66 mmol) was added and the mixture was stirred at room temperature for 0.5 h until formation of the intermediate N-(3-cyano-4-isopropoxybenzoyloxy)-3-methylisonicotinimidamide was observed. The reaction mixture was then heated at 80° C. for 4 h. Upon cooling, the mixture was extracted with DCM and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to produce a brown oil. The crude product recrystallized from MeOH (3 mL) and the resulting crystals were filtered and washed with cold MeOH to yield product as a white crystalline solid. To the product was added Et2O (0.5 mL) followed by 2N HCl in Et2O (0.6 mL). The mixture was stirred at room temperature for 10 minutes then dried under nitrogen and subsequently under vacuum to afford 0.087 g (45%) of 2-isopropoxy-5-(3-(3-methylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile 70 as the HCl salt. LCMS-ESI (m/z) calculated for C18H16N4O2: 320.3; found 321.1 [M+H]+, tR=8.82 min (Method 2). 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J=17.5, 2H), 8.70 (d, J=5.7, 1H), 8.44 (d, J=2.2, 1H), 8.36 (dd, J=8.9, 2.2, 1H), 7.18 (d, J=9.1, 1H), 4.83 (dt, J=12.2, 6.1, 1H), 2.95 (s, 3H), 1.49 (d, J=6.1, 6H). 13C NMR (101 MHz, DMSO) δ 173.90, 166.58, 162.81, 147.11, 142.99, 137.55, 135.01, 134.79, 134.06, 125.00, 115.42, 115.17, 115.00, 102.57, 72.66, 21.48, 18.69.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH2:3]1>Cl.CCOC(C)=O>[CH3:1][C:2]1([CH3:28])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(C)CN(CC2CCNCC2)c2cc([N+](=O)[O-])ccc21
Reaction time: 2 h

Procedure:
3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-6-nitro-2,3-dihydro-1H-indole was dissolved in HCl/EtOAc and stirred for 2 h. The mixture was concentrated in vacuo and partitioned between 1,2-dichloroethane and 1N NaOH. The organic layer was removed, washed with brine, dried (Na2SO4) and filtered. The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:25][C@@H:26]2[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[N:3]=1
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (320 mg, 0.862 mmol), tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (280 mg, 1.293 mmol) and DIPEA (0.226 mL, 1.293 mmol) in ACN (5 mL) was stirred at 85° C. overnight. UPLC indicated the presence of starting material, so the mixture was stirred at 85° C. overnight. UPLC showed about 50% conversion. Additional stirring at 85° C. for 3 d and at 100° C. overnight did not appreciably increase the conversion, so the reaction was stopped and the solvent was removed. The resulting crude material was reconstituted in MeOH/DMF (10 mL) and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (50%, 0.035% TFA). The collected fractions were combined and the ACN was removed via rotary evaporation. The resulting aqueous solution was neutralized with saturated aqueous NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to give the title compound (51 mg, 11%). [M+H] calc'd for C26H32ClFN4O6, 552. found, 552.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCC(P(C2C=CC=CC=2)C2C=CC=CC=2)C)C=CC=CC=1.C([N:34]1[CH2:38][CH2:37][C@@H:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][S:46]([C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:58])([F:57])[F:56])[CH:50]=3)(=[O:48])=[O:47])=[CH:41][CH:40]=2)[CH2:35]1)C=C.SC1C=CC=CC=1C(O)=O>O1CCCC1>[NH:34]1[CH2:38][CH2:37][C@@H:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][S:46]([C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:58])([F:56])[F:57])[CH:50]=3)(=[O:48])=[O:47])=[CH:41][CH:40]=2)[CH2:35]1
Reactant: C=CCN1CC[C@@H](c2ccc(NS(=O)(=O)c3cccc(C(F)(F)F)c3)cc2)C1
Agent: CC(CCP(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Agent: O=C(O)c1ccccc1S
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc([C@@H]2CCNC2)cc1)c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 3.5 %

Procedure:
0.071 g of tris-(dibenzylidenaceton)-dipalladium(0) (0.08 mmol) and 0.033 g of 1,3-bis-(diphenylphosphino)-butane (0.08 mmol) were dissolved in 20 ml tetrahydrofurane and stirred for 30 min. 0.32 g of N-[4-((S)-1-allyl-pyrrolidin-3-yl)-phenyl]-3-trifluoromethyl-benzenesulfonamide (0.78 mmol), dissolved in 5 ml tetrahydrofurane, were added to the solution, followed by 0.129 g 2-mercaptobenzoic acid (0.84 mmol). The reaction mixture was stirred at room temperature for 72 h, the solvent was evaporated, and dichloromethane and 1 N aqueous hydrochloric acid were added. The aqueous phase was adjusted to basic pH, extracted with dichlormethane and the combined organic layers were washed with aqueous sodium chloride solution, dried over sodium sulphate, filtered and evaporated to dryness under reduced pressure. The crude product was purified via silica gel chromatography using a ISCO companion instrument to yield 0.01 g of product.
Reaction SMILES: [O:1]=[S:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[NH:14][C:15](=O)[C:16]3[S:21][C:20]([CH3:22])=[CH:19][C:17]=3[N:18]=2)[CH2:4][CH2:3]1.[CH2:24]([NH2:28])[CH2:25][CH2:26][NH2:27]>>[CH3:22][C:20]1[S:21][C:16]2[C:15]([NH:27][CH2:26][CH2:25][CH2:24][NH2:28])=[N:14][C:13]([N:5]3[CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[S:2](=[O:1])[CH2:3][CH2:4]3)=[N:18][C:17]=2[CH:19]=1
Reactant: NCCCN
Reactant: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2s1
Product: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)nc(NCCCN)c2s1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 3 by using 2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylthieno[3,2-d]pyrimidin-4(3H)-one and 1,3-propandiamine. MS obsd. (ESI+) [(M+H)+] 402, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.78 (d, J=6.6 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.34-7.44 (m, 2H), 6.80 (s, 1H), 5.29 (m, 2H), 3.69-3.83 (m, 2H), 3.27-3.42 (m, 2H), 2.97 (t, J=6.3 Hz, 2H), 2.49-2.58 (m, 5H), 1.87 (m, 2H).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[C:7]([NH:11]N)([CH3:10])([CH3:9])[CH3:8]>C(O)CCCC.C(OC(C)C)(C)C>[NH2:5][C:4]1[N:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:1]=[C:2]([CH3:6])[CH:3]=1
Reactant: CC(C)(C)NN
Reactant: C/C(N)=C/C#N
Solvent: CCCCCO
Solvent: CC(C)OC(C)C
Product: Cc1cc(N)n(C(C)(C)C)n1
Yield: 58.7 %

Procedure:
To a solution of 16.4 g (0.2 mol) of 3-aminocrotononitrile in 100 cm3 of n-pentanol were added 19.4 g (0.22 mol) of tert-butylhydrazine. This solution was heated at reflux for 20 hours. The n-pentanol was subsequently distilled off under reduced pressure. A pale yellow solid was obtained, which was taken up in 100 cm3 of isopropyl ether at room temperature and filtered on a sinter funnel. After drying under vacuum at 40° C., 18 g of the expected product were obtained in the form of a pale yellow solid, the melting point of which was from 172 to 175° C.
Reaction SMILES: OCC(N[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][C:16]2[CH:17]=[C:18]([C@H:23]3[C@H:28]([OH:29])[C@@H:27]([OH:30])[C@H:26]([OH:31])[C@@H:25]([S:32][CH3:33])[O:24]3)[CH:19]=[CH:20][C:21]=2[CH3:22])=[CH:13][CH:12]=1)(C)C.[NH2:36][C:37]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O)=O>>[CH3:22][C:21]1[CH:20]=[CH:19][C:18]([C@H:23]2[C@H:28]([OH:29])[C@@H:27]([OH:30])[C@H:26]([OH:31])[C@@H:25]([S:32][CH3:33])[O:24]2)=[CH:17][C:16]=1[CH2:15][C:14]1[CH:34]=[CH:35][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][NH:36][C:37]2([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:12][CH:13]=1
Reactant: NC(=O)C1(N)CCCC1
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCNC(C)(C)CO)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: O=CO
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCNC4(C(N)=O)CCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The same procedure was employed as for amine 24, using 1-aminocyclopentanecarboxamide, to provide the product 26 with 0.5 equivalents of formic acid. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.52 (s, 0.5 H, formate), 6.98-7.22 (m, 7 H), 4.39 (d, J=9.6 Hz, 1 H), 4.13 (d, J=9.3 Hz, 1 H), 3.91-4.01 (m, 2 H), 3.34-3.51 (m, 3 H), 2.50-2.68 (m, 4 H), 2.21 (s, 3 H), 2.14 (s, 3 H), 2.10 (d, J=7.3 Hz, 2 H), 1.73-1.87 (m, 6 H), 1.63-1.72 (m, 2 H), 1.58 (d, J=7.1 Hz, 2 H). MS (ES+) [M+H]+=543.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13]>C(N(CC)CC)C.C(#N)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.[Cu](I)I>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)Oc1ccc(I)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(OC(F)F)cc1
Yield: 95.7 %

Procedure:
A solution of 1-(difluoromethoxy)-4-iodobenzene (12.7 g, 50 mmol) in triethylamine (175 mL) was treated with tetrakis(triphenylphosphine)palladium (4.0 g, 3.5 mmol), copper iodide (925 mg, 4.85 mmol), and a solution of ethynyl(trimethyl)silane (6.9 mL, 50 mmol) in acetonitrile at room temperature, stirred for 1 h at 60° C. and concentrated in vacuo. The resultant residue was dissolved in Et2O, filtered and the filtrated was concentrated in vacuo. This residue was purified by chromatography (silica gel, EtOAc/hexane: 5/95) to give {[4-(difluoromethoxy)-phenyl]ethynyl}(trimethyl)silane (11.5 g, 96%) as an oil.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[C:12](O)(=[O:22])[C:13]1[CH:21]=[CH:20][C:19]2[O:18][CH2:17][O:16][C:15]=2[CH:14]=1.N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:12]([C:13]3[CH:21]=[CH:20][C:19]4[O:18][CH2:17][O:16][C:15]=4[CH:14]=3)=[O:22])[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2c(c1)OCO2

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and piperonylic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.86-2.63 (m, 7H), 3.46-3.86 (m, 6H), 4.35 (s, 1H), 6.02-6.05 (m, 2H), 6.90 (d, J=8 Hz, 1H), 7.32 (d, J=2 Hz, 1H), 7.44 (dd, J=8, 2 Hz, 1H); MS (APCI/NH3) m/z 301 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:17]([OH:19])=O)=[CH:11][NH:12][C:13]2=[O:16])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:32][CH2:33][C@@H:34]([OH:51])[CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([O:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([Cl:50])[CH:44]=2)[CH2:38][CH2:37]1.O>CN(C)C=O>[Cl:50][C:45]1[CH:44]=[C:43]([CH:48]=[CH:47][C:46]=1[Cl:49])[O:42][CH:39]1[CH2:38][CH2:37][N:36]([CH2:35][C@H:34]([OH:51])[CH2:33][NH:32][C:17]([C:10]2[C:9]3[C:14](=[CH:15][C:6]([S:3]([NH:2][CH3:1])(=[O:4])=[O:5])=[CH:7][CH:8]=3)[C:13](=[O:16])[NH:12][CH:11]=2)=[O:19])[CH2:41][CH2:40]1
Reactant: CNS(=O)(=O)c1ccc2c(C(=O)O)c[nH]c(=O)c2c1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CNS(=O)(=O)c1ccc2c(C(=O)NC[C@@H](O)CN3CCC(Oc4ccc(Cl)c(Cl)c4)CC3)c[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.9 %

Procedure:
7-[(Methylamino)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (0.1 g) in dimethyl formamide (7 ml) was treated with N,N-carbonyldiimidazole (0.06 g) and the mixture was heated at 55° C. for 45 min. (2R)-1-Amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.11 g) in dimethyl formamide (1 ml) was added and the mixture was stirred at ambient temperature for 18 h. 1 Drop of water was added and the solvent was evaporated. Purification using revere phase HPLC (Symmetry C8 column) and acetonitrile/aqueous ammonium acetate as eluent yielded the title compound as a white solid (0.03 g).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=O)=[CH:7][C:6]=1[C:15]1[CH:23]=[C:22]2[C:18]([C:19]3([CH2:28][CH2:27][CH2:26][CH2:25]3)[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1>C(O)C>[CH3:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([NH:2][NH2:3])=[O:11])=[CH:7][C:6]=1[C:15]1[CH:23]=[C:22]2[C:18]([C:19]3([CH2:28][CH2:27][CH2:26][CH2:25]3)[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(c2)NC(=O)C32CCCC2)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)NN)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Temperature: 80 °C
Reaction time: 72 h
Yield: 36.7 %

Procedure:
Hydrazine monohydrate (0.67 mL, 13.8 mmol) was added to a stirred solution of methyl 4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzoate (preparation 53a, 0.46 g, 1.3 mmol) in ethanol (6 mL) and the mixture was stirred at 80° C. After 3 days, the mixture was cooled and concentrated in vacuo. The crude material was purified by flash chromatography (50:1 dichloromethane/methanol) to give the title compound (0.16 g, 19%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9](O)[CH3:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH2:10])=[CH:7][N:8]=1
Reactant: COc1ccc(C(C)O)cn1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=Cc1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.2 %

Procedure:
To a solution of 1-(6-methoxy-pyridin-3-yl)-ethanol (14.3 g, 93.5 mmol) in anhydrous THF was added triethylamine (32.3 mL), followed by MsCl (8.6 mL, 112 mmol). The resulting mixture was stirred at room temperature for 15 hours before it was filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography to afford the desired product (4.7 g, 37% yield). 1H NMR (300 MHz, CDCl3): δ 3.94 (s, 3 H), 5.20-5.23 (m, 1H), 5.61-5.67 (m, 1 H), 6.60-6.78 (m, 2 H), 7.67-7.72 (m, 1 H), 8.12 (s, 1 H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:17][C:16]3[NH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:20][CH2:21][CH3:22]>CN(C)C=O>[C:3]1([CH:9]2[CH2:17][C:16]3[N:15]([CH2:20][CH2:21][CH3:22])[CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CC(c2ccccc2)Cc2[nH]ccc21
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1ccc2c1CC(c1ccccc1)CC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a suspension of 60% sodium hydride (0.18 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.8 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of 1-bromopropane (0.51 g) in dimethylformamide (3 ml), and the mixture was stirred at the same temperature for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give 6-phenyl-1-propyl-4,5,6,7-tetrahydroindol-4-one (0.92 g) as oil.