Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1.CCN(C(C)C)C(C)C.[O:31]1[CH2:35][C@@H:34]([NH2:36])[C@@H:33]([NH2:37])[CH2:32]1>CN(C=O)C.CO>[NH2:36][C@H:34]1[CH2:35][O:31][CH2:32][C@H:33]1[NH:37][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(C)c1
Reactant: N[C@@H]1COC[C@@H]1N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(C#N)cc(N[C@@H]2COC[C@@H]2N)nc1Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a solution of methyl 6-chloro-4-cyano-2-(m-tolylamino)nicotinate (40 mg, 0.133 mmol) in DMF (1 mL) was added DIPEA (0.046 mL, 0.265 mmol) and (3R,4S)-tetrahydrofuran-3,4-diamine (13.54 mg, 0.133 mmol). The mixture was stirred at RT overnight. Additional amine was added and the reaction mixture was stirred at RT for an additional day. The reaction mixture was diluted in MeOH (10 mL) and purified by reverse phase preparative HPLC. The fractions were collected and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3 and washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to yield the title compound (35.5 mg, 73%). [M+H] calc'd for C19H21N5O3, 368. found, 368.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)O1.Br[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([F:30])[C:26]=1[CH:27]([OH:29])[CH3:28]>>[F:30][C:25]1[C:26]([CH:27]([OH:29])[CH3:28])=[C:21]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)[CH:22]=[N:23][CH:24]=1
Reactant: CC(O)c1c(F)cncc1Br
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
Product: CC(O)c1c(F)cncc1-c1ccc2c(c1)COC2=O

Procedure:
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-isobenzofuran-1-one and 1-(3-bromo-5-fluoro-pyridin-4-yl)-ethanol were reacted according to the procedure described in Example 35.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[S:22]([O-:26])([OH:25])(=[O:24])=[O:23].[K+].CC(C)=O>O>[CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[OH:25][S:22]([OH:26])(=[O:24])=[O:23]
Reactant: O=S(=O)([O-])O
Agent: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)(O)O
Reaction time: 0.25 h

Procedure:
To a stirred suspension of clopidogrel base (38.31 g, 0.119 mole) in water (30 mL), was added potassium hydrogen sulfate (32.3 g, 0.237 mole) at 25-30° C. The reaction mixture was stirred for 15 minutes and acetone (250 mL) was added, stirred further for 30 minutes and filtered. Insoluble solid was filtered. The filtrate was distilled at 50-55° C. under reduced pressure (5-10 mm). Dichloromethane (380 mL) was added and distilled at 50-55° C. This operation was repeated twice by adding dichloromethane (350 mL), and finally traces of water was removed under reduce pressure (5-10 mm) to give amorphous clopidogrel hydrogen sulfate (46 g). The amorphous form was similarly characterized by XRD, DSC, IR, chemical purity (HPLC)>99% and chiral purity (chiral HPLC) 99.8% (e.e.), % water 1.91, m.p. 132-135° C. (softens).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9]O)[CH3:2].P(Br)(Br)[Br:12].[OH-].[K+]>CCOCC>[Br:12][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1ccccc1CO
Reactant: BrP(Br)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CCc1ccccc1CBr
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 241.8 %

Procedure:
To a solution of (2-ethyl-phenyl)-methanol (3 g, 22 mmol) in ether (10 mL) at 0° C. was added a solution of PBr3 (2.18 g, 8.1 mmol) in ether (3 mL). The reaction mixture was warmed to r.t for 45 minutes and cooled to 0° C. The reaction mixture was treated with 50% aqueous KOH (15 mL) and separated. The organic layer was dried with KOH pellets and concentrated to give 3.9 g of 1-bromomethyl-2-ethyl-benzene.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:49])[C@@H:8]([NH:16][C:17](=[O:48])[CH2:18][CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([C:29](=[O:47])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](=[O:46])[NH:38][O:39]C2CCCCO2)=[CH:23]3)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O.C(Cl)Cl.CO>[CH:1]1([O:6][C:7](=[O:49])[C@@H:8]([NH:16][C:17](=[O:48])[CH2:18][CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([C:29](=[O:47])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](=[O:46])[NH:38][OH:39])=[CH:23]3)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCCCNC(=O)c1cc2cc(CCC(=O)N[C@@H](Cc3ccccc3)C(=O)OC3CCCC3)ccc2[nH]1)NOC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C(CCCCCCNC(=O)c1cc2cc(CCC(=O)N[C@@H](Cc3ccccc3)C(=O)OC3CCCC3)ccc2[nH]1)NO
Reaction time: 0.5 h
Yield: 11 %

Procedure:
(S)-3-Phenyl-2-(3-{2-[6-(tetrahydro-pyran-2-yloxycarbamoyl)-hexyl-carbamoyl]-1H-indol-5-yl}-propionylamino)-propionic acid cyclopentyl ester (200 mg. 0.297 mmol) was stirred at room temperature for 3.5 h in TFA/DCM/MeOH (1.5 ml/15 ml/15 ml). Further TFA (0.3 ml) was added and the reaction stirred for a further 30 minutes. The solution was concentrated in vacuo, resuspended in DCM and the solvent removed (×3). The crude material was purified by prep HPLC to give pure compound (100) (19.3 mg), LCMS purity 100%, m/z 591 [M++H]+, 1H NMR (400 MHz, MeOD), δ: 1.27-1.70 (16 H, m, alkyl), 1.97 (2H, t, CH2), 2.40 (2H, t, J=7.84 Hz, CH2), 2.76-2.85 (4H, m, 2×CH2), 3.25 (2H, t, J=7 Hz, CH2), 4.41 (1H, m, NHCHCO, 4.95 (1H, m, CH), 6.85 (1 H, s, CH), 6.95 (3H, m, Ar), 7.05 (3H, m, Ar), 7.20-7.26 (2H, s+d, J=8.5 Hz, Ar)
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:19][CH3:20])[C:4]2[C:9]([C:10](=[O:17])[C:11]=1[C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)=[CH:8][CH:7]=[C:6](I)[CH:5]=2.[OH:21][C@@:22]([CH3:28])([CH2:25][O:26][CH3:27])[C:23]#[CH:24]>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Cu](I)I>[NH2:1][C:2]1[N:3]([CH2:19][CH3:20])[C:4]2[C:9]([C:10](=[O:17])[C:11]=1[C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)=[CH:8][CH:7]=[C:6]([C:24]#[C:23][C@:22]([OH:21])([CH3:28])[CH2:25][O:26][CH3:27])[CH:5]=2
Reactant: C#C[C@@](C)(O)COC
Reactant: CCn1c(N)c(-c2ncc[nH]2)c(=O)c2ccc(I)cc21
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: [Fe+2]
Solvent: CN(C)C=O
Product: CCn1c(N)c(-c2ncc[nH]2)c(=O)c2ccc(C#C[C@@](C)(O)COC)cc21
Temperature: 80 °C
Reaction time: 6 h

Procedure:
0.43 mg (1.15 mmol) of 2-amino-1-ethyl-3-(1H-imidazol-2-yl)-7-iodo-1H-quinolin-4-one, 0.262 (23 mmol) of (R)-3-hydroxy-4-methoxy-3-methyl-but-1-yne, and 0.397 g (3.45 mmol) were mixed in 15 ml of DMF. Argon was flushed through this solution for 10 minutes. After addition of 0.126 mg (0.17 mmol) of 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride and 0.033 mg (0.17 mmol) of copper iodide, the reaction mixture was stirred at 80° C. during 6 hours. The reaction mixture was then evaporated to dryness and the residue poured into a mixture of DCM and water. A black insoluble solid was filtered off (100 mg). The aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over MgSO4 and the solvents were evaporated off under reduced pressure. The residue was then purified by column chromatography (DCM/MeOH/NH4OH aq: 9/1/0.1) to yield 0.80 g (1.2 mmol) of yellow solid. This solid was recrystallized in dichloromethane to yield 0.02 g of a beige solid.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[CH:24]=[C:23]([CH3:35])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:34][C:29]1[CH:28]=[C:27]([C:25]2[CH:24]=[C:23]([CH3:35])[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[N:26]=2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 34 %

Procedure:
To a cooled and stirred solution of 3′-[4-(3,4-dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.54 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (diethyl ether) yielded the title compound as a white solid (0.16, 34%). MS (ISP) 470.1 [(M+H)+]; mp 206.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:19])[CH2:14][CH2:15][C:16](=[N:17][NH2:18])[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].C(Cl)(Cl)Cl.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:19])[CH2:14][CH2:15][C:16](=[N:17][NH:18][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2=NN
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2=NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a solution of 2.0 g. (7.57 millimoles) of ethyl-9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate and 20 ml. of anhydrous chlorform 1.6 ml. (11.35 millimoles) of triethylamine and 1.3 ml. (11.35 millimoles) of benzoyl chloride are added. The mixture is heated to boiling for 2 hours, whereupon it is cooled to room temperature and thoroughly admixed with 20 ml. of water. The organic phase is separated and the aqueous layer is extracted with 10 ml. of chloroform. The united organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is recrystallized from methanol. Thus 1.5 g. (53.8%) of ethyl-9-(benzoyl-hydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate are obtained. Mp.: 209°-210° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O1CCN(C2C=CC(C=O)=CC=2)CC1.S1C=CC=C1[Mg]Br.[CH3:41][O:42][C:43]([O:47][Si](C)(C)C)=[C:44]([CH3:46])[CH3:45]>[Ti](Cl)(Cl)(Cl)Cl>[CH3:45][C:44]([CH3:46])([CH:13]([C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:8][CH:9]=1)[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[C:43]([O:42][CH3:41])=[O:47]
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: OC(c1ccc(N2CCOCC2)cc1)c1cccs1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Br[Mg]c1cccs1
Agent: O=Cc1ccc(N2CCOCC2)cc1
Product: COC(=O)C(C)(C)C(c1ccc(N2CCOCC2)cc1)c1cccs1
Yield: 82.3 %

Procedure:
In a similar manner to Preparation 1, Step 2, the reaction of (4-morpholinophenyl)-(thiophen-2-yl)methanol (675 mg, 2.45 mmol), prepared from 4-morpholinobenzaldehyde and thiophen-2-ylmagnesium bromide, and (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (2.48 ml, 12.3 mmol) in the presence of titanium tetrachloride (1M in DCM, 5.40 ml. 5.40 mmol) afforded methyl 2,2-dimethyl-3-(4-morpholinophenyl)-3-(thiophen-2-yl)propanoate (725 mg, 82.5% yield).). 1H NMR (400 MHz, CDCl3): δ 1.15 (s, 3H), 1.20 (s, 3H), 3.06 (m, 4H), 3.51 (s, 3H), 3.78 (m, 4H), 4.59 (s, 1H), 6.76 (d, 1H, J=8.5 Hz), 6.83 (m, 1H), 6.87 (m, 1H), 7.06 (m, 1H), 7.20 (d, 1H, J=8.5 Hz). HPLC Rt: 3.181 min.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][CH:7]=[C:8]([N+:17]([O-])=O)[C:9]=2[N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([C:4]2[C:9]([N:10]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]3)=[C:8]([NH2:17])[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CN1CCN(c2c(C3CC3)cncc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2c(N)cncc2C2CC2)CC1

Procedure:
To a solution of 1-(3-cyclopropyl-5-nitro-4-pyridyl)-4-methyl-piperazine (220.4 mg, 0.8403 mmol) in methanol (25 mL) was added Pd on carbon (10%, Degussa, 6.387 mg, 0.006002 mmol). The reaction mixture was stirred at room temperature under a balloon of hydrogen, for 7 h. The reaction was filtered through a plug of Celite, washed with MeOH and the filtrate was concentrated in vacuo yielding 5-cyclopropyl-4-(4-methylpiperazin-1-yl)pyridin-3-amine as an orange residue. (194 mg, 99%).
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].N1CCCC1.[CH3:16][C:17]([CH3:19])=[O:18]>>[CH3:16][C:17]1([CH3:19])[CH2:2][C:3](=[O:4])[C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:18]1
Reactant: O=C(CO)c1ccccc1
Reactant: CC(C)=O
Solvent: C1CCNC1
Product: CC1(C)CC(=O)c2ccccc2O1

Procedure:
The reaction of 2-hydroxyacetophenone with acetone in the presence of pyrrolidine analogously to Synthesis 886, 1978 gives 2,2-dimethyl-4-chromanone of melting point 80°-85° C. 2,2-Dimethyl-4-hydroxy-chroman (oil) is obtained from 2,2-dimethyl-4-chromanone by reduction using sodium borohydride in ethanol.
Reaction SMILES: [C:1]([S@:5]([N:7]=[C:8]([C:10]1[N:15]=[C:14]2[C:16]([Cl:24])=[CH:17][N:18](C(OCC)=O)[C:13]2=[CH:12][CH:11]=1)[CH3:9])=[O:6])([CH3:4])([CH3:3])[CH3:2].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[Cl:24][C:16]1[C:14]2=[N:15][C:10]([C@@H:8]([NH:7][S@@:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[O:6])[CH3:9])=[CH:11][CH:12]=[C:13]2[NH:18][CH:17]=1
Reactant: CCOC(=O)n1cc(Cl)c2nc(C(C)=N[S@](=O)C(C)(C)C)ccc21
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](N[S@](=O)C(C)(C)C)c1ccc2[nH]cc(Cl)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.7 %

Procedure:
To (R)-ethyl 5-(1-((tert-butylsulfinyl)imino)ethyl)-3-chloro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (2.06 g, 5.569 mmol) in anhydrous THF (36.2 mL) at 0° C. was added dropwise L-selectride (1.0 mol/L) in THF (8.4 mL). The resultant orange reaction mixture was then warmed to RT and stirred at this temperature under N2 for 16 h. Volatile solvent was removed under reduced pressure, and the crude residue was diluted with EtOAc. The EtOAc layer was washed with sat'd. aq. NaHCO3, water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 chromatography eluting with MeOH/EtOAc+1% TEA. Trituration with DCM afforded 1.08 g (65.03%) of (R)—N—((S)-1-(3-chloro-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)-2-methylpropane-2-sulfinamide as pale yellow solid (100% ee). 1H NMR (400 MHz, DMSO) δ 11.52 (s, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.29 (d, J=8.5 Hz, 1H), 5.43 (d, J=5.4 Hz, 1H), 4.62-4.51 (m, 1H), 1.53 (d, J=6.8 Hz, 3H), 1.11 (s, 9H); MS (ESI) m/z: 300.0 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[CH:16][C:17](OCC)=[O:18])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.C(O)(C)C.O>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[CH:16][CH2:17][OH:18])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(=CCO)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A reaction flask was charged with 3-ethoxycarbonylmethylene-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester (2.70 g, 9.1 mmol) in dry THF (15 mL) under Argon. The solution was cooled to −78° and DIBAL-H (1.5 M in toluene, 13.7 mL, 20.5 mmol) was added dropwise over 20 min. The reaction was stirred at −78° for 1 h then the temperature was raised to rt. The reaction mixture was added i-propanol (5 mL) and stirred at rt for 5 min followed by addition of water (10 mL). DCM was added and the suspension was stirred at rt for 15 min. The suspension was filtered and the collected organic phase was dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 1:1; EtOAc) to give the title compound (1.908 g, 82%). 1H NMR (CDCl3) δ 5.57-5.51 (m, 1H), 4.24-4.17 (m, 2H), 4.36-4.06 (m, 2H), 2.54-2.46 (m, 1H), 2.40-2.34 (m, 1H), 2.24-2.18 (m, 1H), 2.01-1.96 (m, 1H), 1.90-1.78 (m, 3H), 1.60-1.46 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [C:1]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:2][NH:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl.ClCCl>[C:14]([O:13][C:1]([CH2:2][N:3]([CH2:4][C:5]([O:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[O:6])[C:18]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:24])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CNCC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)CCC(=O)O
Reaction time: 48 h
Yield: 72.6 %

Procedure:
Compound 14 (0.88 g, 3.59 mmol), succinic anhydride (0.377 g, 3.77 mmol), ethyldiisopropylamine (625 μL, 3.59 mmol) and 4-di(methylamino)pyridine (44 mg, 0.359 mmol) were dissolved in CHCl3 (15 mL) and stirred for 48 h. The mixture was diluted with dichloromethane (140 mL) and the organic layer was washed with H2O (2×75 mL) and saturated aqueous NaCl, dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (80% EtOAc in hexanes) to give the compound 15 (0.9 g, 72.6%). 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 1.47 (s, 9H), 2.62 (t, J=5.8, 2H), 2.69 (t, J=5.8, 2H), 4.02 (s, 2H), 4.06 (s, 2H). ESI-MS calculated for C16H27NO7, 345.59 found 368.1 (M+Na).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[CH2:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.C1C[O:31]CC1>O.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][OH:31])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2cc(CCO)ccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76 %

Procedure:
To a solution of 5-vinyl-indole-1-carboxylic acid tert-butyl ester (4.5 g, 18.5 mmol, 1.0 eq.) in THF (46 mL) at 0° C. was added 9-BBN (0.5 M in THF, 87 mL, 2.4 eq.) over 10 min. The resulting reaction mixture was stirred for 2.5 h and diluted with THF (150 mL) and water (150 mL) while keeping the temperature at 0° C. Then NaBO3.4H2O (44 g) was introduced and resulting reaction mixture was stirred and warmed to room temperature and stirred. The reaction mixture was diluted with methylene chloride (100 mL) and the separated aqueous layer was extracted 3×100 mL methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (methylene chloride to 5% acetone/methylene chloride) to give 5-(2-hydroxy-ethyl)-indole-1-carboxylic acid tert-butyl ester (3.82 g, 76%) or similarly 6-(2-hydroxy-ethyl)-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:17]=O)=[C:12]3[C:16]=2[S:15][CH:14]=[CH:13]3)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].N1C=CC=CC=1>CO.CCOCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:17]=[N:20][OH:21])=[C:12]3[C:16]=2[S:15][CH:14]=[CH:13]3)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2ccc(O)cc2)c2sccc12
Reactant: NO
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CO
Product: ON=Cc1ccc(-c2ccc(O)cc2)c2sccc12
Yield: 77.4 %

Procedure:
To a 10 ml round bottom flask was added 7-(4-hydroxyphenyl)-1-benzothiophene-4-carbaldehyde (61.7 mg, 0.24 mmol), hydroxylamine hydrochloride (34 mg, 0.49 mmol), and anhydrous pyridine (0.04 ml, 0.49 mmol) in MeOH (1.5 ml) was heated to reflux for 1 h and then allowed to cool. The mixture was then diluted with ether, washed with water and the organic layer was dried over anhydrous Na2SO4 then passed through a silica plug. Concentration under reduced pressure produced 60 mg of a slightly yellow solid and purification by column chromatography (40% EtOAc-hexanes) afforded 50 mg (92%) product as a slightly yellow solid: mp 230–231° C.; 1H NMR (300 MHz, DMSO-d6): δ 6.93 (2H, d, J=8.55 Hz), 7.38 (1H, d, J=7.63), 7.57 (2H, d, J=8.53 Hz), 7.68 (1H, d, J=7.71 Hz), 7.91 (1H, d, J=5.61 Hz), 8.12 (1H, d, J=5.64 Hz), 8.57 (1H, s), 9.77 (1H, s), 11.41 (1H, s); MS (ESI) m/z 270 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:18])[NH:10][CH:11]([C:15]([OH:17])=O)[NH:12]2)=[CH:7][CH:6]=1)=[O:4].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:48][CH:49]1[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]1>O.CN(C=O)C>[C:58]([O:57][C:55]([N:52]1[CH2:53][CH2:54][CH:49]([NH:48][C:15]([CH:11]2[NH:10][C:9](=[O:18])[C:8]3[C:13](=[CH:14][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[NH:12]2)=[O:17])[CH2:50][CH2:51]1)=[O:56])([CH3:61])([CH3:59])[CH3:60]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)c1ccc2c(c1)NC(C(=O)O)NC2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc2c(c1)NC(C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1)NC2=O
Reaction time: 0.25 h
Yield: 23.1 %

Procedure:
A mixture of 7-(methoxycarbonyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-2-carboxylic acid (0.15 g, 0.6 mmol), DMF (8 mL), N-methylmorpholine (66 μL, 0.6 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.23 g, 1.2 mmol) and 1-hydroxybenzotriazole (81 mg, 0.6 mmol) was stirred for 15 min and 4-amino-1-Boc-piperidine (144 mg, 0.72 mmol) was added. The reaction mixture was stirred at rt for 1 d. Water was added and the mixture was extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 100% EtOAc/DCM) to afford to afford methyl 2-({[1-(tert-butoxycarbonyl)piperidin-4-yl]amino}carbonyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (60 mg, 20%). LC-MS: (FA) ES+ 333.