Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])=O.[Na+].[Br:6]Br.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]=1[NH2:19]>CC(O)=O>[Br:6][C:14]1[CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]([NH2:19])=[C:10]([O:9][CH3:8])[CH:15]=1
Reactant: COc1cccc([N+](=O)[O-])c1N
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(Br)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
NaOAc (17.6 g) and Br2 (6.76 mL) was added to a solution of 2-methoxy-6-nitrobenzenamine (21.74 g) in HOAc (250 mL). The mixture was stirred at room temperature for 20 min. The resulting precipitate was filtered, washed with water and dried in-vacuo to afford the desired product as a yellow solid (26.43 g, 83%). 1H NMR (300 MHz, DMSO-d6) δ 3.91 (s, 3H), 7.18 (d, 1H, J=1.8 Hz), 7.70 (d, 1H, J=1.8 Hz); LC-MS: m/e=247 [M+1]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][CH:7]1[NH:12][C:11](=O)[CH2:10][NH:9][C:8]1=O.C1COCC1.CSC>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][CH:7]1[CH2:8][NH:9][CH2:10][CH2:11][NH:12]1
Reactant: COc1cccc(CC2NC(=O)CNC2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CSC
Solvent: C1CCOC1
Product: COc1cccc(CC2CNCCN2)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 85.9 %

Procedure:
To a 100-mL round-bottomed flask was added 3-(3-methoxybenzyl)-2,5-piperazinedione (201 mg, 0.858 mmol), 5 mL of THF and BH3.DMS (0.326 mL, 3.43 mmol, Aldrich, St. Louis, Mo.). The reaction mixture was stirred at 70° C. for 18 h and then diluted with 1N NaOH (12 mL) and extracted with CH2Cl2 (2×50 mL). The organic extracts were washed with saturated aqueous NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude 2-(3-methoxybenzyl)piperazine (152 mg) as a colorless tar.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:12][CH:11]=1>CN(C=O)C>[CH3:23][O:22][N:20]([CH3:21])[C:18]([CH:17]1[CH2:4][CH:16]1[C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1)=[O:19]
Reactant: C[S+](C)(C)=O
Reactant: CON(C)C(=O)C=Cc1ccc(F)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
NaH (8 g, 60% oil dispersion) was added to a suspension of trimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 0.5 h. A solution of 3-(4-fluoro-phenyl)-N-methoxy-N-methyl-acrylamide (20.4 g) was added to the above reaction mixture at 0° C., and the resulting reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography over silica gel (elution with 50% hexanes in ethyl acetate) to give the title compound (15 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:8]([CH2:19][N:20]1C(=O)C3C(=CC=CC=3)C1=O)=[CH:7]2.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH:77]1[CH2:82][CH2:81][O:80][CH2:79][CH2:78]1.NN>O1CCOCC1.CCO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:18][C:14]1[CH:13]=[C:12]([C:9]2[C:8]([CH2:19][NH2:20])=[CH:7][C:2]3[C:11](=[C:6]([N:77]4[CH2:82][CH2:81][O:80][CH2:79][CH2:78]4)[CH:5]=[CH:4][CH:3]=3)[N:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: C1COCCN1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc2cccc(Br)c2nc1-c1cccc(F)c1
Agent: [Pd]
Agent: NN
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCO
Solvent: C1COCCO1
Product: NCc1cc2cccc(N3CCOCC3)c2nc1-c1cccc(F)c1
Temperature: 120 °C

Procedure:
A mixture of 2-((8-bromo-2-(3-fluorophenyl)quinolin-3-yl)methyl)isoindoline-1,3-dione (100 mg, 0.22 mmol), racemic BINAP (16.2 mg, 0.12 eq), Pd2(dba)3 (10 mg, 0.05 eq), NaOBut (29.2 mg, 1.4 eq) and morpholine (38 mg, 2 eq) in dioxane (2 mL) was heated to 120° C. under N2 for 8 h. LCMS showed a mixture of starting material and product. To the reaction was added the reactants again. The reaction was further heated for 2 h before partitioned between water and EtOAc. The water layer was extracted once with EtOAc and acidified to pH 2 by 3 N HCl and extracted with DCM (5 mL×3). Removal of solvent gave a foam, which was treated with NH2NH2 (0.5 mL) in EtOH (2 mL) at reflux. Solvents were removed and the residue was worked up and purified by CombiFlash® (DCM/MeOH/Et3N, 20/1/0.1). A white solid was obtained as (2-(3-fluorophenyl)-8-morpholinoquinolin-3-yl)-methanamine. N-((2-(3-fluorophenyl)-8-morpholinoquinolin-3-yl)methyl)-9H-purin-6-amine was prepared according to Procedures H. 1H-NMR (400 Hz, CD3OD) δ 8.77 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.25 (d, J=8.0 Hz, 2H), 7.85 (t, J=8.0 Hz, 1H), 7.61-7.54 (m, 3H), 7.24 (t, J=8.0 Hz, 1H), 5.24 (s, 2H), 4.20 (s, 4H), 4.02 (s, 4H). Mass Spectrum (ESI) m/e=456 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1[CH3:8].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:5][C:6]=1[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(F)cc(S(N)(=O)=O)cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: NS(=O)(=O)c1cc(F)c(CBr)c(F)c1
Yield: 30.5 %

Procedure:
A mixture of 3,5-difluoro-4-methylbenzenesulfonamide (1.237 g, 6 mmol), N-bromosuccinimide (1.4 g, 1.3 eq) and benzoyl peroxide (87 mg, 0.1 eq) in carbon tetrachloride (24 mL) was heated to reflux for 6 h under a halogen light. After the reaction was determined to be complete by GC-MS, the mixture was concentrated and purified by column chromatography (silica, EtOAc-hexane, 1:4 to 4:1) to give the title compound (524 mg). 1H NMR (400 MHz, CD3OD) δ 7.75 (d, 2H), 4.83 (s, 3H); GC-MS (ES) m/z 285 (M+), 287 (M+2).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([CH2:17][CH3:18])=[CH:6][C:7]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15].[C:19](=O)([O:21]CC)[NH2:20]>[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[C:3]2[S:4][C:5]([CH2:17][CH3:18])=[CH:6][C:7]=2[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[N:20][C:19]1=[O:21]
Reactant: CCOC(N)=O
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(NC)s1
Agent: [Cl-]
Agent: [Zn+2]
Product: CCc1cc2c(-c3ccccc3Cl)nc(=O)n(C)c2s1
Temperature: 200 °C

Procedure:
A mixture of 11.7 g of 2-methylamino-3-(o-chlorobenzoyl)-5-ethylthiophene, 11.18 g of ethyl carbamate and 0.86 g of zinc chloride is heated at 200°C for 1 hour. After cooling, the reaction mixture is extracted with chloroform. The extracts are combined, washed with water, dried over sodium sulfate and contentrated to dryness under reduced pressure. The residue is chromatographed on silica gel using chloroform as an eluent to give 1-methyl-4-(o-chlorophenyl)-6-ethyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 99°-χ°C (after recrystallization from isopropanol).
Reaction SMILES: [N:1]1([C:6]2([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=O)[CH2:8][CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1.O.[NH2:19][NH2:20]>C(O)C>[N:1]1([C:6]2([C:9](=[N:19][NH2:20])[C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH2:8][CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(c1ccc(Cl)cc1)C1(n2cncn2)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NN=C(c1ccc(Cl)cc1)C1(n2cncn2)CC1
Yield: 98 %

Procedure:
37.1 g (0.15 mol) of 4-chlorophenyl 1-(1, 2, 4-triazol-1-yl)-cyclopropyl ketone were refluxed for 6 hours with 37.5 g (0.3 mol) of 80% strength hydrazine hydrate in 150 ml of ethanol. After removing the solvent by distillation in vacuo, 38.5 g (98%) of the title compound were obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18].C(N(CC)CC)C>C(O)CCC>[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: NCCCCCN
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: NCCCCCNc1nc(Cl)nc2[nH]ccc12
Yield: 84.1 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (70 mg, 0.37 mmol), 1,5-diaminopentane (0.130 mL, 1.11 mmol) and triethylamine (0.150 mL, 1.08 mmol) in nBuOH (3 mL) was stirred at 70° C. for 1 h. It was then purified by HPLC to give N-(5-aminopentyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a solid (79 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[CH:20]=[CH:19][C:18]([S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30]CC5C=CC=CC=5)[CH:25]=4)(=[O:23])=[O:22])=[CH:17][C:15]=3[O:16][C:10]=2[CH2:9]1)=O)(C)(C)C>CO.CCOC(C)=O.[Pd]>[CH2:9]1[C:10]2[O:16][C:15]3[CH:17]=[C:18]([S:21]([C:24]4[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=4)(=[O:22])=[O:23])[CH:19]=[CH:20][C:14]=3[C:11]=2[CH2:12][CH2:13][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(oc3cc(S(=O)(=O)c4cccc(OCc5ccccc5)c4)ccc23)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=S(=O)(c1cccc(O)c1)c1ccc2c3c(oc2c1)CNCC3

Procedure:
To a solution of 7-(3-benzyloxy-benzenesulfonyl)-3,4-dihydro-1H-benzofuro[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (50 mg, 0.1 mmol) in 5 mL methanol and 1 mL EtOAc was added Pd black (10% on carbon, 45 mg, 3.4 mmol). The mixture was kept under hydrogenation at 40 psi overnight and the solvent was evaporated. After filtration, the debenzylated product was taken to the next step without further purification. Removal of N-Boc protecting group with 4N HCl using a general procedure afforded the title product. mp 279-281° C., MS m/z 330 [M+H]+. 1H-NMR (400 MHz, DMSOd6): δ 10.26 (s, 1H), 9.76 (br s, 2H), 8.24 (s, 1H), 7.84 (m, 2H), 7.39 (m, 2H), 7.30 (s, 1H), 7.02 (m, 1H), 4.47 (s, 2H), 3.44 (m, 2H), 2.94 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(O)(=O)C>O>[C:12]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)(=[O:14])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
7.6 g (0.05 mol) of 4-nitrobenzyl alcohol, 4.7 ml (0.05 mol) of acetic anhydride and 5.8 ml (0.1 mol) of acetic acid were introduced into a round-bottomed flask and the mixture was heated at reflux for eight hours. The reaction medium was poured into water, extracted with ethyl ether, the organic phase decanted off, dried over magnesium sulfate and evaporated. The residue was triturated in hexane, filtered and dried. 6.1 g (62%) of 4-nitrobenzyl acetate of melting point 77°-78° C. were recovered.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=1[OH:20])=[O:10].CCCCCC.CCOC(C)=O>CC(O)=O>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]([C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[OH:1])=[O:10])=[C:12]([OH:20])[CH:13]=1
Reactant: O=C(c1ccc(O)cc1O)c1ccc([N+](=O)[O-])cc1O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)c2ccc(O)cc2O)c(O)c1
Yield: 29.4 %

Procedure:
(2,4-Dihydroxy-phenyl)-(2-hydroxy-4-nitro-phenyl)-methanone (395) (0.255 g, 0.927 mmol) was dissolved in warm AcOH (10 mL) and TiCl3 (2.0 M solution in aqueous 1M HCl, 5 mL) was added portion wise over a period of 2 hours until the color of the solution remained purple. TLC (Rf: 0.5 compared to Rf: 0.35 for compound 395 in 1:1 hexane/EtOAc, single spot) indicated complete reaction at this point. The mixture was concentrated to remove nearly all the AcOH. The mixture was diluted with EtOAc (100 mL), washed with NaHCO3 (aqueous sat., 500 mL) and brine (500 mL) via extraction, dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of hexane and EtOAc (eluding with 15–100% EtOAc/hexane in 30 minutes) gave the desired product (396) as a yellow/orange oil (0.067 g, 0.273 mmol, 29.4% yield). LC-MS (ESI): (exact mass: 245.07) m/e=246.2 [M+1]+.
Reaction SMILES: O[C:2]1([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[O:24][CH2:23][CH2:22]3)[O:7][CH2:6][C@@H:5]2[CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][N:4]2[CH2:3]1.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>>[CH2:6]1[C@@H:5]2[CH2:8][NH:9][CH2:10][CH2:11][N:4]2[CH2:3][C@@H:2]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[O:24][CH2:23][CH2:22]3)[O:7]1
Reactant: CC(C)(C)OC(=O)N1CCN2CC(O)(c3ccc4c(c3)CCOC4=O)OC[C@@H]2C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1OCCc2cc([C@@H]3CN4CCNC[C@H]4CO3)ccc21
Temperature: 0 °C
Reaction time: 18 h

Procedure:
tert-Butyl(9aS)-3-hydroxy-3-(1-oxo-3,4-dihydro-1H-isochromen-6-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (1.84 g, 4.55 mmol) was diluted with TFA (18 mL, 234 mmol) and cooled to 0° C. Some off gassing was apparent and after a few minutes a homogenous solution had been formed. Approximately 5 minutes post-TFA addition, Et3SiH (5.09 mL, 31.8 mmol) was added and the reaction mixture allowed to slowly warm to RT (allowed to warm naturally in the ice bath) where it was stirred for 18 h. The trans:cis diastereomeric ratio appeared to be ˜95:5. The reaction vessel was transferred to a rotary evaporator and concentrated in vacuo to a two phase liquid. This crude material was diluted with CH2Cl2 washed with NaHCO3,aq then water. The separately kept aqueous layers were subsequently extracted once with the same portion of CH2Cl2, the combined organics dried with MgSO4, filtered and concentrated in vacuo. The crude residue was dried under house vacuum then the mixture was further purified by flash chromatography (2% MeOH 2% Et3N in CH2Cl2) to afford the title compound.
Reaction SMILES: [CH2:1]([C:4]1([OH:9])[CH2:7][CH:6]([CH3:8])[CH2:5]1)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.O([Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])S(C(F)(F)F)(=O)=O.O>C(Cl)Cl>[CH2:1]([C:4]1([O:9][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:7][CH:6]([CH3:8])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(O)CC(C)C1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC1(O[Si](C)(C)C(C)(C)C)CC(C)C1

Procedure:
1-Allyl-3-methylcyclobutanol (2.25000 g, 17.8 mmol) (the 4:1 mixture of cis/trans-isomers) was dissolved in 50 ml of CH2Cl2 and DIEA (5.59 ml, 32.1 mmol) and tert-butyldimethylsilyl triflate (5.73 ml, 25.0 mmol) were added. The mixture was stirred for 2 h and hydrolyzed with water, extracted with 200 ml Et2O (3× each), dried over MgSO4 and evaporated. Glass col. chrom. (10-30% EtOAc in Hex.) provided (1-allyl-3-methylcyclobutoxy)(tert-butyl)dimethylsilane as a yellow oil. Mixture of cis/trans at the cyclobutylring (4:1)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[N:8][N:7]=1.S(=O)(=O)(O)O.[CH2:20](O)[CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][O:13][C:12](=[O:14])[CH2:11][N:10]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:7][N:8]=[N:9]1
Reactant: O=C(O)Cn1nnnc1-c1cccs1
Reactant: OCCO
Agent: O=S(=O)(O)O
Product: O=C(Cn1nnnc1-c1cccs1)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 88.5 %

Procedure:
To a solution of a 1 g (4.7 mM) of [5-(2-thienyl)tetrazol-1-yl] acetic acid in 5 ml of ethylene glycol was added 0.5 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=50/1) for separation and purification, to give 1 g (yield 88.5%) of [5-(2-thienyl)tetrazol-1-yl] acetic acid 2-hydroxyethyl ester.
Reaction SMILES: C(OC([N:11]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]([NH2:19])([CH3:18])[C:12]1=[O:20])=O)C1C=CC=CC=1.[ClH:21].O>C(O)C.[Pd]>[ClH:21].[NH2:19][C:13]1([CH3:18])[CH2:14][CH2:15][C:16](=[O:17])[NH:11][C:12]1=[O:20]
Reactant: CC1(N)CCC(=O)N(C(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1(N)CCC(=O)NC1=O
Temperature: 25 °C
Yield: 93 %

Procedure:
N-Benzyloxycarbonyl-α-amino-α-methylglutarimide (2.3 g, 8.3 mmol) was dissolved in ethanol (200 mL) with gentle heat and the resulting solution allowed to cool to room temperature. To this solution was added 4N hydrochloric acid (3 mL) followed by 10% Pd/C (0.4 g). The mixture was hydrogenated in a Parr apparatus under 50 psi of hydropen for 3 hours. To the mixture was added water (50 mL) to dissolve the product. This mixture was filtered through a Celite pad which was washed with water (50 mL). The filtrate was concentrated in vacuo to afford a solid residue. The solid was slurried in ethanol (20 mL) for 30 min. The slurry was filtered to afford 1.38 g (93%) of α-amino-α-methylglutarimide hydrochloride as a white solid: 1H NMR (DMSO-d6) δ11.25 (s, 1H), 8.92 (s, 3H), 2.84-2.51 (m, 2H), 2.35-2.09 (m, 2H), 1.53 (s, 3H); HPLC, Waters Nova-Pak C18 column, 4 micron, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4(aq), 1.03 min (94.6%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:10]([CH3:11])=[C:9]([N+:12]([O-])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1>CO.[Pd]>[NH2:12][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([CH3:1])[NH:3][C:4]=2[C:10]=1[CH3:11]
Reactant: Cc1nc2ccc([N+](=O)[O-])c(C)c2[nH]1
Agent: [Pd]
Solvent: CO
Product: Cc1nc2ccc(N)c(C)c2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.7 %

Procedure:
To a solution of 700 mg of 2,4-dimethyl-5-nitrobenzimidazole in 50 mL of methanol is added a catalytic amount of palladium-on-carbon. The resulting suspension is stirred at room temperature under hydrogen at atmospheric pressure for 15 hours. The reaction mixture is filtered on Celite with a methanol wash of the solids and the filtrate is concentrated. The residue is purified by flash column chromatography on silica gel, eluting with 5% methanol/ethyl acetate to provide 565 mg of 5-amino-2,4-dimethybenzimidazole as a tan solid.
Reaction SMILES: [OH:1][C:2]([CH3:34])([CH3:33])[CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.C[CH2:36][N:37](C(C)C)[CH:38](C)C.N(C)C.C1COCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:1][C:2]([CH3:34])([CH3:33])[CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([CH3:26])([CH3:25])[C:22]([N:37]([CH3:38])[CH3:36])=[O:23])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(C#CC(C)(C)C(=O)O)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(C#CC(C)(C)C(=O)N(C)C)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a stirred solution of 4-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-2,2-dimethylbut-3-ynoic acid (5.0 mg, 0.011 mmol) and i-Pr2NEt (0.01 mL) in CH2Cl2 (1 mL) were added 2 M Me2NH in THF (0.1 mL, 0.2 mmol) and solid HATU (8.5 mg, 0.022 mmol). The mixture was stirred overnight at rt, concentrated and the residue purified by prep HPLC to afford 4-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-N,N,2,2-tetramethylbut-3-ynamide (1.0 mg, 19%). LC-MS Method 1 tR=1.65 min, m/z=491, 433; 1H NMR (CDCl3) 1.13 (s, 3H), 1.18 (s, 3H), 1.52 (d, 3H), 1.55 (s, 6H), 2.10-2.40 (5H), 2.82 (m, 1H), 5.64 (q, 1H), 6.88 (d, 2H), 7.13 (d, 2H), 7.30-7.40 (5H)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]([OH:25])([C:23]#[CH:24])[CH:21]=[CH2:22]>C(N(CC)CC)C.CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:22]#[C:21][C:20]([OH:25])([CH3:19])[CH:23]=[CH2:24])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(C)(O)C=C
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(C)(O)C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Yield: 63.5 %

Procedure:
7.47 g (20 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 2.88 g (30 mmol) of 3-methyl-1-penten-4-yn-3-ol, 110 mg of bis(triphenylphosphine)-palladium(II) dichloride and 35 mg of copper(I) iodide were heated to boiling under reflux for 12 hours in 60 ml of triethylamine and 30 ml of dimethyl-formamide. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. By recrystallization of the residue from acetonitrile there was obtained 4.34 g (63%) of 7-chloro-4,5-dihydro-3-(3-hydroxy-3-methyl-4-penten-1-ynyl)-5-methyl-6H-imidazo[1,5-a][1,4-]benzodiazepin-6-one of melting point 185-187°.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][C:8]2[CH2:11][CH2:12][N:6]3[C:7]=2[C:2]=1[C@H:3]1[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C@H:4]1[CH2:5]3.FC(F)(F)C(O)=O.CCOCC.[ClH:35]>C(Cl)Cl.C(O)C>[ClH:35].[ClH:35].[CH:1]1[CH:10]=[CH:9][C:8]2[CH2:11][CH2:12][N:6]3[C:7]=2[C:2]=1[C@H:3]1[CH2:15][NH:14][CH2:13][C@H:4]1[CH2:5]3
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCc4cccc(c43)[C@H]2C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCOCC
Product: c1cc2c3c(c1)[C@H]1CNC[C@H]1CN3CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
To a solution of (±)-cis tert-butyl 4,5,7a,8,10,10a-hexahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline-9(7H)-carboxylate (400 mg, 1.33 mmol) in 10 mL of methylene chloride was added trifluoroacetic acid (3 mL). This mixture was stirred at ambient temperature for 2 h and then concentrated in vacuo. The residue was basified with sat'd aq Na2CO3 and extracted with chloroform. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo to afford the free base. A portion of this residue (100 mg, 0.50 mmol) was dissolved in 1 mL absolute ethanol and 5 mL ether and then 2M HCl in ether (0.75 mL, 1.5 mmol) was added and a solid fell out of solution. The solvents were decanted and the solid was triturated twice with ether and dried in vacuo to afford 50 mg (37%) of the title compound of EXAMPLE 109 as an off white powder. 1H NMR (dmso-D6) δ: 9.70 (broad s, 1H), 9.40 (broad s, 1H), 6.99 (app t, 2H), 6.73 (app t, 1H, J=7.3 Hz), 3.70-3.60 (m, 1H), 3.50-3.39 (m, 2H), 3.37-3.28 (m, 1H), 3.21 (q, 1H, J=8.2 Hz), 3.10-2.99 (m, 2H), 2.95-2.79 (m, 5H). LRMS (ES)+: 200.8 (M+H)+.