Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].CO.[C:4]([O:10][CH3:11])(=[O:9])[C:5]([O:7]C)=O.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:21])[CH3:20]>CCOCC>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:21])[CH2:20][C:5](=[O:7])[C:4]([O:10][CH3:11])=[O:9]
Reactant: CC(=O)c1ccccc1Br
Reactant: COC(=O)C(=O)OC
Agent: [Na]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1ccccc1Br
Reaction time: 12 h
Yield: 90.2 %

Procedure:
Sodium (120 mg, 0.0051 mol) was added slowly to MeOH (2.5 mL, 0.062 mol) at −5° C. To this solution were added dimethyl oxalate (500 mg, 0.0042 mol) and 1-(2-bromophenyl)ethanone (840 mg, 0.0042 mol) in Et2O (5 mL). The reaction mixture was allowed to stir for 12 h and then concentrated and partitioned between Et2O and water. The aqueous solution was separated and cooled in an ice bath. AcOH was added followed by 1N HCl until the solution was acidic. The mixture was extracted with Et2O, and organic solution was dried over Na2SO4, filtered and concentrated to afford methyl 4-(2-bromophenyl)-2,4-dioxobutanoate (1.08 g, 89%) which was used without purification in the next step. LCMS: (FA) ES+ 287.0
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[CH2:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)[CH2:12][CH3:13].C(N(CC)CC)C>C1COCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([CH2:11][CH2:12][CH3:13])=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CCCc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)c1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1ccc(C(=O)Nc2ccc(C(C)=O)cc2)cc1
Yield: 78.6 %

Procedure:
Reaction of 4-aminoacetophenone (76 mg, 0.56 mmol) in THF (6 mL) with 4-propylbenzoyl chloride (100 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-acetyl-phenyl)-4-propyl-benzamide (125 mg, 0.44 mmol, 78% yield) as a white powder after washing by dichloromethane and hexane.
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].[CH2:6]([C:8]1[CH:20]=[C:19]2[C:11]([C:12]3[CH2:13][CH2:14][N:15]=[C:16]([CH3:21])[C:17]=3[NH:18]2)=[CH:10][C:9]=1[O:22][CH3:23])[CH3:7].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C>[CH3:23][O:22][C:9]1[CH:10]=[C:11]2[C:12]3[CH2:13][CH2:14][N:15]4[C:16]([C:17]=3[NH:18][C:19]2=[CH:20][C:8]=1[CH2:6][CH3:7])=[CH:21][CH2:3][CH2:2][C:1]4=[O:5]
Reactant: CCc1cc2[nH]c3c(c2cc1OC)CCN=C3C
Reactant: C=CC(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCc1cc2[nH]c3c(c2cc1OC)CCN1C(=O)CCC=C31
Reaction time: 6 h
Yield: 23 %

Procedure:
Acrylic acid (0.23 mL) is added to a solution of 7-ethyl-6-methoxy-1-methyl-3,4-dihydro-β-carboline (740 mg, 3.05 mmol) in DMF (6 mL), followed by dropwise addition of diphenylphosphoryl azide dissolved in DMF (1.5 mL). The medium is left stirring for 6 h. Separation on silica gel allows the 9-methoxy-10-ethyl-2,3,4,6,7,12-hexahydroindolo[2,3-a]quinolizin4-one to be recovered (23% yield).
Reaction SMILES: [C:1]1(/[C:7](=[N:9]/[NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O)(=O)=O.O.[H][H]>CC(C)=O>[C:1]1([CH:7]([NH:9][NH:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C/C(=N\NC(=O)c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(NNC(=O)c1ccccc1)c1ccccc1

Procedure:
In a 120 mL high-pressure autoclave were charged (E)-N′-(1-phenylethylidene)benzohydrazide (119 mg) [mw. 238.28, 0.5 mmol], [Rh(cod) (S,S)-ptbp-skewphos)]OTf (5.1 mg) [mw. 1025.08, 5.0 μmol, s/c 100], and methanesulfonic acid (0.5 mg) [mw. 96.11, 5.0 μmol, 0.01 eq.]. The system was substituted with argon 7 times. 10 mL Schlenk flask was substituted with argon, pure water (9 mg) [mw. 18.02, 0.5 mmol, 1.0 eq.] and dehydrated acetone for organic synthesis (5 mL) were added, and the solution was fed into an autoclave by argon pressure supply. The system was substituted with hydrogen gas, and the mixture was stirred with hydrogen gas pressurization at 1.0 MPa for 2 hr. The system was depressurized, and analyzed by high performance liquid chromatography to find that the starting material, (E)-N′-(1-phenylethylidene)benzohydrazide, remained by 43%, and the resultant product, N′-(1-phenylethyl)benzohydrazide was produced by 45%, and the decomposed product, acetophenone, was produced by 7%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[C:4]([C:16]2NN=N[N:17]=2)[CH:3]=1.[N-]=[N+]=[N-].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[C:4]([C:16]#[N:17])[CH:3]=1
Reactant: O=C(Nc1ccc(Br)cc1-c1nnn[nH]1)c1cccs1
Agent: Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#Cc1cc(Br)ccc1NC(=O)c1cccs1
Temperature: 10 °C

Procedure:
To a solution of 2-amino-5-bromobenzonitrile (1 g, 5.1 mmol) in 20 mL of DCM, DIPEA (27.9 mmol, 5.5 eq.) was added followed by thiophene-2-carbonyl chloride (25.4 mmol, 5.0 eq.). The reaction was stirred at room temperature overnight. The organic solution of the crude reaction mixture was extracted twice with aqueous HCl (0.1 M), twice with aqueous sodium hydroxide (0.1 M), and once with a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20% EtOAc in hexane eluant) to afford 120 mg of N-(4-bromo-2-cyanophenyl)thiophene-2-carboxamide. MS (EI) for C12H7BrN2OS: 307 (M+H). Step 2: N-[4-Bromo-2-(1H-tetrazol-5-yl)phenyl]thiophene-2-carboxamide: To a mixture of the nitrile N-(4-bromo-2-cyanophenyl)thiophene-2-carboxamide (120 mg, 0.4 mmol), sodium azide (0.5 mmol, 1.3 eq.), and triethylamine hydrochloride (0.5 mmol, 1.3 eq.) in a sealed tube, 1 mL of toluene was added. The tube was tightly capped and the reaction was stirred and heated to 10° C. overnight. The mixture was cooled to room temperature, diluted with another 5 mL of toluene, transferred to a separatory funnel and washed 3×10 mL with water. The aqueous layer was collected and acidified to a pH of 4 with concentrated HCl. The solid was collected by filtration, washed with acetonitrile, and dried under vacuum to afford 18 mg of desired product. 1H-NMR (400 MHz, d6-DMSO): δ 11.60 (s, 1H), 8.44 (d, 1H), 8.23 (d, 1H), 7.99-7.95 (m, 21), 7.82 (dd, 1H), 7.33 (t, 1H). MS (EI) for C12H8BrN5OS: 350 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:15][C:16]2[S:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Sc1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Sc2nc3ccccc3s2)CC1

Procedure:
By a similar manner to Reference Example 35, 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) was reacted with 2-mercaptobenzothiazole (1.00 g, 6.0 mmol) to give the titled compound as a colorless oily substance (1.54 g, 88%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:28][CH:29]=2)=[CH:4][CH:5]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.80 g), methyl 4-hydroxyphenylacetate (0.42 g), anhydrous potassium carbonate (0.35 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.70 g, 63%) of methyl 2-[4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 93-94° C.
Reaction SMILES: [CH3:1][C:2]1[C:15](=[O:16])[N:14]=[C:13]2[N:4]([C@@H:5]3[O:9][C@H:8]([CH2:10][OH:11])[C@H:7]([O:12]2)[CH2:6]3)[CH:3]=1.N1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:22]=[CH:21]\[CH2:20]/[CH:19]=[CH:18]\[CH2:22]/[CH:21]=[CH:20]\[CH2:19][CH2:18][CH2:6][CH2:7][C:8]([O:11][CH2:10][CH:8]1[O:9][CH:5]2[N:4]3[C:13]([O:12][CH:7]1[CH2:6]2)=[N:14][C:15](=[O:16])[C:2]([CH3:1])=[CH:3]3)=[O:9]
Reactant: c1ccncc1
Reactant: Cc1cn2c(nc1=O)O[C@@H]1C[C@H]2O[C@@H]1CO
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCC1OC2CC1Oc1nc(=O)c(C)cn12
Reaction time: 8 h

Procedure:
Anhydrothymidine (0.520 g, 2.319 mmol, as a dry white powder) was dissolved in anhydrous pyridine (10 ml) under an atmosphere of dry nitrogen, and to this stirred solution at room temperature was added GLA acid chloride (0.900 g, 3.02 mmol). Stirring was continued overnight after which period, TLC indicated complete loss of the starting material. The pyridine was
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([CH2:10][CH3:11])[CH:3]=1.[CH3:12][NH:13][CH3:14]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:13]([CH3:14])[CH3:12])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(Br)ccc1CBr
Reactant: CNC
Solvent: CO
Product: CCc1cc(Br)ccc1CN(C)C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-1-bromomethyl-2-ethyl-benzene (1.12 g, 4.03 mmol) in MeOH (20 mL) was added dimethylamine (2.5 mL, 40% solution in water). The mixture was stirred for 1 hour, at which time the volatiles were removed in vacuo. The residue was dissolved in EtOAc, washed with H2O, dried over MgSO4, and concentrated to a clear oil (0.910 g, 93%). 1H NMR (300 MHz, CDCl3): δ 1.19 (t, J=7.5 Hz, 3 H), 2.21 (s, 6 H), 2.69 (q, J=7.5 Hz, 2 H), 3.32 (s, 2 H), 7.14 (m, 1 H), 7.28 (m, 2 H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:19]([CH3:20])=[CH:18][N:17]([CH:21]([O:36][CH2:37][CH3:38])[C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=[NH:35])[NH:33]O)=[CH:28][CH:27]=2)=[O:23])[N:16]=1)C1C=CC=CC=1.C([OH:41])C>C(O)(=O)C.[Pd]>[C:37]([OH:41])(=[O:36])[CH3:38].[C:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][NH:24][C:22](=[O:23])[CH:21]([O:36][CH2:37][CH3:38])[N:17]2[CH:18]=[C:19]([CH3:20])[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[OH:8])=[N:16]2)=[CH:31][CH:30]=1)(=[NH:33])[NH2:35]
Reactant: CCOC(C(=O)NCc1ccc(C(=N)NO)cc1)n1cc(C)c(-c2ccccc2OCc2ccccc2)n1
Reactant: CCO
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(C(=O)NCc1ccc(C(=N)N)cc1)n1cc(C)c(-c2ccccc2O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (RS)-2-[3-(2-benzyloxy-phenyl)-4-methyl-pyrazol-1-yl]-2-ethoxy-N-[4-(N-hydroxycarbamimidoyl)-benzyl]-acetamide (90 mg) at r.t. in ethanol were added acetic acid (3 drops) and 10% Pd/C (9 mg). Stirring at r.t. under a hydrogen atmosphere was continued for 18 hrs. The catalyst was filtered off and washed with ethanol. The filtrate was concentrated. The crude product was purified by chromatography (silica gel, EtOAc/acetone/H2O/HOAc 6:2:1:1) to give (RS)-N-(4-carbamimidoyl-benzyl)-2-ethoxy-2-[3-(2-hydroxy-phenyl)-4-methyl-pyrazol-1-yl]-acetamide acetate (28 mg) as off-white solid. MS 408.5 ([M+H]+).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25]>ClCCl>[CH3:27][O:26][C:24]([NH:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (R)-tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (1.0 equiv.) and triethylamine (3.0 equiv.) in dichloromethane (0.1 M) was added methyl chloroformate (1.1 equiv.). The resulting mixture was stirred at RT for 45 min. After concentration, the residue was partitioned between EtOAc and water. The organic phase was washed with water and then with brine. After drying over sodium sulfate the solution was concentrated in vaccuo to give crude (R)-tert-butyl 2-(((methoxycarbonyl)amino)methyl)morpholine-4-carboxylate which was used in the next step without further purification. LCMS (m/z) (M+H)=175.1 (-Boc), Rt=0.63 min.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:16]([O:23][CH2:24][C@H:25]([NH:29]C(OC(C)(C)C)=O)[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:29][C@@H:25]([CH2:24][O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:26]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:27]
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Product: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 48.7 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-chlorophenoxy)aniline (329 mg, 1.5 mmoles) and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid (487 mg, 1.65 mmoles), gave (S)-2-amino-3-(benzyloxy)-N-(4-(4-chlorophenoxy)phenyl)propanamide (290 mg, 48%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.Cl[S:15](O)(=[O:17])=[O:16]>>[O:16]=[S:15]1(=[O:17])[O:1][CH2:2][CH2:3][C:4]2[C:12]1=[CH:11][CH:10]=[C:9]1[NH:8][C:7](=[O:13])[CH2:6][C:5]1=2
Reactant: O=S(=O)(O)Cl
Reactant: O=C1Cc2c(CCO)cccc2N1
Product: O=C1Cc2c(ccc3c2CCOS3(=O)=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
4-Hydroxyethyl-2-oxindole (5 g, 28.2 mmol) was dissolved in 20 mL of chlorosulfonic acid with stirring at room temperature. After 30 min, the reaction mixture was slowly added to ice water (300 mL) with stirring. The solid was filtered and dried to afford 1.9 g (28%) of 6,6-dioxo-3,6,8,9-tetrahydro-1H-7-oxa-6λ6-thia-3-aza-cyclopenta[α]naphthalen-2-one as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:8][CH:7]=1.CO.[OH-].[K+]>O>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([CH:5]=[CH:4][C:3]([OH:20])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)C=Cc1ccc(OCCCCCCO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C=Cc1ccc(OCCCCCCO)cc1
Reaction time: 24 h
Yield: 94 %

Procedure:
To a 1L round-bottom flask were added 3-[4-(6-Hydroxy-hexyloxy)-phenyl]-acrylic acid methyl ester (27.82 g, 100 mmol) and MeOH (250 mL) and H2O (80 mL) to render a yellow solution. KOH pellets (8.42 g, 150 mmol) was added in portions. The resulting solution was placed in an oil bath at 50° C. under N2 after the flask was equipped with a water condenser. After 24 h, HPLC analysis indicated more than 95% conversion. The solution was concentrated by rotary evaporation to remove most organic solvent. The remaining solution was diluted with ice cold H2O (400 mL) and cooled in an ice bath. Upon vigorous stirring, concentrated HCl solution (ca. 12 mL) was added dropwise to result in a white slurry (pH 3). The slurry was filtered with a Büchner funnel and the solid was rinsed with additional H2O (ca. 500 mL) and then transferred to a recrystallization dish. After drying overnight in the air, the solid was transferred to an amber bottle, cooled in a dry ice box for 1 h and then lyophilized for 16 h. The hydroxy acid weighed 24.9 g (94% yield).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:14]([N:15]2[C:24](=[O:25])[C:23]3[C:18](=[C:19]4[CH:38]=[CH:37][CH:36]=[CH:35][C:20]4=[C:21]([CH2:26][C:27]4[CH:28]=[N:29][C:30]([CH2:33]O)=[CH:31][CH:32]=4)[CH:22]=3)[N:17]=[CH:16]2)[CH2:13][CH2:12][O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COCCN(S(F)(F)[F:49])CCOC>ClCCl>[Si:1]([O:8][C@@H:9]1[C@@H:14]([N:15]2[C:24](=[O:25])[C:23]3[C:18](=[C:19]4[CH:38]=[CH:37][CH:36]=[CH:35][C:20]4=[C:21]([CH2:26][C:27]4[CH:28]=[N:29][C:30]([CH2:33][F:49])=[CH:31][CH:32]=4)[CH:22]=3)[N:17]=[CH:16]2)[CH2:13][CH2:12][O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1COCC[C@@H]1n1cnc2c(cc(Cc3ccc(CO)nc3)c3ccccc32)c1=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1COCC[C@@H]1n1cnc2c(cc(Cc3ccc(CF)nc3)c3ccccc32)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-((3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydro-2H-pyran-4-yl)-6-{[6-(hydroxymethyl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one (Example 21, 0.035 g, 0.066 mmol) in 1 mL of dichloromethane at −78° C. was added [bis(2-methoxyethyl)amino]sulfur trifluoride (0.015 mL, 0.079 mmol). The reaction was warmed to rt, and after 3 h, the solution was purified via silica gel chromatography, eluting with 0-3% methanol in dichloromethane to provide 3-((3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydro-2H-pyran-4-yl)-6-{[6-(fluoromethyl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 534.0 for [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH2:66][CH:67]1[CH:72]2[CH2:73][CH2:74][N:69]([CH2:70][CH2:71]2)[CH2:68]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:13][CH2:14]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:66][CH:67]5[CH:72]6[CH2:73][CH2:74][N:69]([CH2:70][CH2:71]6)[CH2:68]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Reactant: NC1CN2CCC1CC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CN3CCC2CC3)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (25 mg, 0.057 mmol, 1 eq), DIPEA (20 μL, 0.11 mmol, 2 eq) and TBTU (20 mg, 0.063 mmol, 1.1 eq) were added to 0.5 mL DMF and the resulting solution stirred at rt for 15 min before the addition of 3-aminoquinuclidine dihydrochloride (11 mg, 0.055 mmol, 1.1 eq) and DIPEA (40 μL). The RM was then stirred at rt for 16 hours before purifying by preparative RP-HPLC-MS (Preparative—1) to provide (±)-4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxy-N-(quinuclidin-3-yl)benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:26]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)Nc1ccc(CC(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
(S)-2-(4-chlorobenzenesulfonylamino)hexanoic acid (3 g) and ethyl 4-aminophenylacetate (2.116 g) were dissolved in dichloromethane (50 ml). To the solution, N,N'-dicyclohexylcarbodiimide (2.43 g) was added, and then the whole was stirred at room temperature overnight under argon. The reaction mixture was concentrated, poured in a saturated saline solution and extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (1.493 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:8]([CH3:12])=[CH:9][C:10]=1[NH2:11])[NH2:7])([O-:3])=[O:2].C(=O)([O-])[O-].[Ca+2].Cl[CH2:19][CH2:20][CH2:21][OH:22]>O>[N+:1]([C:4]1[CH:5]=[C:6]([C:8]([CH3:12])=[CH:9][C:10]=1[NH2:11])[NH:7][CH2:19][CH2:20][CH2:21][OH:22])([O-:3])=[O:2]
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1N
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: Cc1cc(N)c([N+](=O)[O-])cc1NCCCO

Procedure:
16.7 g (0.1 mol) of 3-nitro-4-amino-6-methylaniline, 40 ml of water, 6.6 g (0.066 mol) of calcium carbonate and 12.42 g (0.132 mol) of 3-chloropropan-1-ol are heated on a boiling water-bath for 7 hours 30 minutes, whilst stirring.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH2:54]([O:61][NH2:62])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C(Cl)Cl>[CH2:54]([O:61][NH:62][C:14](=[O:16])[C:13]([NH:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:10])=[O:11])([CH3:18])[CH3:17])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: COc1ccc(S(=O)(=O)NC(C)(C)C(=O)O)cc1
Reactant: NOCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NC(C)(C)C(=O)NOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
A solution of 2-(4methoxybenzenesulfonylamino)-2-methylpropionic acid (1.08 grams, 3.95 mmole) in methylene chloride (120 mL) was cooled in an ice bath. Triethylamine (2.2 mL, 15.8 mmole), (benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate (2.6 grams, 5.88 mmole) and O-benzylhydroxylamine hydrochloride (0.95 grams, 5.95 mmole) were subsequently added. The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was taken up in ethyl acetate. The solution was washed successively with aqueous 1 N hydrochloric acid solution, aqueous saturated sodium bicarbonate solution, water and brine. After drying over sodium sulfate, the solvent was evaporated to afford an oil from which the desired product, N-benzyloxy-2-(4-methoxybenzenesulfonylamino)-2-methyl-propionamide (1.41 grams, 95%), a white solid, was obtained by chromatography on silica gel eluting with 1:2 ethyl acetate/hexanes.