Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]([Cl:13])=[C:11]2[C:7](=[N:8][CH:9]=[N:10]2)[N:6]=[C:5]1[NH:14][C:15](=[O:17])[CH3:16])(=O)C.C(O[CH2:22][O:23][CH:24]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:25][O:26][C:27](=[O:29])[CH3:28])(=O)C.C(S(O)(=O)=O)C>ClCCl>[C:32]([O:31][CH2:30][CH:24]([O:23][CH2:22][N:8]1[CH:9]=[N:10][C:11]2[C:7]1=[N:6][C:5]([NH:14][C:15](=[O:17])[CH3:16])=[N:4][C:12]=2[Cl:13])[CH2:25][O:26][C:27](=[O:29])[CH3:28])(=[O:34])[CH3:33]
Reactant: CC(=O)OCOC(COC(C)=O)COC(C)=O
Reactant: CC(=O)Nc1nc2ncnc-2c(Cl)n1C(C)=O
Agent: CCS(=O)(=O)O
Solvent: ClCCl
Product: CC(=O)Nc1nc(Cl)c2ncn(COC(COC(C)=O)COC(C)=O)c2n1
Yield: 23.7 %

Procedure:
A round-bottomed flask (10 ml) was charged with N-acetyl-2-acetamido-6-chloropurine (2.0 g, 7.9 mmoles), 1,3-diacetoxy-2-propoxymethyl acetate (2.7 g, 10.9 mmoles), and ethanesulfonic acid (63 mg). The mixture was heated in an oil bath maintained at 130° and a vacuum was applied. Thin layer chromatography showed no heterocyclic starting material after 1.5 hours and heating was discontinued. The mixture was dissolved in dichloromethane (50 ml) and filtered through Celite. The filtrate was evaporated to a residue and chromatographed on silica gel using dichloromethane/methanol (98:2) as the eluant. The product-containing fractions were combined and evaporated to give 0.75 g of pure product, m.p. 139°-140°.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[S:13])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12.O1CCOC[CH2:18]1.[OH-].[K+].S([O-])(OC)(=O)=O>CO>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]([S:13][CH3:18])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12
Reactant: C1COCCO1
Reactant: CN1c2ccccc2NC(=S)c2cscc21
Agent: COS(=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSC1=Nc2ccccc2N(C)c2cscc21
Reaction time: 3 h

Procedure:
To a stirred suspension of 0.7 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-thione in 10 ml. of dioxane is added dropwise and simultaneously at 30°-40° C., a solution of 0.95 g. of potassium hydroxide in 10 ml. of methanol and 0.8 ml. of methyl sulfate. After addition is complete the mixture is stirred for 3 hours, diluted with methanol and filtered. The filtrate is concentrated to about 20 ml., diluted with water and extracted with chloroform. The chloroform solution is concentrated to give a solid, which is recrystallized from methanol-water to give orgnae crystals, m.p. 113°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]4)[CH:15]=[N:16][C:12]=3[CH:11]=[C:10]([C:25]#[N:26])[N:9]=2)[CH:5]=[N:6][CH:7]=1.P([O-])([O-])(O)=O.[Na+].[Na+].[Br:34]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1.CCOC(C)=O>[Br:34][C:15]1[N:14]([CH2:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]2)[C:13]2[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:9][C:10]([C:25]#[N:26])=[CH:11][C:12]=2[N:16]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (1 g, 2.73 mmol) was dissolved in THF (10 mL). Disodium hydrogen phosphate (1.16 g, 8.20 mmol) was added and the reaction was warmed to 35° C. with stirring. 1,3-dibromo-5,5-dimethylhydantoin (0.938 g, 3.28 mmol) was added in 1 portion and the reaction was continued with stirring at 35° C. After 1 hour, the reaction was diluted with EtOAc (100 mL) and washed with aqueous NaHSO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column with 0 to 75% EtOAc/hexanes provided 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:36])[NH:20][CH2:21][CH2:22][C:23]3[C:24]([CH:33]4[CH2:35][CH2:34]4)=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:37]([O:39]CC)=[O:38].[OH-].[Na+].C(O)C>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:36])[NH:20][CH2:21][CH2:22][C:23]3[C:24]([CH:33]4[CH2:34][CH2:35]4)=[N:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:37]([OH:39])=[O:38]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C(F)(F)F)nc4C4CC4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCCc1ccc(C(F)(F)F)nc1C1CC1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
Ethyl 6-chloro-7-(4-(2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate (15 mg, 0.025 mmol) was diluted with THF (200 μL) followed by the addition of aq. 1N NaOH (127 μL, 0.13 mmol) and ethanol (100 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N aqueous HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 6-chloro-7-(4-(2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (14 mg, 0.025 mmol, 98% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](O)=[O:15])[CH:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([C:27]([O:31][N:32]1N=NC2C=CC=N[C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNOC.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:27][O:31][N:32]([CH3:33])[C:14]([CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH:10]1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:15]
Reactant: O=C(O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
In a 100 mL round bottom flask with a magnetic stirrer 900 mg (2.72 mmol) (3RS,4SR)-1-benzyl-3-(4-chloro-phenyl)-piperidine-4-carboxylic acid and 1.14 g (3 mmol) HATU was dissolved in 20 mL dry DMF. The greenish solution was stirred for 15 min, 320 mg (3.28 mmol) N,O-dimethylhydroxylamine hydrochlorideowed and 2.32 mL DIPEA was added. The mixture was stirred for 3 h at room temperature and concentrated under high vacuum. The green viscous oil was taken up in 60 mL ethyl acetate and 75 mL 5% aqueous NaHCO3-solution. The aqueous layer was separated and extracted once with 60 mL ethyl acetate. The combined organic layers were washed with 75 mL 1% AcOH/water-solution and once with 100 ml brine, dried over Na2SO4, filtered off and concentrated under vacuum. The residue was purified over silica eluting with a gradient formed from ethyl acetate/heptane to yield after evaporation of the product containing fractions 990 mg (97%) of the title compound as colorless viscous oil. MS (m/e): 373.3 [(M+H)+].
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1
Reactant: COc1ccc(/C=C/c2cccc(I)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(/C=C/c2cccc(I)c2)cc1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
To a solution of 8 (350 mg, 1.00 mmol) in CH2Cl2 (200 mL) was added BBr3 (10 mL, 1M in hexane) dropwise at −78° C. in a dry ice-acetone bath. The mixture was allowed to warm up to room temperature. Water was added while the reaction mixture was cooled at 0° C. in an ice bath. The mixture was extracted with CH2Cl2. The organic phase was dried and filtered. The filtrate was purified by flash chromatography (EtOAc: Hex, 1:9) to give 9 (296 mg, 92%). 1H NMR (200 MHz, CDCl3): δ 4.81 (s, 1H), 6.83 (d, J=16.17 Hz, 1H), 6.84 (m, 2H), 7.03 (d, J=16.32 Hz, 1H), 7.06 (t, J=7.8 Hz, 1H), 7.36-7.57 (m, 4H), 7.84 (s, 1H); 13C NMR (50 MHz, CDCl3): 94.75, 115.67, 124.96, 125.49, 128.09, 129.48, 129.87, 130.25, 135.01, 135.96, 139.90, 155.53; HRMS: m/z Calcd for C14H11IO: 321.9855; Found: 321.9840.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CN(C)C=O.C(OCC)C>[CH2:16]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CCc1ccccc1O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CCc1ccccc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To an ice-bath cooled suspension of sodium hydride (60% dispersion in mineral oil, 0.40 g) in dimethylformamide (18 ml) were added dropwise methyl 3-(2-hydroxyphenyl)propionate (1.80 g) and benzyl bromide successively. After being stirred for 30 minutes, the mixture was poured into a mixture of diethyl ether (20 ml) and 1N hydrochloric acid solution (90 ml). The organic layer was separated and the aqueous layer was extracted by diethyl ether. The combined organic layer was washed with aqueous sodium bicarbonate solution, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography [eluting with ethyl acetate n-hexane (1:1)] to provide methyl 3-(2-benzyloxyphenyl)-propionate (2.33 g).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[NH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][N:32]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[C:35]([C:34]1[CH:37]=[CH:38][C:31]([NH:30][C:20]([C:19]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2/[CH:11]=[CH:10]/[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:1])[F:29])[C:5]=2[O:23][CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:21])=[N:32][CH:33]=1)#[N:36]
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Reactant: N#Cc1ccc(N)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)Nc2ccc(C#N)cn2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (80 mg, 0.189 mmol) with 6-aminonicotinonitrile (27 mg, 0.226 mmol) in the presence of EDCI hydrochloride (72 mg, 0.378 mmol), DMAP (22 mg, 0.189 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 25 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 9H), 3.56 (s, 2H), 7.17 (t, J=74.1 Hz, 1H), 7.19-7.25 (m, 2H), 7.42-7.50 (m, 2H), 7.55-7.62 (m, 1H), 7.82 (d, J=15.6 Hz, 1H), 8.02-8.08 (m, 1H), 8.18-8.24 (m, 1H), 8.28-8.35 (m, 1H), 8.83-8.90 (m, 1H), 11.39 (br s, 1H); APCI-MS (m/z) 524.25 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1[O:24][CH3:25])[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[OH-].[K+].[C:28](=[O:30])=O>O1CCCCC1CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([O:24][CH2:25][CH:4]3[CH2:3][CH2:2][CH2:1][CH2:28][O:30]3)=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Reactant: O=C=O
Agent: OCC1CCCCO1
Agent: [K+]
Agent: [OH-]
Product: COC12C(CO)C3=C(C(=O)C(C)=C(OCC4CCCCO4)C3=O)N1CC1NC12
Product: NC(=O)O
Yield: 46 %

Procedure:
A solution of mitomycin A (100 mg of 0.286 mmole) in 4 ml of tetrahydropyran-2-methanol was stirred at room temperature and under nitrogen for 45 minutes with 240 mg of a 1.6% solution of KOH in tetrahydropyran-2-methanol. The reaction mixture was decomposed with excess dry ice while immersing the flask into a water bath at room temperature. The reaction mixture was chromatographed on a silica gel column using CHCl3 and then CHCl3 -MeOH 9.5:0.5. The product was further purified by preparative thin layer chromatography (silica gel, CHCl3 -MeOH 9.5:0.5). Thus, there was obtained 57 mg (46%) of the desired product having a melting point of 135°-138° C. (decomposition) and providing the following analysis:
Reaction SMILES: N#N.C[O:4][C:5]([C:7]1[N:8]=[CH:9][O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:13]=1)=[O:6].C1COCC1.O.[OH-].[Li+]>CC(=O)OCC.O>[C:21]([SiH2:20][O:19][C:18]([CH3:26])([CH3:25])[C:14]1[CH:13]=[C:12]([C:11]2[O:10][CH:9]=[N:8][C:7]=2[C:5]([OH:6])=[O:4])[CH:17]=[CH:16][CH:15]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1ncoc1-c1cccc(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: N#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2ocnc2C(=O)O)c1
Reaction time: 2.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-[3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-oxazole-4-carboxylic acid methyl ester (673 mg, 1.94 mmol) in 1:1 THF:H2O (6.4 mL) was treated with lithium hydroxide monohydrate (115 mg, 2.71 mmol). The resulting mixture was stirred for 2.5 h. EA (20 mL) was added and the organic phase was washed with 1N HCl (10 mL), dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a white solid. LC-MS-conditions 02: tR=1.07 min, [M+H]+=334.13.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][N:23]([CH3:26])C=O>CNCCC1C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:23]([CH3:26])[CH2:22][CH2:6][C:5]4[CH:20]=[CH:21][CH:2]=[CH:3][CH:4]=4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Agent: CNCCc1ccccc1
Solvent: CCO
Product: CN(CCc1ccccc1)C[C@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and N-methylphenethylamine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=421.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25](OC)=[O:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[Cl:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]21.[BH4-].[Li+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[Cl:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH2:25][OH:26])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(OC)cc1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(N2CCCCn3c2nc2c(Cl)ccc(CO)c23)c(Cl)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 99.8 %

Procedure:
To a stirred solution of methyl 10-chloro-1-(2-chloro-4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole-7-carboxylate (336 mg, 0.800 mmol) in tetrahydrofuran (6 mL) was added lithium borohydride (69.7 mg, 3.20 mmol) at 0° C. After being stirred for 20 h at 60° C., the reaction mixture was diluted with ethyl acetate, quenched with aqueous ammonium chloride, washed with water and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo to give the title compound as a colorless solid (318 mg, 0.798 mmol, 99%).
Reaction SMILES: C(=O)(OC)O[C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][CH:4]=1.[CH:14]([NH:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+].C[N:33](C)C(=O)C>>[CH:6]([C:7]1[N:33]=[C:5]([N:23]2[CH2:24][CH2:25][N:20]([C:18]([NH:17][CH:14]([CH3:16])[CH3:15])=[O:19])[CH2:21][CH2:22]2)[CH:4]=[CH:3][CH:8]=1)=[O:9]
Reactant: COC(=O)Oc1ccc(OC)cc1
Reactant: CC(=O)N(C)C
Reactant: CC(C)NC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)NC(=O)N1CCN(c2cccc(C=O)n2)CC1
Temperature: 80 °C
Yield: 24 %

Procedure:
A mixture of 6-bromopicolinaldehyde (5, 1.00 g, 5.38 mmol) and N-isopropylpiperazine-1-carboxamide (4, 1.10 g, 6.45 mmol) in N,N-dimethylacetamide (20 mL) was treated with K2CO3 (2.23 g, 16.1 mmol) and heated at 80° C. for 18 h. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with hexanes to 100% EtOAc to 4:1 EtOAc/MeOH to afford the title compound (0.35 g, 24%) as an impure yellow solid: Multimode MS m/z 172 [M+H]+.
Reaction SMILES: CI.[NH:3]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:4]([C:9]([NH:11][C@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH3:13])=[O:10])[CH2:5][CH2:6]SC>CN(C=O)C.ClCCl>[C:21]([O:20][C:18]([NH:3][C@@H:4]1[CH2:5][CH2:6][N:11]([C@@H:12]([CH3:13])[C:14]([O:16][CH3:17])=[O:15])[C:9]1=[O:10])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)N1CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 5 °C
Reaction time: 16 h
Yield: 61.3 %

Procedure:
Note: This sequence must be conducted under dry conditions with dry solvents otherwise epimerisation will occur. Methyl iodide (10 ml) was added to Boc-(D)-Met-(L)-Ala-OMe (8 g) in a mixture of DMF (20 ml) and dichloromethane (20 ml) and the mixture was allowed to stand for 16 hours and then evaporated to dryness. Further dichloromethane (2×50 ml) was added and evaporated to remove residual methyl iodide and the residue was dissolved in a mixture of DMF (300 ml) and dichloromethane (300 ml). The mixture was cooled to ˜5° C. and sodium hydride (0.76 g of an 80% dispersion in mineral oil) was added in one portion and the mixture was stirred at this temperature for 2 hours. Saturated aqueous ammonium chloride (50 ml) was added and the mixture was evaporated to dryness and then partitioned between water and ether. The ether extract was washed with brine and dried and evaporated to give a gum which was purified by flash chromatography on a sinter funnel (25% ethyl acetate:hexane to 100% ethylacetate) to give methyl (2S)-2-[(3R)-3-(N-[tert-butyloxycarbonyl]amino)-2-oxo-pyrrolidin-1-yl]propionate as a gum (4.2 g) which crystallised on standing: NMR (CDCl3): 1.4 (s, 9H), 1.4 (d, 3H), 1.8 (m, 1H), 2.6 (m, 1H), 3.4 (m, 2H), 3.7 (m, 3H), 4.2 (m, 1H), 4.9 (q, 1H), 5.2 (bs, 1H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:8]1([C:14]([CH2:19][CH2:20][Cl:21])([CH2:17][CH3:18])[C:15]#[N:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.C12CCC(CC1)CN2.C1(C(C2C=CC=CC=2)(CCBr)C#N)C=CC=CC=1>>[ClH:21].[C:8]1([C:14]([CH2:19][CH3:20])([CH2:17][CH2:18][N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:15]#[N:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CCNCC1
Reactant: CCC(C#N)(CCCl)c1ccccc1
Agent: C1CC2CCC1CN2
Agent: Cl
Agent: N#CC(CCBr)(c1ccccc1)c1ccccc1
Product: CCC(C#N)(CCN1CCCCC1)c1ccccc1

Procedure:
When equivalent quantities of piperidine hydrochloride and 2-phenyl-2-(2-chloroethyl)butyronitrile are substituted for the 2-azabicyclo[2.2.2]octane hydrochloride and 2,2-diphenyl-4-bromobutyronitrile used in Example 12, and the procedure described therein substantially repeated, there is obtained 2-phenyl-2-ethyl-4-piperidino-butyronitrile hydrochloride melting at about 200° - 203° C.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:11]([CH2:14][CH3:15])CC)C.[C:16](Cl)(=[O:26])[C:17]1[CH:25]=[CH:24][CH:23]=[C:19]([C:20](Cl)=[O:21])[CH:18]=1.Cl>C(Cl)Cl.O>[CH:1]1([NH:8][C:16](=[O:26])[C:17]2[CH:25]=[CH:24][CH:23]=[C:19]([C:20]([NH:11][CH:14]3[CH2:15][CH2:6][CH2:7][CH2:1][CH2:2][CH2:3]3)=[O:21])[CH:18]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: CCN(CC)CC
Reactant: NC1CCCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(NC1CCCCCC1)c1cccc(C(=O)NC2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
20.8 g of cycloheptylamine and 20.25 g of triethylamine were dissolved in 500 ml of methylenechloride, and then, 17.0 g of iso-phthaloyl chloride was added to thereto. The mixture was stirred at room temperature for 2 hours, and 500 ml of water was added to the reaction mixture. Then, conc. HCl was added thereto while stirring. Precipitated soli material was collected by filtration, washed with methylene chloride and water successively, and dried giving 28.7 g of N,N'-dicycloheptylisophthalamide.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[O:31][C:30](=[O:35])[CH:29]=[C:28]2OS(C(F)(F)F)(=O)=O>C(#N)C>[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[O:31][C:30](=[O:35])[CH:29]=[C:28]2[NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]=[CH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:4][CH2:3]1
Reactant: NC1CCN(CC=Cc2ccccc2)CC1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2cc(Br)ccc2o1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Br)ccc2o1
Temperature: 150 °C
Yield: 34.1 %

Procedure:
To a solution of 4-amino-1-cinnamylpiperidine (1.3 g, 6 mmol) and triethylamine (1.6 mL, 7.2 mmol) in dry acetonitrile (125 mL) was added trifluoromethanesulfonic acid 6-bromo-2-oxo-2H-chromen-4-yl ester (2.23 g, 6 mmol). About 5 mL of solution was added to each of 25 dry microwave vials equipped with stir bars. The vials were capped and each was heated at 150° C. for 5 minutes in the microwave. The solutions were combined, concentrated and dissolved in chloroform. The solution was washed with water and brine and dried over Na2SO4, and concentrated. The residue was purified by flash chromatography through a silica gel column with dichloromethane and methanol (95:5 v/v) to provide the desired compound (900 mg, 34%) as a yellow solid. MS (ESI(+)Q1MS m/z 440 (M+2H)+; 1H NMR (300 MHz, DMSO) δ ppm 1.57-1.67 (m, 2H), 1.89-1.95 (m, 2H), 2.13 (m, 2H), 2.92 (m, 2H), 3.13 (m, 2H), 3.50 (m, 1H), 5.28 (sd, 1H), 6.35 (dt, 1H), 6.56 (d, 1H), 7.24-7.47 (m. 7H), 7.74 (dd, 1H), 8.45 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:13])=[C:4]([CH3:12])[C:5]2[O:9][CH2:8][S:7][C:6]=2[C:10]=1[CH3:11].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C)C=O>[Si:19]([O:1][C:2]1[C:3]([CH3:13])=[C:4]([CH3:12])[C:5]2[O:9][CH2:8][S:7][C:6]=2[C:10]=1[CH3:11])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: Cc1c(C)c2c(c(C)c1O)SCO2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)SCO2
Temperature: 50 °C
Reaction time: 7 h
Yield: 94.8 %

Procedure:
0.84 g of 5-hydroxy-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 64) was dissolved in 5 ml of dimethylformamide, and then 0.58 g of imidazole and 1.29 g of t-butyldimethylsilyl chloride were added to the resulting solution. The mixture was then stirred for 7 hours at 50° C., after which it was allowed to stand overnight at room temperature. The solvent was then distilled off under reduced pressure, and the residue was extracted with benzene. The extract was washed with a saturated aqueous solution of sodium bicarbonate and with water, and then dried over anhydrous sodium sulfate. The solvent was then distilled off. The resulting residue was subjected to column chromatography through 40 g of silica gel eluted with hexane and with mixtures of hexane and benzene ranging from 10:1 to 2:1 by volume, to yield 1.26 g of the title compound as a colorless oily substance.