Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: COc1cccc(COc2ccc(Br)cc2C(=O)O)c1
Reactant: Nc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cccc(COc2ccc(Br)cc2C(=O)Nc2cccnc2)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Solid pyridin-3-amine (154 mg, 1.63 mmol) was added in one charge to a stirred solution of 5-bromo-2-({[3-(methyloxy)phenyl]methyl}oxy)benzoic acid (may be prepared as described in Description 30; 275 mg, 0.82 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (188 mg, 0.98 mmol) and 1-Hydroxybenzotriazole (132 mg, 0.98 mmol) in DMF (20 ml) under nitrogen at 20° C. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3×30 ml), dried over sodium sulphate, evaporated in vacuo and purified by column chromatography (petroleum ether:ethyl acetate=2:1) to yield the title compound as a white solid. 270 mg.
Reaction SMILES: [F-].[K+].[CH2:3]([OH:5])[CH3:4].S(F)([O:9][C:10](F)(F)[C:11]([F:17])([I:16])[C:12]([F:15])([F:14])[F:13])(=O)=O>O>[I:16][C:11]([F:17])([C:12]([F:15])([F:14])[F:13])[C:10]([O:5][CH2:3][CH3:4])=[O:9]
Reactant: O=S(=O)(F)OC(F)(F)C(F)(I)C(F)(F)F
Reactant: CCO
Agent: [F-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)C(F)(I)C(F)(F)F
Temperature: 70 °C
Yield: 56 %

Procedure:
A 500 mL flask was charged with potassium fluoride (17.5 g, 0.31 mol) and absolute ethanol (110 mL), and was cooled in an ice-water bath. 2-iodo-hexafluoropropyl fluorosulfate (112.8 g, 0.3 mol) was added slowly. The reaction was exothermic and the reaction temperature was controlled at 20°-25° C. After addition was complete, the reaction mixture was heated at 70° C. for 4 hr and then poured into cold water. The bottom organic layer was separated, washed with saturated NaCl aqueous solution and dried over MgSO4. Evaporation of the solvent in vacuo followed by distillation gave 50 g (56% yield) of ethyl 2-iodotetrafluoropropionate product, formula above, having a boiling point of 60°-65° C. at 50 mmHg.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5](=[O:22])[CH2:6][N:7]([CH:9]1[CH2:14][CH2:13][N:12](CC2C=CC=CC=2)[CH2:11][CH2:10]1)[CH3:8]>[Pd]>[ClH:1].[ClH:1].[CH3:3][O:4][C:5](=[O:22])[CH2:6][N:7]([CH3:8])[CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1
Reactant: COC(=O)CN(C)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Product: COC(=O)CN(C)C1CCNCC1

Procedure:
Prepared from N-[1-benzyl-4-piperidinyl]-N-methyl-glycine methyl ester dihydrochloride by exhaustive hydrogenation over palladium-on-charcoal (10%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][CH2:25][C:26](=O)[CH2:27][CH3:28].C(O)(=O)C>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[C:22]([NH:23][CH:26]([CH2:27][CH3:28])[CH2:25][CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccnc1N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCC(=O)CC
Solvent: CC(=O)O
Solvent: CO
Product: CCC(CC)Nc1cccnc1N1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
Following the general procedure of PREPARATION 3 and making non-critical variations but starting with 1-[benzyloxycarbonyl]-4-[(3-amino)-2-pyridinyl]piperazine (PREPARATION 33, 10.5 g), 3-pentanone (0.15 g) sodium cyanoborohydride (0.11 g), acetic acid (52.3 ml) and methanol (3.2), the title compound is obtained, NMR (300 MHz, CDCl3) 7.66, 7.38-7.33, 6.90, 6.79, 5.17, 4.21, 3.65, 3.15, 3.04, 1.66-1.46 and 0.93 δ.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>CN(C)C=O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
To a mixture of 3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.10 g, 0.00026 mol, 1 eq.) and potassium carbonate (0.072 g, 0.000526 mol, 2 eq.) in anhydrous N,N-dimethylformamide (8 mL) was added tert-butyl 2-bromoacetate (0.0768 g, 0.00039 mol, 1.5 eq.) at room temperature. The mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (5 mL) and washed with water (3 mL). The solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using methanol/dichloromethane (5:95) as mobile phase to yield tert-butyl 2-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}acetate (0.10 g, 0.0002 mol).
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]([C:26]3[N:30]([CH2:31][C:32](O)=[O:33])[C:29](=[O:35])[N:28]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=4)[C:27]=3[CH3:46])=[CH:24][CH:23]=[N:22]2)=[CH:17][CH:16]=1)#[N:14].CN>C1COCC1>[C:13]([C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:25]([C:26]3[N:30]([CH2:31][C:32]([NH:3][CH3:1])=[O:33])[C:29](=[O:35])[N:28]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:44])([F:45])[F:43])[CH:37]=4)[C:27]=3[CH3:46])=[CH:24][CH:23]=[N:22]2)=[CH:19][CH:20]=1)#[N:14]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)n(CC(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 1.25 h
Yield: 52.4 %

Procedure:
1,1′-carbonyl diimidazole (45 mg, 0.278 mmol) was added to a solution of {5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-1-yl}acetic acid (Example 22) (65 mg, 0.139 mmol) in THF (2.0 mL). The mixture was stirred for 1.25 h then a 2M methylamine in THF (0.278 mL, 0.556 mmol) was added. The mixture was stirred for 45 min then a second aliquot of 2M methylamine in THF (0.278 mL, 0.556 mmol) was added. The mixture was stirred for a further 40 minutes then partitioned between EtOAc and water. The phases were partitioned. The organic phase was dried over Na2SO4 and evaporated. The product was purified by chromatography on a 12 g silica gel column, eluting with 5% methanol in DCM. The material thus obtained was freeze dried from acetonitrile-water to afford the title compound (35 mg) a white solid.
Reaction SMILES: [CH2:1]([SH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.O.O.C([O-])(=O)C.[Na+].[C:16]1([N:22]2[C:26](=[O:27])[CH:25]=[C:24](Br)[C:23]2=[O:29])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:16]1([N:22]2[C:26](=[O:27])[CH:25]=[C:24]([S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:23]2=[O:29])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCCCCS
Reactant: O=C1C=C(Br)C(=O)N1c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCSC1=CC(=O)N(c2ccccc2)C1=O
Yield: 48.1 %

Procedure:
To hexanethiol (111 μL, 0.79 mmol) and sodium acetate trihydrate (108 mg, 0.79 mmol) in methanol (60 mL) was added in N-phenyl monobromomaleimide (200 mg, 0.79 mmol) in methanol (60 mL) dropwise over 1 hour with vigorous stirring. After 5 minutes solvent was removed in vacuo. Purification by column chromatography (gradient elution in 10% ethyl acetate in petroleum ether to 30% ethyl acetate in petroleum ether) afforded the desired compound as a pale yellow solid (109 mg, 0.38 mmol) in 48% yield. δH (600 MHz, CDCl3) 7.45 (dd, 2H, J=7.1 and 8.0, 2×H-12), 7.36 (d, 2H, J=6.0, H-11), 7.35 (d, 2H, J=8.1, 2×H-13), 6.19 (s, 1H, H-2), 2.96 (t, 2H, J=7.9, H2-10), 1.81-1.76 (m, 2H, H2-9), 1.50-1.45 (m, 2H, H2-8), 1.34-1.32 (m, 4H, H2-6 and H2-7), 0.91 (t, 3H, J=6.9, H3-5); δC (125 MHz, CDCl3) 168.59 (C═O), 166.96 (C═O), 152.20 (C3), 131.53 (C14), 129.21 (2×Ar—H), 127.93 (C11), 126.09 (2×Ar—H), 117.24 (C2), 32.03 (C10), 31.33 (CH2), 28.68 (CH2), 27.78 (CH2), 22.59 (CH2), 14.11 (C5); IR (oil, cm−1) 2931 (w), 1703 (s); MS (CI+) m/z (relative intensity): 290 ([M+H], 100); Exact Mass Calcd for [C16H20NO2S]+H requires m/z 290.1215 Found 290.1224 (CI+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][N:18]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[N:19]1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:21]3[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=3)[CH:7]=2)[CH:14]=[CH:13][C:12]=1[NH2:15]
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2cc(Oc3ccc(N)c(F)c3)ccn2)cn1
Temperature: 100 °C
Yield: 55.8 %

Procedure:
A solution of 4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine (3 g, 12.6 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (5.2 g, 25.2 mmol), and Na2CO3 (2.7 g, 25.2 mmol) in DME (18 mL)/water (6 mL) was sparged with nitrogen for 20 min. Pd(PPh3)4 (729 mg, 0.63 mmol) was added and the resulting mixture was heated to 100° C. for 16 h. The solvent was removed under reduced pressure and the crude product was suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated in vacuo and purified via silica gel chromatography to give 2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (2 g, 56% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.31 (d, J=5.7 Hz, 1 H), 8.21 (s, 1 H), 7.92 (s, 1 H), 7.12 (d, J=2.4 Hz, 1 H), 6.96 (m, 1 H), 6.85-6.72 (m, 2 H), 6.56 (m, 1 H), 5.15 (s, 2 H), 3.84 (s, 3H); MS (ESI) m/z: 285.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[NH:9][C:10]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(=O)CC>[CH2:22]([N:9]1[C:10]2[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:6](=[O:15])[C:7]2=[CH:14][CH:13]=[CH:12][N:8]12)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1c2ccc(Cl)cc2[nH]n2cccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=c1c2ccc(Cl)cc2n(Cc2ccccc2)n2cccc12
Reaction time: 2 h

Procedure:
To a slurry of 7-chloropyrrolo[1,2-b]cinnolin-10(5H)-one (35.0 g) and potassium carbonate (66.34 g) in 150 ml of 2-butanone was added benzyl bromide (44.47 g) and the mixture was stirred at 50° for 2 h. The reaction was quenched with 750 ml of H2O, mixture was neutralized with 2N HCl to pH 8 and extracted with chloroform. The organic layer was washed successively with dilute HCl, H2O and brine and thereafter dried (MgSO4), charcoaled, filtered and concentrated. The yellow-orange residue was purified by flash chromatography (silica, dichloromethane) and recrystallized from ethanol to give 2.0 g of light yellow microcrystals, mp 163°-165°.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:13][CH3:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[Br:15]Br>>[Br:15][C:10]1[CH:11]=[CH:12][C:5]([O:4][CH2:3][C@@H:2]([CH3:1])[CH2:13][CH3:14])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: BrBr
Reactant: CC[C@H](C)COc1ccccc1C#N
Product: CC[C@H](C)COc1ccc(Br)cc1C#N
Reaction time: 24 h

Procedure:
A mixture of compound 39 (4.25 g, 0.-22 mol), bromine (12.31 g, 0.077 mol was then added and heating continued for another 24 h. The resultant solution was washed with a saturated solution of sodium thiosulphate and finally with water. The dichloromethane solution was dried (MgSO4) and evaporated in vacuo and the crude oil was purified by column chromatography (10% petrol/dichloromethane) to yield a fawn oil.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([CH:17]=O)[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([CH:17]=[CH2:1])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: [Li]CCCC
Reactant: COC(=O)c1cc(Br)cc(C=O)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(Br)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of methyltriphenylphosphonium bromide (350 mg, 0.97 mmol) in THF (3 mL) at −78° C. under nitrogen was added dropwise 2.5 M of n-butyllithium in tetrahydrofuran (0.31 mL, 0.78 mmol). The mixture was gradually warmed until a yellow color persisted. The mixture was cooled to 0° C. and a solution of methyl 3-bromo-5-formylbenzoate (157 mg, 0.65 mmol) in THF (2 mL) was added dropwise. After being stirred for 20 min at 0° C., the mixture was quenched with saturated aq. NH4Cl and extracted with EtOAc. The organic layer was separated and washed with brine, dried, and concentrated. The residue was purified by flash column to afford the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([CH:14]=O)[C:11]([NH:16][CH3:17])=[C:10]2[CH:18]=[CH:19][N:20]=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:23](=[O:35])[CH2:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([N:8]1[CH:13]=[C:12]2[C:11]([N:16]([CH3:17])[C:23](=[O:35])[C:24]([C:25]3[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=3[CH3:34])=[CH:14]2)=[C:10]2[CH:18]=[CH:19][N:20]=[C:9]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cc([N+](=O)[O-])ccc1C
Reactant: CNc1c(C=O)cn(Cc2ccccc2)c2nccc1-2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1-c1cc2cn(Cc3ccccc3)c3nccc-3c2n(C)c1=O
Temperature: 120 °C

Procedure:
A mixture of 7-benzyl-4-methylamino-7H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (400 mg, 1.5 mmol), (2-methyl-5-nitro-phenyl)-acetic acid methyl ester (350 mg, 1.67 mmol) and cesium carbonate (1.1 g, 3 mmol) in 5 ml anhydrous DMF is heated to 120° C. for 30 min. The reaction mixture is cooled down to room temperature. The reaction mixture is partitioned in water and ethyl acetate, extracted with ethyl acetate three times. The organic phase is combined and washed with brine, dried over Na2SO4. The crude product is purified by silica gel flash chromatography, eluted with 40% to 100% ethyl acetate in hexane to give the title compound as light yellow solid. MS m/z 426.2 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].[CH:13]([Si:15](Cl)([CH3:17])[CH3:16])=[CH2:14]>>[CH2:1]([NH:3][C:4](=[O:12])[C:5]1[C:10]([Si:15]([CH:13]=[CH2:14])([CH3:17])[CH3:16])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2]
Reactant: C=C[Si](C)(C)Cl
Reactant: CCNC(=O)c1ccccc1Cl
Product: C=C[Si](C)(C)c1cccc(Cl)c1C(=O)NCC

Procedure:
The title compound was prepared from the compound of Example f and 1.5 eq vinyldimethylsilyl chloride according to General Method C. Purification by HPLC with 1:4 ethyl acetate/hexanes gave 630 mg of the desired product as a white solid, a 9% yield. m.p. 86-89° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27].CN(C)C=O>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21][N:28]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:26][CH3:27])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2cccc(Cl)c2C1=O
Reactant: CCCNCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1csc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)n1
Yield: 44.5 %

Procedure:
A suspension of 1.0 g (0.00263 mol) of 7-chloro-3-(4-chloromethyl-thiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo-[1,5-a][1,4]benzodiazepin-6-one in 60 ml of tetrahydrofuran was treated with 7.2 ml (0.0527 mol) of dipropylamine and 5 ml of dimethylformamide. After stirring at reflux for 16 hrs. the suspension obtained was filtered and the solution was completely freed from the solvents. The residue was chromatographed over silica gel with ethyl acetate as the eluent and recrystallized from hot isopropyl ether. There was obtained 0.52 g (44%) of 7-chloro-3-(4-dipropylaminomethyl-thiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 121°-123°.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[CH2:24](Br)[CH:25]([CH3:27])[CH3:26]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([O:3][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: CC(C)CBr
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CC(C)COC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 60.5 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (20.0 mg) and isobutyl bromide (9.3 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-(2-methylpropyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (14.2 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:21][N:22]=[C:23]=[S:24]>O1CCCC1>[CH3:21][NH:22][C:23]([C:8]1([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14])=[S:24]
Reactant: CN=C=S
Reactant: O=C1CCCCC1c1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=S)C1(c2ccc(Cl)nc2)CCCCC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 52 %

Procedure:
A vigorously stirred solution of 2-(6-chloropyrid-3-yl)cyclohexanone (0.36 g 1.7 mmol) in anhydrous tetrahydrofuran (10 ml) under argon at -15° C. was treated with potassium t-butoxide (0.19 g, 1.7 mmol). The resulting mixture was stirred for 2 hours at room temperature before the addition of a solution of methyl isothiocyanate (0.12 g, 1.7 mmol) in dry tetrahydrofuran (2 ml). The mixture was stirred for a further 48 hours at room temperature, concentrated in vacuo and the residue treated with water (30 ml) and extracted with ethyl acetate (50 ml). The organic extract was dried over magnesium sulphate and then concentrated in vacuo (30° C.; 14 mmHg) to give a yellow oil which was purified by flash chromatography over silica gel eluting with ethyl acetate: hexane 4:6 to give (±)-N-methyl-2-oxo-1-(6-chloropyrid-3-yl) -cyclohexanecarbothioamide (0.25 g) m.p. 172°-3° C. NMR (CDCl3) 1.64-2.14(m 4H); 2.4-2.65(m 2H); 2.7-2.8(m 2H); 3.14-3.16(d,3H); 7.26-7.34 (ddd,1H); 7.6-7.66(dd,1H); 8.2(d,1H); 8.84-9.06 (broad singlet, 1H). Calculated for C13H15ClN2OS; C,55.2%; H,5.35%; N,9.91%, C1,12.5%; Found C,55.3%; H,5.3%; N,9.8%;C1,12.6%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH:9]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:23][O:24][C:25](=[O:32])[C@H:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH2:27].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:23][O:24][C:25](=[O:32])[C@H:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:27][C:13]([CH:12]1[CH2:11][S:10][CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)C1CSC(c2cccnc2)N1C(=O)OC(C)(C)C
Yield: 98.5 %

Procedure:
To a solution of 600 mg of N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4 carboxylic acid in 5 ml of tetrahydrofuran, there were added, at 4° C. or below, 350 mg of L-leucine methyl ester hydrochloride, 390 mg of 1-hydroxybenzotriazole, 190 mg of N-methylmorpholine and 440 mg of dicyclohexylcarbodiimide, in that order, and the mixture was stirred overnight in an icehouse. The resultant precipitate was filtered off, the filtrate was concentrated under reduced pressure, 50 ml of ethyl acetate was added, the insoluble matter was filtered off, and the filtrate was washed in sequence with 0.5M aqueous citric acid, water, saturated aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 830 mg of oily [N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carbonyl]-L-leucine methyl ester. Trifluoroacetic acid (3 ml) was added to 800 mg of the thus obtained compound with ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, 10 ml of ethyl acetate was added and the solution was again concentrated under reduced pressure. The residue was dissolved in 10 ml of ethyl acetate, 3 ml of 2.2N hydrogen chloride solution in dioxane was added with ice colling, and the mixture was allowed to stand overnight in an icehouse. The resultant crystals were collected by filtration, washed with ethyl acetate and dried to give 510 mg of [2-(3-pyridyl)thiazolidine-4-carbonyl]-L-leucine methyl ester dihydrochloride. Melting point 97°-100° C.