Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[CH:16]=[CH:15][C:14]2[O:17][C:18]([CH3:20])=[CH:19][C:13]=2[C:12]1=[O:21].C(=O)([O-])[O-].[K+].[K+].[CH2:28]([N:30]1[C:36](=[O:37])[C:35]([CH3:39])([CH3:38])[C:34](=[O:40])[N:33]([CH3:41])[C:32]2[CH:42]=[C:43]([O:46][CH2:47][CH2:48][CH2:49]I)[CH:44]=[CH:45][C:31]1=2)[CH3:29]>CN(C=O)C>[CH2:28]([N:30]1[C:36](=[O:37])[C:35]([CH3:38])([CH3:39])[C:34](=[O:40])[N:33]([CH3:41])[C:32]2[CH:42]=[C:43]([O:46][CH2:47][CH2:48][CH2:49][N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[C:2]3[CH2:10][N:11]3[CH:16]=[CH:15][C:14]4[O:17][C:18]([CH3:20])=[CH:19][C:13]=4[C:12]3=[O:21])[CH:44]=[CH:45][C:31]1=2)[CH3:29]
Reactant: Cc1cc2c(=O)n(Cc3nc4ccccc4[nH]3)ccc2o1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(Cn4ccc5oc(C)cc5c4=O)nc4ccccc43)ccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
5-(1H-Benzimidazol-2-ylmethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.28 g) and potassium carbonate (0.9 g) were added to a DMF solution (2 ml) of 1-ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.43 g). The mixture was stirred at 60° C. overnight. After the reaction liquid was condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1→4:1). The purified product was condensed to dryness under reduced pressure to give the title compound (0.43 g) as a white amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([SH:11])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:19](Br)[CH:20]=[CH2:21]>C(=O)([O-])O.[Na+]>[CH2:21]([S:11][C:4]1[CH:5]=[C:6]([CH:10]=[C:2]([NH2:1])[C:3]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]([OH:9])=[O:8])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: Nc1cc(C(=O)O)cc(S)c1Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCSc1cc(C(=O)O)cc(N)c1Oc1ccccc1

Procedure:
A solution of 5-amino-3-mercapto-4-phenoxybenzoic acid (2.6 g) in saturated sodium hydrogen carbonate (120 ml) is cooled to 4° C. While cooling and stirring, allyl bromide (1 g) is added, and the reaction mixture is kept under nitrogen. After additional stirring for 10 minutes, 3-allylthio-5-amino-4-phenoxybenzoic acid is precipitated by addition of hydrochloric acid until pH 3. After collection by filtration, recrystallisation from aqueous ethanol, and drying in vacuo, the compound is obtained with a melting point of 142°-143° C.
Reaction SMILES: [C:1]([C:3]([C:9]1[CH:23]=[CH:22][C:12]([N:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6])#[N:2].[O:24]1CCCC1>C(C(C)=O)C>[C:9]1(=[O:24])[CH2:23][CH2:22][CH2:12][CH2:11][CH2:10]1.[C:1]([C:3]([C:9]1[CH:23]=[CH:22][C:12]([N:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)=[C:4]([C:5]#[N:6])[C:7]#[N:8])#[N:2]
Reactant: C1CCOC1
Agent: CCCCN(CCCC)c1ccc(C(C#N)=C(C#N)C#N)cc1
Solvent: CCC(C)=O
Product: O=C1CCCCC1

Procedure:
A dye solution containing 3.37 wt-% dibutyl magenta dye (4-tricyanovinyl-N,N-dibutylaniline), 0.84 wt-% butyl magenta (structure shown below), 3.94 wt-% GEON® 178 (polyvinyl chloride, B. F. Goodrich Co., Cleveland, Ohio), 0.28 wt-% VITEL™ PE-200 (polyester resin from Goodyear Chemicals Co., Akron, Ohio), 1.57 wt-% TROYSOL™ CD 1 dispersing agent (CAS registry No.: 64742-88-7, purchased from Troy Chemical, Newark, N.J.), 13.5 wt-% tetrahydrofuran, 36.0 wt-% methyl ethyl ketone, and 40.5 wt-% cyclohexanone was prepared. The individual components were first dissolved in an appropriate solvent and then mixed. ##STR1## This dye solution was coated onto the antistatic layer using a No. 9 Mayer bar and dried at 85° C. for five minutes to give an antistatic thermal dye transfer donor film. The static decay time for the antistatic thermal dye transfer donor film was 0.04 second. In comparison, the dye solution was applied to unprimed and untreated 5.7 micron Teijin F22G polyester film using a No. 9 Mayer bar and dried at 85° C. for 5 minutes to give a non-antistatic thermal dye transfer film. The non-antistatic film did not exhibit decay of a triboelectrically generated charge and could not be charged by the Electro-tech Static Decay Meter.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][C@H:13]1[C:17](=[O:18])[N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][C@H:14]1[C:25]([O:27]CC)=[O:26])=[O:11].[OH-].[Li+].O>CCO.C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][C@@H:13]1[C:17](=[O:18])[N:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:15][C@H:14]1[C:25]([OH:27])=[O:26])=[O:11]
Reactant: CCOC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)c1cc2ccccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(N[C@@H]1C(=O)N(c2ccccc2)C[C@H]1C(=O)O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.7 %

Procedure:
To the ethyl ester of Example 4 (68 mg, 0.174 mmol) dissolved in 4:1 EtOH/THF was added an aqueous solution of lithium hydroxide (13 mg, 0.521 mmol). After stirring for 16 h at room temperature, 2.5 ml of water was added and the solution was extracted with chloroform. The aqueous layer was then acidified with 1N HCl to pH2 and extracted again with chloroform. The combined organic layers were dried over MgO4, filtered and concentrated in vacuo to give the crude acid which was chromatographed on silica gel eluting with 5/95/1 EtOH/CH2Cl2 /HOAc to give the title compound (27 mg, 42%) as a colorless powder. Anal calcd for C20H17N3O4 : C, 64.51; H, 4.87; N, 11.28. Found: C, 64.26; H, 4.62; N, 10.88. MS M+1 calcd for C20H17N3O4 364, found 364.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[CH:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=3)[N:10]=[C:9]([C:27]#[N:28])[C:8]=2[N:7]=[CH:6]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C.CO>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[N:10]=[C:9]([C:27]#[N:28])[C:8]3[N:7]=[CH:6][N:5]([CH2:4][CH2:3][CH2:2][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:13]=3[CH:12]=2)=[CH:15][C:16]=1[C:23]([F:26])([F:25])[F:24])[CH3:22]
Reactant: C1COCCN1
Reactant: CCOc1ccc(-c2cc3c(ncn3CCCBr)c(C#N)n2)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1ccc(-c2cc3c(ncn3CCCN3CCOCC3)c(C#N)n2)cc1C(F)(F)F
Temperature: 120 °C

Procedure:
1-(3-Bromo-propyl)-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile was dissolved in DMF (0.5 ml) and morpholine (19 mg, 0.22 mmol) was added. The mixture was heated to 120° C. in a Smith Creator microwave. Mixture was diluted with methanol and passed through an SCX cartridge, then eluted with 2M methanolic ammonia. Mixture was then prep HPLC purified and acetonitrile was removed under reduced pressure. Resulting aqueous solution was made basic with sodium bicarbonate, extracted into DCM (5 ml), then organics were dried and evaporated to afford 6-(4-ethoxy-3-trifluoromethyl-phenyl)-1-(3-morpholin-4-yl-propyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile as a white solid (8 mg). 1H NMR (CDCl3) δ 8.25 (d, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.11 (d, 1H), 4.42 (t, 2H), 4.21 (q, 2H), 3.71 (m, 4H), 2.37 (m, 4H), 2.26 (t, 2H), 2.08 (m, 2H), 1.49 (t, 3H). MS m/z 460.6 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@@H:12]1[CH2:18][C:19]#N)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[OH2:28]>O1CCCC1.C(OCC)(=O)C.O1CCOCC1.Cl.[Zn].BrCC(OCC)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[CH2:18][C:19](=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1C[C@H](CC#N)N(C(=O)OCc2ccccc2)C1
Reactant: O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCOC(=O)CC(=O)C[C@@H]1C[C@@H](OC)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
0.5 ml (4.51 mmol) of ethyl bromoacetate were added at 90° C. to a suspension of 57.19 g (875 mmol) of zinc powder in 600 ml of tetrahydrofuran and the resulting reaction mixture was heated under reflux for 1 hour. A solution of 30.00 g (109 mmol) of (2S,4R)-1-benzyloxycarbonyl-2-cyanomethyl-4-methoxypyrrolidine [prepared as described in Preparative Example 1(i)′ above] in 30 ml of tetrahydrofuran and 84.9 ml (766 mmol) of ethyl bromoacetate were added successively to this reaction mixture, and the resulting mixture was then heated under reflux for a further 1.5 hours. After being cooled to room temperature, the reaction mixture was filtrated and the filtrate was concentrated by evaporation under reduced pressure. The residue thus obtained was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium hydrogencarbonate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue thus obtained was dissolved in a mixture of 200 ml of dioxane and 100 ml of a 1N aqueous solution of hydrochloric acid and then allowed to stand at room temperature for 3 hours. At the end of this time, water was added to the reaction mixture which was then extracted with ethyl acetate. The organic extract was washed with water and then concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 2:3 by volume mixture of ethyl acetate and hexane as the eluant to afford 28.23 g (yield: 71%) of the title compound as a pale yellow oil.
Reaction SMILES: N[CH:2]1[CH:7]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:6][CH2:5][N:4]([CH2:18][CH:19]([OH:21])[CH3:20])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].[ClH:28].[C:29](#[N:31])[CH3:30]>C(O)C>[ClH:28].[ClH:28].[F:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([CH:7]3[CH2:6][CH2:5][N:4]([CH2:18][CH:19]([OH:21])[CH2:20][N:31]4[CH2:11][C:12]5[C:30](=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH2:29]4)[CH2:3][CH2:2]3)=[N:9][O:10][C:11]=2[CH:16]=1
Reactant: CC(O)CN1CCC(c2noc3cc(F)ccc23)C(N)C1
Reactant: CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1Cc2ccccc2C1

Procedure:
To a stirred mixture of 1-(3-amino-2-hydroxypropyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.24 g, 7.6 mmol), K2CO3 (1.61 g, 11.7 mmol) in acetonitrile (100 ml) was added αα'-dibromo-o-xylene (1.54 g, 6.1 mmol). The mixture was heated at reflux for 4 hours then cooled. The insolubles were filtered. The dark red solution was concentrated down. The residue was purified by flash chromatography over s silica gel column (SiO2, 30 g; eluted with 1% CH3OH in dichloromethane). The product so obtained weighed 940 mg as an oil. This oil was dissolved in ethanol and was treated with a solution of HCl in ethanol (188 mg of AcCl in ethanol). The dark solids were collected and recrystallized again in ethanol to yield off-white crystals (1.01 g), m.p. 240°-243° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[O:55]1[C:59]([C:60](Cl)=[O:61])=[CH:58][CH:57]=[N:56]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:60]([C:59]2[O:55][N:56]=[CH:57][CH:58]=2)=[O:61])[CH2:49][CH2:48]1
Reactant: O=C(Cl)c1ccno1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2ccno2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 59 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and isoxazole-5-carbonyl chloride as starting materials in 59% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.50 (d, 2H), 9.16 (s, 1H), 8.83 (s, 1H), 8.40 (s, 2H), 8.33 (s, 1H), 7.78 (s, 1H), 7.40 (d, 1H), 7.19 (d, 1H), 7.00 (s, 1H), 4.52 (m, 1H), 3.88 (m, 1H), 3.32 (m, 1H), 3.03 (s, 4H), 2.42 (m, 2H), 2.21 (m, 1H), 1.93 (m, 2H), 1.39 (m, 2H). LCMS for C28H28ClN8O3 (M+H)+: m/z=559.2.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[NH2:27][C:28]1[CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:32][CH:33]=1>>[F:15][C:16]1[CH:17]=[C:18]([S:23]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=2)=[N:9]3)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Product: O=S(=O)(Nc1cccc2nc(Nc3cccc(C(F)(F)F)c3)ccc12)c1cc(F)cc(F)c1

Procedure:
The title compound, MS: m/e=480.4 (M+H+), was prepared in accordance with the general method of example 61 from 5-nitro-2-chloroquinoline, 3,5-difluorophenyl-sulfonylchloride and 3-aminobenzotrifluoride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1.CO>C1COCC1>[OH:19][CH2:18][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(CO)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)benzoic acid (10 g, 32.64 mmol) was dissolved in anhydrous THF (200 mL) under nitrogen at 0° C. and BH3.THF (1M in THF, 65.3 mL, 65.3 mmol) was added over 15 min. The reaction was maintained at this temperature and after 3 h a further portion of BH3.THF (1M in THF, 10 mL, 10 mmol) was added. After 2 h, MeOH (30 mL) was added and the reaction was warmed to rt. The reaction mixture was partitioned between EtOAc (150 mL) and brine (200 mL). The aqueous layer was re-extracted with EtOAc (100 mL) and the combined organics were washed with a saturated aqueous solution of NaHCO3 (150 mL) and then dried (MgSO4) and filtered. On concentration of the solution the title compound (8.57 g, 90%) precipitated as a white solid and was collected by filtration. 1H NMR (CDCl3) 1.51 (9H, s), 8.14 (4H, t), 3.62 (4H, t), 4.62 (2H, d), 6.94 (2H, d), 7.31 (2H, d).
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])O.[CH3:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C1C=CC=CC=1>O>[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH:2]([CH3:4])[C:1]#[N:5])[CH2:9][CH2:8]1
Reactant: CC(O)C#N
Reactant: CN1CCNCC1
Solvent: c1ccccc1
Solvent: O
Product: CC(C#N)N1CCN(C)CC1

Procedure:
Lactonitrile (71.08 g.) is added in a dropwise manner to a stirred solution of 100.1 g. of 1-methyl-piperazine in 500 ml. of benzene. The resulting warm solution is heated at reflux under a water separator until the theoretical amount of water is collected (about 4 hours). The solution is evaporated at reduced pressure and the residue is fractionated. The product, 2-(4-methyl-1-piperazinyl)propionitrile, is obtained as an oil, b.p. 128°-130° C./23 mm.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][NH:7][C:8]([C:10]1[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9].[CH3:31]N(C)C=O.CI.O>[Cl-].[Na+].O.C(Cl)Cl>[F:1][C:2]([F:29])([F:30])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][N:7]([CH3:31])[C:8]([C:10]1[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: O=C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1-c1ccccc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CI
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1ccccc1-c1ccccc1
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of 0.63 g (1.50 mmol) biphenyl-2-carboxylic acid 3,5-bis-trifluoromethyl-benzylamide in 10 ml N,N-dimethylformamide 0.08 g (1.98 mmol) sodiumhydride (60% dispersion in mineral oil) was added and the reaction mixture was stirred for 1 hr. After the addition of 0.15 ml (2.4 mmol) methyl iodide at 0°, the reaction mixture was stirred for 3 hrs. at RT. The reaction mixture was distributed between 50 ml H2O, 50 ml brine and 50 ml CH2Cl2. The phases were separated, the aqueous layer washed twice with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/CH2Cl2 15:1) to give 0.50 g (76%) biphenyl-2-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as colorless solid, m.p. 97-88°.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([OH:20])=O)=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.Cl.[NH2:24][CH2:25][C:26]#[N:27]>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:27][CH2:26][C:25]#[N:24])=[O:20])=[C:13]([C:15]([NH2:16])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:21]=1
Reactant: N#CCN
Reactant: NC(=O)c1nc2n(c1C(=O)O)CCOc1cc(F)c(Br)cc1-2
Agent: Cl
Product: N#CCNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2

Procedure:
10-Bromo-2-carbamoyl-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (85 mg) was reacted with aminoacetonitrile hydrochloride similar to as described in Example 2 to produce 75 mg crude 10-bromo-N3-(cyanomethyl)-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide which was then reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similar to as described in Procedure E to afford 26.1 mg of N3-(cyanomethyl)-9-fluoro-10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 479 (M)+. 1H NMR (400 MHz, DMSO) δ 12.05 (t, J=5.3 Hz, 1H), 8.68 (d, J=8.4 Hz, 1H), 8.57 (s, 1H), 8.06 (s, 1H), 7.06 (d, J=10.5 Hz, 1H), 6.55 (s, 1H), 6.35 (s, 1H), 5.05-4.95 (m, 2H), 4.61-4.54 (m, 2H), 4.40 (d, J=5.3 Hz, 2H), 2.41 (s, 3H), 1.82 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O-:25])=[O:24])=[CH:21][CH:20]=1.[Na+].C(O)C.S(O[CH:45]([CH3:51])[C:46]([O:48][CH2:49][CH3:50])=[O:47])(C1C=CC(C)=CC=1)(=O)=O>O>[F:1][C:2]([F:28])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH3:51])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C([O-])c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: CCOC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)OC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
To a warm mixture of 7 g. sodium 4-[15-(trifluoromethyl)pentadecylamino]benzoate in 100 ml. ethanol is added 4.7 g. ethyl α-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield the product as colorless crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[C:3]1([CH3:10])[CH3:9].Cl[C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[OH:8][CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:12]2[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=2)[C:3]1([CH3:10])[CH3:9]
Reactant: CC1(C)C(N)CCCC1O
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CSc1ncc(C#N)c(NC2CCCC(O)C2(C)C)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
A mixture of 3-amino-2,2-dimethylcyclohexanol (1.30 g, crude) and 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (1.35 g, 7.27 mmol), and DIEA (1.93 g, 15.0 mmol) in isopropanol (14 mL) was stirred at 90° C. for 1 h. After removal of the solvent, the residue was purified by silica gel column chromatography (10%-30% ethyl acetate in petroleum ether) to afford the title compound (820 mg, 2.81 mmol, 38% yield), which was separated by chiral column (Superchiral S-AD, 0.46 cm I.D.×25 cm L, 5 μl, CO2/MeOH/DEA=80/20/0.05 (v/v/v); Flow: 2.5 ml/min, 254 nm, T=35° C.), then by chiral column: Chiralpak IC, 0.46 cm I.D.×25 cm L, 5 μl, CO2/MeOH/DEA=70/30/0.05 (v/v/v); Flow: 2.5 ml/min, 254 nm, T=35° C.) to give four isomers (peak 1: 90 mg, d.e.=100%, e.e.=100%, peak 2: 220 mg, d.e.=99.7%, e.e.=100%, peak 3: 210 mg, d.e.=100%, e.e.=97.3%, peak 4:125 mg, d.e.=99.6%, e.e.=100%. Peak 1 and peak 4 were determinated to be cis-isomers and peak 2 and peak 3 were determinated to be trans-isomers by 2D-NMR). MS (ESI) m/z 293.1 [M+H]+
Reaction SMILES: Cl.[C:2]([O:6][C:7]([N:9]1[CH2:14][C@@H:13]2[CH2:15][CH2:16][C@H:10]1[CH2:11][NH:12]2)=[O:8])([CH3:5])([CH3:4])[CH3:3].[C:17](OC(=O)C)(=[O:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:2]([O:6][C:7]([N:9]1[CH2:14][C@@H:13]2[CH2:15][CH2:16][C@H:10]1[CH2:11][N:12]2[C:17](=[O:19])[CH3:18])=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC[C@H]1CN2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1C[C@@H]2CC[C@H]1CN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of (S,S)-2,5-diaza-bicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester hydrochloride (645 mg, 2.59 mmol) in DCM (26 mL) was added acetic anhydride (490 μL, 5.19 mmol) and triethylamine (1.08 mL, 7.77 mmol) and the mixture was stirred (rt, 16 h). The reaction mixture was washed with water (3×8 mL) and brine (1×8 mL). The organic layer was dried, filtered and concentrated in vacuo to provide (S,S)-5-acetyl-2,5-diaza-bicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (658 mg, 100%). This intermediate was dissolved in DCM (3.5 mL), treated with HCl (4 M in dioxane, 3.5 mL) and stirred (rt, 16 h). The dispersion was concentrated in vacuo to provide the title compound as a beige powder (494 mg, 100%). MS (ESI): mass calcd. for C8H14N2O, 154.11; m/z found, 155.2 [M+H]+. 1H NMR (500 MHz, MeOD): 4.71 (s, 0.5H), 4.25 (s, 0.5H), 3.97 (dt, J=12.1, 2.8, 0.5H), 3.87 (d, J=2.6, 1H), 3.84-3.73 (m, 1H), 3.68 (m, 1H), 3.64 (dd, J=13.8, 1.6, 0.5H), 3.54 (m, 0.5H), 3.45 (m, 1.5H), 2.12 (m, 4.5H), 2.06-1.91 (m, 2.5H).