Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14][CH2:13]3)[N:4]=[CH:3]1.C([CH2:24][C:25]1[S:29][C:28]([CH:30]=[O:31])=[CH:27][CH:26]=1)(O)=O.[OH-:32].[K+]>CCO>[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[C:15](=[CH:24][C:25]2[S:29][C:28]([C:30]([OH:31])=[O:32])=[CH:27][CH:26]=2)[CH2:14][CH2:13]3)[N:4]=[CH:3]1
Reactant: O=Cc1ccc(CC(=O)O)s1
Reactant: O=C1CCCc2cc(OCCc3c[nH]cn3)ccc21
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc(C=C2CCc3cc(OCCc4c[nH]cn4)ccc3C2=O)s1
Yield: 75 %

Procedure:
According to the method of Example 34, 6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one, monohydrochloride (0.220 g, 0.75 mmol) was reacted with 5-carboxymethyl-2-thiophene carboxaldehyde (0.191 g, 1.12 mmol) in 5 mL of 4% KOH in EtOH overnight, and the resulting solid was purified by preparative HPLC (C18, 0.1% TFA in H2O:0.1% TFA in AcCN; gradient 80:20 to 20:80) to afford 0.302 g (75%) of the title compound as a light tan powder, mp dec. >200° C.: APCI-MS m/e 395 (M+ +1).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH3:22])[C:9]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:10]=2[O:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])=[CH:4][C:3]=1[C:25]1[CH:26]=[N:27][C:28]([C:32]#[N:33])=[CH:29][C:30]=1[CH3:31].[C:34](Cl)(=O)[C:35](Cl)=O.C(O)C>C(Cl)Cl.CN(C=O)C>[CH2:34]([O:15][C:14](=[O:16])[CH2:13][CH2:12][O:11][C:10]1[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:9]=1[N:8]([C:6](=[O:7])[C:5]1[CH:23]=[CH:24][C:2]([Cl:1])=[C:3]([C:25]2[CH:26]=[N:27][C:28]([C:32]#[N:33])=[CH:29][C:30]=2[CH3:31])[CH:4]=1)[CH3:22])[CH3:35]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C#N)ncc1-c1cc(C(=O)N(C)c2cccc(C)c2OCCC(=O)O)ccc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)CCOc1c(C)cccc1N(C)C(=O)c1ccc(Cl)c(-c2cnc(C#N)cc2C)c1
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a solution of 3-(2-{[4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-6-methyl-phenoxy)-propionic acid (160 mg, 0.35 mmol) in DCM (15 mL) was added oxalyl chloride (45.2 μl, 0.52 mmol) and 1 drop of DMF. The solution was stirred for 30 minutes before addition of ethanol (5 mL). The solution was stirred for a further 30 minutes at which time the solvent was evaporated and the residue purified by preparative TLC [eluent: 50% ethyl acetate in hexane] to yield 3-(2-{[4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-6-methyl-phenoxy)-propionic acid ethyl ester 16-1 (125 mg). MS [M+H]+: 492.4; tR=5.45 min. (method 4).
Reaction SMILES: [NH2:1][C@H:2]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:29][CH:28]=1)[C:3]([NH:5][C@@H:6]([C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16][CH3:17])[N:14]=1)=[O:8])=[O:4].C(N(C(C)C)CC)(C)C.[O:51]=[C:52](Cl)OC(Cl)(Cl)Cl>O1CCCC1>[N:36]1([CH2:35][CH2:34][O:33][C:30]2[CH:31]=[CH:32][C:27]([CH:2]3[C:3](=[O:4])[N:5]([C@@H:6]([C@H:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH3:20])[C:7]([NH:9][C:10]4[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16][CH3:17])[N:14]=4)=[O:8])[C:52](=[O:51])[NH:1]3)=[CH:28][CH:29]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc(OCCN3CCOCC3)cc2)[C@@H](C)c2ccccc2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)NC(c3ccc(OCCN4CCOCC4)cc3)C2=O)n1
Reaction time: 0.33 h

Procedure:
Crude (2S,3S)-2-{(R)-2-amino-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetylamino}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (≈0.19 mmol) was dissolved in tetrahydrofuran (10 mL) that contained diisopropylethylamine (160 μL, 122 mg, 0.94 mmol) and was transferred via cannula to a solution of diphosgene (16 μL, 26 mg, 0.13 mmol) in tetrahydrofuran (15 mL) at 0° C. The reaction mixture was stirred for 20 minutes and then partitioned between ethyl acetate and water. The organic layer was separated and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel gradient eluted with 0-100% ethyl acetate in hexanes and the isolated material further purified by preparative thin layer chromatography using silica gel eluted with ethyl acetate. Precipitation of the isolated product from dichloromethane with an excess of hexanes gave (2S,3S)-2-{4-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide as an off white solid (32 mg, 29%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([OH:10])[C:4]([CH3:12])([CH3:11])[CH2:3]1.OO.Cl.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17]>O>[OH:1][CH:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:17][C:16]([OH:20])([CH3:19])[CH3:18])[C:4]([CH3:12])([CH3:11])[CH2:3]1
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: Cl
Agent: OO
Solvent: O
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A solution of 34.5 g (200 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine dissolved in 75 mL of water and a solution of 49.5 g (0.73 mol) of 50% aqueous hydrogen peroxide are added simultaneously over seven hours at 40° C. to a mixture of 1.61 g (8.1 mmol) of ferrous chloride tetrahydrate, 50 mL of water, 1.6 mL of 37% hydrochloric acid and 390 mL of tert-butyl alcohol. About four hours into the addition, a solution of 0.22 g (1.1 mmol) of ferrous chloride tetrahydrate, 0.2 mL of 37% hydrochloric acid and 1-2 mL of water are added to the reaction mixture. The reaction mixture is stirred overnight at room temperature. The reaction is then completed by adding a solution of 0.11 g (0.55 mmol) of ferrous chloride tetrahydrate, 0.1 mL of 37% hydrochloric acid and 1-2 mL of water and a solution of 5.8 g (85 mmol) of 50% aqueous hydrogen peroxide while heating the reaction mixture at 40° C. The reaction mixture is filtered to remove solids, quenched with sodium sulfite, treated with sodium hydroxide and sodium borohydride and concentrated. The residue is dissolved in ethyl acetate and passed through silica gel to afford 42.6 g (87% yield) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([C:17](C(OCC)=O)(C(OCC)=O)[C:18]([O:20]CC)=[O:19])[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[CH:33]([CH3:35])[CH3:34])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[NH3:9].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[CH:33]([CH3:35])[CH3:34])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCc2nc(C(C)C)n(Cc3ccc(Cl)cc3)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CC(=O)O)CC2
Product: N

Procedure:
Intermediate 20 (50 mg) was dissolved in methanol (3 ml) and the resulting soln. was treated with sodium hydroxide, 3M aq. (1 ml). The resulting suspension was heated to reflux for 4 hr. The reaction mixture was allowed to cool and concentrated in vacuo. The crude residue was taken up in acetic acid (10 ml) and heated to reflux for 2 h.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C(N(CCCC)CCCC)CCC.[C:26]([NH:34][C:35]1[CH:47]=[C:46]([CH:48]=[CH2:49])[CH:45]=[CH:44][C:36]=1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C>[C:26]([NH:34][C:35]1[CH:47]=[C:46](/[CH:48]=[CH:49]/[C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)[CH:45]=[CH:44][C:36]=1[C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccc(OC(F)(F)F)cc2)cc1NC(=O)c1ccccc1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
0.10 mL of 1-bromo-4-(trifluoromethoxy)benzene, 0.22 mL of tributylamine and 5.2 mg of palladium acetate were added to 2.0 mL of N,N-dimethylacetamide solution containing 0.15 g of tert-butyl 2-(benzamido)-4-vinylbenzoate at room temperature and stirred under nitrogen atmosphere at 110° C. for 3 hours. After the reaction mixture was cooled to room temperature, 0.07 mL of 1-bromo-4-(trifluoromethoxy)benzene, 0.11 mL of tributylamine and 5.2 mg of palladium acetate were added at room temperature and stirred under nitrogen atmosphere at 110° C. for 2 hours. After the reaction mixture was cooled to room temperature, 10% citric acid aqueous solution and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia chemical Ltd., eluent; toluene; ethyl acetate=20:1] to obtain 0.10 g of tert-butyl 2-(benzamido)-4-((E)-2-(4-(trifluoromethoxy)phenyl)vinyl)benzoate as white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH3:17])[CH:3]=1.[CH2:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][NH:19]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH2:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][N:19]1[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH3:17])[CH:3]=1
Reactant: Cc1cc(Br)nc(C)c1NC(=O)CC(C)(C)C
Reactant: c1ccc2c(c1)CCNC2
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3ccccc3C2)nc(C)c1NC(=O)CC(C)(C)C
Temperature: 100 °C
Yield: 79 %

Procedure:
In a tube, a mixture of 1d (0.299 g, 1.0 mmol), 1,2,3,4-tetrahydroisoquinoline (0.20 g, 1.5 mmol) in toluene (10 ml) was degassed by nitrogen flow for 15 minutes. To this mixture was added tris(dichlorobenzylidenacetone)palladium (0) (0.046 g, 0.05 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.06 g, 0.15 mmol) and potassium tert-butoxide (0.168 g, 1.5 mmol). The tube was heated under microwave irradiation (Biotage Initiator®) for 2 hour at 100° C. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, concentrated and chromatographed to yield the title product (0.278 g, 0.79 mmol, 79%). 1H NMR (CDCl3, 400 MHz) δ 1.14 (s, 9H), 2.19 (s, 3H), 2.27 (s, 2H), 2.35 (s, 3H), 2.93 (t, J=6.2 Hz, 2H), 3.84 (t, J=6.2 Hz, 2H), 4.66 (s, 2H), 6.39 (s, 1H), 6.49 (bs, 1H), 7.15-7.19 (m, 4H).
Reaction SMILES: O.[F-].[CH2:3]([N+](CCCC)(CCCC)CCCC)[CH2:4][CH2:5]C.[CH3:20][C:21]1([CH3:55])[C@@H:51]([OH:52])[CH2:50][CH2:49][C@@:48]2([CH3:53])[C:22]1=[CH:23][CH:24]=[C:25]1[C@@H:47]2[CH2:46][CH2:45][C@@:44]2([CH3:54])[C@H:26]1[CH2:27][CH2:28][C@@H:29]2[C@@H:30]([CH2:32][O:33][Si](C(C)C)(C(C)C)C(C)C)[CH3:31].[O:56]1[CH2:60][CH2:59][CH2:58][CH2:57]1>>[C:60]([OH:56])(=[O:33])[C:59]1[CH:5]=[CH:4][CH:3]=[CH:57][CH:58]=1.[CH3:55][C:21]1([CH3:20])[C@@H:51]([OH:52])[CH2:50][CH2:49][C@@:48]2([CH3:53])[C:22]1=[CH:23][CH:24]=[C:25]1[C@@H:47]2[CH2:46][CH2:45][C@@:44]2([CH3:54])[C@H:26]1[CH2:27][CH2:28][C@@H:29]2[C@H:30]([CH3:31])[CH2:32][OH:33]
Reactant: C1CCOC1
Reactant: CC(C)[Si](OC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)(C(C)C)C(C)C
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: C[C@H](CO)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 g pulverized molecular sieve (4 Å) and 1.27 g tetrabutylammoniumfluoride hydrate were added to a solution of 2.0 g (20S)-4,4-dimethyl-20-[((triisopropylsilyl)oxy)methyl]-pregna-5,7-dien-3β-ol in 50 ml tetrahydrofuran were added. The mixture was stirred overnight at room temperature, concentrated under reduced pressure and purified by column chromatography to give 1.17 g of (20S)-4,4,20-trimethyl-pregna-5,7-dien-3β,21-diol benzoate.
Reaction SMILES: C([Li])CCC.[Cl-].[Cl:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:28]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH:32]=[CH:31][C:30](=O)[CH2:29]1>O1CCCC1.CCCCC>[Cl:7][CH:8]=[C:30]1[CH:31]=[CH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:28][CH2:29]1
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1C=Cc2ccccc2OC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: ClC=C1C=Cc2ccccc2OC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
1.1 eq. of n-butyllithium are added to 104 mg (0.3 mmol) of chloromethyltriphenylphosphonium chloride in solution in tetrahydrofuran cooled to 0° C. After stirring for one hour, 40 mg (0.25 mmol) of 1-benzoxepin-3(2H)-one, prepared according to example 25, are added at ambient temperature and the mixture is left for 1 hour. After the usual treatments and evaporating the solvent under reduced pressure, the crude reaction product is taken up in pentane in order to precipitate triphenylphosphine oxide, to give 25 mg (52%) of 3-(chloromethylene)-2,3-dihydro-1-benzoxepin in the form of two isomers as a Z/E mixture (90/10); 1H NMR (300 MHz, C6D6) 6.98–6.78 (m, 4H), 6.02 (d, J=11.8 Hz, 1H), 5.80 (d, J=11.8 Hz, 1H), 5.68 (s, 1H), 4.65 (4.06) (s, 2H).
Reaction SMILES: [CH2:1]([NH:8][CH:9]([CH2:12]Cl)[C:10]#[N:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClS([N:18]=C=O)(=O)=O.[C:21](=[O:24])([O-])O.[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([N:8]1[C:9](=[CH2:12])[C:10](=[NH:18])[NH:11][C:21]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC(CCl)NCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C1C(=N)NC(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of 4 g. (17.3 mmol) 2-benzylamino-3-chloropropionitrile in 40 ml. dry methylene chloride and 2.4 ml. triethylamine is added dropwise a solution of 1.64 ml. (18.9 mmol) chlorosulphonyl isocyanate in 20 ml. dry methylene chloride. Subsequently, the reaction solution is further stirred for 2 hours at 0° C., then warmed to ambient temperature and mixed with 300 ml. of a 5% aqueous solution of sodium hydrogen carbonate. The organic phase is then separated off, dried over anhydrous sodium sulphate and evaporated to dryness. Subsequently, the residue is chromatographed on silica gel (elution age t: merhaol/methylene chloride 1:10 v/v) to give 0.8 g. (24% of theory) of the title compound; m.p. 225° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:12]=O)[S:10][CH:11]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9](/[CH:12]=[CH:22]/[CH:23]=[O:24])[S:10][CH:11]=1
Reactant: O=Cc1cc(-c2cnccn2)cs1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1cc(-c2cnccn2)cs1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 30 by substituting 4-pyrazinyl-2-thiophenecarboxaldehyde (prepared as described in Reference Example 92) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 217 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[F:25])[N:13]=2)=[CH:23][CH:22]=1
Reactant: Fc1ccccc1CCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Fc1ccccc1Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 59 %

Procedure:
The title compound (0.042 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2-fluorobenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C20H19ClFN3, 355.13; found, m/z 356.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.55-7.48 (br m, 4H), 7.39-3.37 (br m, 1H), 7.20-7.14 (m, 3H), 5.54 (s, 2H), 3.48-3.46 (br m, 2H), 3.40-3.38 (br m, 2H), 3.31-3.29 (br m, 2H), 3.13-3.11 (br m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:18]([C:26](Cl)=[O:27])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.CC(OC)(C)C>[CH3:7][N:6]1[C:2]([NH:1][C:26](=[O:27])[C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:3][C:4]([CH3:8])=[N:5]1
Reactant: O=C(Cl)C(=O)c1ccccc1
Reactant: Cc1cc(N)n(C)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COC(C)(C)C
Product: Cc1cc(NC(=O)C(=O)c2ccccc2)n(C)n1
Reaction time: 18 h
Yield: 48.2 %

Procedure:
To a solution of 5-amino-1,3-dimethylpyrazole (2.00 g, 18.0 mmol) in THF (20 mL) was added at ambient temperature N,N-diisopropyl ethyl amine (4.62 mL, 27.0 mmol) and over a period of 5 min benzoylformic acid chloride (which might be prepared according to Synlett (11) 1763-1765, 1999, 3.64 g, 21.6 mmol) and the reaction mixture was stirred for 18 h at this temperature. It was diluted with TBME (50 mL) and washed twice with water (50 mL) and brine (50 mL). The combined aqueous layers were extracted with TBME (50 mL) and the combined organic layers were dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=50:50 to 0:100) afforded the title compound (2.11 g, 48%) as a light brown oil. MS m/e: 244.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]([CH3:13])[CH3:12])=[N:4][CH:5]=[N:6][C:7]=1[N:8]([CH3:10])[CH3:9].[C:14](=O)(OC(Cl)(Cl)Cl)[O:15]C(Cl)(Cl)Cl.C(N(CC)CC)C.[CH2:33]1[O:41][C:40]2[C:35](=[C:36]([C@@H:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:43][NH2:44])[CH:37]=[CH:38][CH:39]=2)[O:34]1.N>C(Cl)Cl.O>[CH2:33]1[O:41][C:40]2[C:35](=[C:36]([C@@H:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:43][NH:44][C:14]([NH:1][C:2]3[C:3]([N:11]([CH3:13])[CH3:12])=[N:4][CH:5]=[N:6][C:7]=3[N:8]([CH3:9])[CH3:10])=[O:15])[CH:37]=[CH:38][CH:39]=2)[O:34]1
Reactant: CN(C)c1ncnc(N(C)C)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCC[C@@H](CN)c1cccc2c1OCO2
Agent: N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCC[C@@H](CNC(=O)Nc1c(N(C)C)ncnc1N(C)C)c1cccc2c1OCO2
Temperature: 25 °C
Yield: 158.1 %

Procedure:
To a solution of 23.78 g (0.1405 mol) of 5-amino-4, 6-bis (dimethylamino) pyrimidine in 476 ml of methylene chloride were added 17.4 g (0.0586 mol) of bis(trichloromethyl) carbonate (namely triphosgene) and 34.1 g (0.337 mol) of triethylamine, and the resultant mixture was refluxed with heating for 1.5 hours. The reaction mixture was allowed to cool at room temperature, mixed with 33.0 g (0.1402 mol) of (R)-2-(2, 3-methylenedioxyphenyl)-heptylamine and allowed to react at room temperature overnight. The reaction mixture was mixed with a small amount of aqueous ammonia and water, and the aqueous layer was extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was chromatographed on a silica gel column, eluting with chloroform-1% methanol/chloroform-2% methanol/chloroform and recrystallized from heptane and ethyl acetate to give 41.0 g of the titled compound.
Reaction SMILES: C(OC(=O)N[C@H]1C[C@H](NC2SC3C=CC=CC=3N=2)C1)(C)(C)C.Cl.Cl.[NH2:25][C@H:26]1[CH2:29][C@H:28]([N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[N:32]([CH3:39])[C:31]2=[O:40])[CH2:27]1.C(N(C(C)C)CC)(C)C.Cl[C:51]1[O:52][C:53]2[CH:59]=[CH:58][CH:57]=[CH:56][C:54]=2[N:55]=1>CN(C)C1C=CN=CC=1.CS(C)=O>[O:52]1[C:53]2[CH:59]=[CH:58][CH:57]=[CH:56][C:54]=2[N:55]=[C:51]1[NH:25][C@H:26]1[CH2:29][C@H:28]([N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[N:32]([CH3:39])[C:31]2=[O:40])[CH2:27]1
Reactant: Cn1c(=O)n([C@H]2C[C@H](N)C2)c2ncccc21
Reactant: Clc1nc2ccccc2o1
Agent: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)n([C@H]2C[C@H](Nc3nc4ccccc4o3)C2)c2ncccc21

Procedure:
The title compound was synthesized following the procedure described for INTERMEDIATE 10, using 3-(trans-3-aminocyclobutyl)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one dihydrochloride (0.146 g, 0.501 mmol), diisopropylethylamine (1 ml, 5.75 mmol), 4-dimethylaminopyridine (6.13 mg, 0.050 mmol), and 2-chlorobenzoxazole (0.057 ml, 0.501 mmol) in DMSO (0.5 mL) to afford 3-(trans-3-(benzo[d]oxazol-2-ylamino)cyclobutyl)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.102 g, 0.304 mmol, 60.7% yield). m/z: 336.2 (M+1); 1H NMR (400 MHz, DMSO-dh) δ: ppm 8.44 (d, J=5.87 Hz, 1 H), 8.04 (d, J=4.69 Hz, 1 H), 7.50 (d, J=7.43 Hz, 1 H), 7.37 (d, J=7.82 Hz, 1 H), 7.28 (d, J=7.63 Hz, 1 H), 7.05-7.19 (m, 2 H), 6.92-7.03 (m, 1 H), 5.26 (t, J=8.22 Hz, 1 H), 4.53 (br. s., 1 H), 3.23-3.46 (m, 5 H), 2.38-2.61 (m, 2 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:13]2[CH:12]=[CH:11][C:10]3[CH:14]=[CH:15][CH:16]=[C:17]([I:18])[C:9]=3[CH:8]([OH:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(Cl)Cl.CN(C)C1C=CN=CC=1.O1CCCC1>[C:20]([O:1][CH2:2][C:3]1[C:13]2[CH:12]=[CH:11][C:10]3[CH:14]=[CH:15][CH:16]=[C:17]([I:18])[C:9]=3[CH:8]([OH:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1cccc2c1C=Cc1cccc(I)c1C2O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)OCc1cccc2c1C=Cc1cccc(I)c1C2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
310 mg of the mixture of 1-(hydroxymethyl)-6-iodo-5H-dibenzo[a,d]cyclohepten-5-ol with its 4-iodo form prepared in Example 6-e was dissolved in 15 ml of methylene chloride, and 100 mg of 4-(dimethylamino)pyridine and 0.8 ml of 1M solution of acetic anhydride in tetrahydrofuran were added under ice-cooling, followed by stirring at room temperature for 2 hours. The solvent was evaporated, and the residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=3:17), to give 230 mg of a mixture of the title compound with its 4-iodo form as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Cl)[N:8]2[C:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=3[C:12]([C:20]3C=[CH:24][CH:23]=[CH:22][C:21]=3Cl)=[N:11][CH2:10][C:9]=12)=[O:4].[CH3:28][O-:29].[Na+].CO.[CH:33]([Cl:36])(Cl)Cl>>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]2[N:8]3[C:7]([O:29][CH3:28])=[N:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:9]3[CH2:10][N:11]=[C:12]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:33]=3[Cl:36])[C:13]=2[CH:18]=1
Reactant: C[O-]
Reactant: COC(=O)c1nc(Cl)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Reactant: ClC(Cl)Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nc(OC)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2

Procedure:
A mixture of 2.9 g. (0.007 mole) of 6-(2-chlorophenyl)-1,8-dichloro-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylic acid methyl ester, 1.1 g (0.02 mole) of sodium methoxide and 100 ml of dry methanol was heated in a steel bomb at 115°-120° for 20 hrs. The solvent was removed at reduced pressure. The residue was dissolved in methylene chloride, washed with dilute hydrochloric acid to give pale yellow amorphous solid. An ethereal solution (60 ml) of the solid was washed with dilute ammonium hydroxide solution, dried, filtered and concentrated on a steam bath to about 20 ml. White crystals were obtained after keeping the solution at room temperature for several hours with occasional scratching. Recrystallization from ether gave white crystals with mp 155°-160°. UV λ sh 213 mμ (ε=36,000) max 266 (20,500) ir (CHCl3) 1715 cm-1 (COOCH3); nmr (CDCl3) δ 3.93 ppm (s, 3, COOCH3) 4.23 (s, 3, OCH3) 4.08 (d, 1) and 6.06 (d, 1) AB-system, J=12 Hz, C4 -H) 7.1-7.9 (m, 7, aromatic H).