Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:33]1([O:40][CH3:41])[C:34](=[CH:36][CH:37]=[CH:38][CH:39]=1)[OH:35].CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:35][C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[O:40][CH3:41])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1O
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of 3.0 g (8.2 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole, 1.59 g (11.4 mmol) of powdered potassium carbonate, 1.48 g (11.5 mmol) of guaiacol and 20 ml of dry dimethylformamide is stirred at room temperature for 23 hours, then poured into 60 ml of water and extracted three times with methylene chloride. The organic extracts are washed twice with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The crude product is chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate, there is obtained o-methoxyphenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 205°-206°.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([CH2:19][C:20]([O:22]CC)=[O:21])[CH2:15][CH2:14]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:25]>FC(F)(F)C(O)=O>[ClH:25].[C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][N:13]3[CH2:14][CH2:15][CH:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:17][CH2:18]3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Temperature: 25 °C

Procedure:
A solution of the compound prepared in Example 57 (600 mg) in trifluoroacetic acid (2 mL)-aqueous 18% hydrochloric acid (4 mL) was refluxed for two hours. The reaction was cooled to room temperature and concentrated to obtain the title compound (699 mg) having the following physical data. 1H NMR (DMSO-d6): δ 11.26-11.11 (m, 1H), 7.94-7.85 (m, 2H), 7.61-7.50 (m, 3H), 7.37 (s, 1H), 4.56 (s, 2H), 3.51-3.39 (m, 2H), 3.12-2.97 (m, 2H), 2.23-2.15 (m, 2H), 1.99-1.82 (m, 3H), 1.65-1.49 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5]O.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:11][C:10]1[C:9]([O:12][CH3:13])=[CH:8][CH:7]=[C:3]([C:4]#[N:5])[C:2]=1[Cl:1])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C=NO)c(Cl)c1O
Product: COc1ccc(C#N)c(Cl)c1OC(C)=O
Reaction time: 1 h

Procedure:
21 g of 2-chloro-3-hydroxy-p-anisaldehyde oxime are heated under reflux for 20 hours together with 400 ml of acetic anhydride. Thereupon, the reaction mixture is evaporated, the residue is treated with 300 ml of ice-water, stirred for 1 hour, decanted, the thus-cooled residue is partitioned between methylene chloride and water, the organic phase is dried over sodium sulfate, evaporated, the residue is dried in a high vacuum, chromatographed on 200 g of silica gel with methylene chloride and recrystallized from methylene chloride/petroleum ether. There is obtained 2-chloro-3-cyano-6-methoxyphenyl acetate of m.p. 97°-99°.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[CH3:11][C:12]([SH:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C(Cl)Cl>[C:12]([S:15][CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1)([CH3:14])([CH3:13])[CH3:11]
Reactant: N#Cc1ccc(CBr)nc1
Reactant: CC(C)(C)S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)SCc1ccc(C#N)cn1
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Dissolve 6-bromomethyl-pyridine-3-carbonitrile (6.2 g, 31.4 mmol) in anhydrous DMF (60 mL) under nitrogen. Add tert-butylthiol (5.32 mL, 47.2 mmol) followed by cesium carbonate (15.3 g, 47.2 mmol) and stir the resulting suspension overnight. Dissolve the reaction mixture in DCM (200 mL) and add water (200 mL). Extract the aqueous phase with DCM (2×200 mL) and dry the combined organic extracts over MgSO4. Filter, add silica gel and concentrate the mixture in vacuo. Purify the residue by chromatography on silica gel (40 g) eluting with cyclohexane/EtOAc (98:2 to 65:35 gradient) to obtain the desired material as a yellow solid (4.92 g, 76%). MS (ES+) m/z: 207 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11][C:5]=3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1.CC(C)([O-])C.[Na+].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[Cl-].[Na+].O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:30]1([NH:29][C:2]2[C:3]3[C:4]4[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:5]=4[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cccc(Br)c3c2CC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: O
Product: c1ccc(Nc2cccc3[nH]c4c(c23)CCNCC4)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (600 mg), sodium t-butoxide (220 mg), tris(dibenzylideneacetone) dipalladium (23 mg), aniline (183 mg) toluene (1.64 ml) was added 2-(di-t-butylphosphino)biphenyl (30 mg) and the reaction mixture was heated at 50° C. The reaction mixture stirred 16 h, was poured into brine, extracted with CH2Cl2, dried over MgSO4, filtered and concentrated. The crude product was stirred in CH2Cl2 (8 ml) and TFA (2 ml) was added. The reaction mixture stirred 1 h, was quenched with 2N NaOH, extracted with CH2Cl2, dried over MgSO4, filtered and concentrated. Purification via flash chromatography (silica gel, CH2Cl2/MeOH, 9/1 with 0.5% NH4OH) provided the title compound: 1H NMR (DMSO-d6) δ 2.68, 2.83-2.90, 6.58-6.67, 6.89, 7.06, 7.54, 10.71.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37].C([O-])(=O)C.[K+].[B:45]1(B2OC(C)(C)C(C)(C)O2)[O:49]C(C)(C)C(C)(C)[O:46]1>O1CCOCC1.CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:33]1([C:32]2[C:13]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([B:45]([OH:49])[OH:46])=[C:3]([C:36]([F:37])([F:39])[F:38])[CH:4]=3)[S:9]([CH3:12])(=[O:10])=[O:11])=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[C:17]([C:27](=[O:28])[NH:29][CH3:30])[C:16]=3[CH:31]=2)[CH2:34][CH2:35]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(C(F)(F)F)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(B(O)O)c(C(F)(F)F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
A solution of 6-(N-(4-bromo-3-(trifluoromethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.20 g, 0.32 mmol), potassium acetate (0.13 g, 1.28 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.026 g, 0.032 mmol), bis(pinacolato)diboron (0.24 g, 0.96 mmol) in 1,4-dioxane (4 ml) was degassed, purged with nitrogen and heated at 80° C. for 4 h. The reaction mixture was diluted with EtOAc and water, filtered through celite, and evaporated. The brown residue was dissolved in 10 mL THF, and 5 mL 1M HCl. NaIO4 (0.64 g, 3.20 mmol) was added and the suspension was stirred for 3 h and diluted with EtOAc and water. The organic layer was washed with water, brine, dried (Na2SO4), filtered, evaporated and purified by reverse phase chromatography (5-100% CH3CN/H2O (0.1% formic acid)) to afford the title compound (0.092 g, 49%) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.85-8.00 (m, 3H), 7.59-7.72 (m, 2H), 7.47 (d, 1H), 7.29-7.34 (m, 1H), 7.20-7.29 (m, 2H), 3.35 (s, 3H), 2.94 (s, 3H), 2.12 (tt, 1H), 0.28-1.10 (m, 4H). LCMS (m/z, ES+)=591.3 (M+H+).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(-c2cc3cc(C=O)ccc3o2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1csc(-c2cc3cc(CO)ccc3o2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a cooled mixture of 4-tert-butyl-2-(5-formylbenzofuran-2-yl)thiazole (2.85 g) in methanol (28 ml), sodium borohydride (0.38 g) was added in small portions. After being stirred at the same temperature for 2 hours, the resulting solution was poured into ice-water. The resulting precipitates were collected by filtration and washed with water to give 4-tert-butyl-2-(5-hydroxymethylbenzofuran-2-yl)thiazole (2.87 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([N:14]=[C:15](SC)[S:16][CH3:17])#[N:13]>CO>[C:12]([NH:14][C:15](=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[S:16][CH3:17])#[N:13]
Reactant: CSC(=NC#N)SC
Reactant: NCCSCc1ccccn1
Solvent: CO
Product: CSC(=NCCSCc1ccccn1)NC#N
Reaction time: 0.5 h

Procedure:
A solution of 2-[(2-pyridyl)methylthio]ethylamine (from the dihydrobromide, 20.0 g; 60.6 mmoles) and dimethyl cyanodithioimidocarbonate [prepared according to the procedure described in J. Org. Chem., 32, 1566 (1967)] (8.86 g; 60.6 mmoles) in methanol (150 ml) was stirred at ambient temperature under a positive pressure of nitrogen for 16 hours and then a reflux temperature for 0.5 hours to complete the reaction. The reaction mixture was evaporated under reduced pressure and the crude product was recrystallized from acetonitrile to give N-cyano-N'-{2-[(2-pyridyl)methylthio]-ethyl}-S-methylisothiourea; mp 85°-86.5° C.
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:6][N:7]=1)=O.[CH3:15][C:16]([S@@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].O>C(Cl)Cl>[C:16]([S@@:19](/[N:21]=[CH:1]/[C:3]1[S:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:6][N:7]=1)=[O:20])([CH3:18])([CH3:17])[CH3:15]
Reactant: CC(C)(C)OC(=O)c1cnc(C=O)s1
Reactant: CC(C)(C)[S@@](N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cnc(/C=N/[S@@](=O)C(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of tert-butyl 2-formylthiazole-5-carboxylate (15.7 g, 74 mmol) and (S)-2-methylpropane-2-sulfinamide (10.7 g, 88 mmol) in DCM (750 mL) at 0° C. was added cesium carbonate (48.2 g, 148 mmol). The mixture was warmed to rt and stirred for 8 h. To the solution was added water (200 mL). After separation, the aqueous phase was extracted with DCM (3×200 mL). The combined organic phases were dried (Na2SO4), and concentrated. Flash column chromatography (petroleum ether:EtOAc, 100:1 to 10:1) afforded (S,E)-tert-butyl 2-((tert-butylsulfinylimino)methyl)thiazole-5-carboxylate (18.9 g, 81%). 1H NMR (CDCl3, 400 MHz) δ 8.67 (s, 1H), 8.39 (s, 1H), 1.52 (s, 9H), 1.22 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[C:27]1([C:33]2[N:37]=[C:36]([NH2:38])[S:35][N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl.CN1C(=O)CCC1>[C:27]1([C:33]2[N:37]=[C:36]([NH:38][C:13]([C:10]3[CH:11]=[N:12][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8][CH:9]=3)=[O:15])[S:35][N:34]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Reactant: Nc1nc(-c2ccccc2)ns1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1nc(-c2ccccc2)ns1)c1cnc(-c2ccccc2)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.6 %

Procedure:
To a suspension of 2-phenyl-pyrimidine-5-carboxylic acid (400 mg, 2 mmol) in DCM (10 mL), oxalyl chloride (0.2 mL, 2.3 mmol) is added at 0° C. followed by DMF (0.23 mL, 3 mmol). The mixture is stirred at 0° C. for 20 minutes, warmed to room temperature and stirred for 20 additional min. The mixture is concentrated in vacuo. The residue is dissolved in DCM and 3-phenyl-[1,2,4]thiadiazol-5-ylamine (248 mg, 1.4 mmol) is added followed by NMP (0.5 mL). The mixture is stirred at room temperature for two hours, and concentrated in vacuo. The residue is triturated in DCM to afford 2-phenyl-pyrimidine-5-carboxylic acid (3-phenyl-[1,2,4]thiadiazol-5-yl)-amide (300 mg) as a solid. MS: 360 (M+H); IC50=30 nM.
Reaction SMILES: C[O:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:12]=[CH:11]3)=[CH:5][CH:4]=1.N[C@H](C(O)=O)CCSC.[OH-].[Na+].C(=O)(O)[O-].[Na+]>CS(O)(=O)=O.O>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N:13]2[C:14]3[C:10](=[CH:9][C:8]([O:7][C:6]4[CH:23]=[CH:24][C:3]([OH:2])=[CH:4][CH:5]=4)=[CH:16][CH:15]=3)[CH:11]=[N:12]2)[CH:18]=1
Reactant: COc1ccc(Oc2ccc3c(cnn3-c3cccnc3)c2)cc1
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Agent: O=C([O-])O
Solvent: O
Product: Oc1ccc(Oc2ccc3c(cnn3-c3cccnc3)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.1 %

Procedure:
A solution of 5-(4-Methoxy-phenoxy)-1-pyridin-3-yl-1H-indazole (0.11 grams, mmol) in 2 mL of methanesulfonic acid was treated with 0.2 grams of methionine. After stirring for 24 hours at room temperature, the mixture was treated with 1.2 grams of sodium hydroxide in 50 mL of water with cooling in an ice bath, neutralized with aqueous sodium bicarbonate, extracted 3 times with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo, affording 0.10 grams of 4-(1-Pyridin-3-yl-1H-indazol-5-yloxy)-phenol as a colorless syrup. MS: 304.4 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH2:15])[CH:6]=[C:7]([O:12][CH3:13])[C:8]=1[CH:9]([CH3:11])[CH3:10].Br[C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=1[F:25]>>[CH3:13][O:12][C:7]1[CH:6]=[C:5]([CH:14]=[CH:15][C:21]2[C:22]([F:23])=[CH:17][C:18]([F:25])=[CH:19][C:20]=2[F:24])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[CH:9]([CH3:11])[CH3:10]
Reactant: C=Cc1cc(OC)c(C(C)C)c(OC)c1
Reactant: Fc1cc(F)c(Br)c(F)c1
Product: COc1cc(C=Cc2c(F)cc(F)cc2F)cc(OC)c1C(C)C
Yield: 58 %

Procedure:
This compound was synthesized from (3,5-dimethoxy-4-i-propylphenyl)ethene and 1-bromo-2,4,6-triflurobenzene in 58% yield in the same procedure as described in preparation of 31B. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.0 Hz, 6H), 3.62 (qint, J=7.1 Hz, 1H), 3.89 (s, 6H), 6.73 (s, 2H), 6.79-7.55 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1([C:11]#[N:12])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O-]CC.[Na+].[NH4+:18].[Cl-].N.CO>CCO>[C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1([C:11](=[NH:18])[NH2:12])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(C#N)CC1
Reactant: [NH4+]
Agent: CC[O-]
Agent: N
Agent: [Cl-]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(C(=N)N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109 %

Procedure:
(1-Cyano-cyclopropyl)-carbamic acid tert-butyl ester (2.44 g, 13.40 mmol) was dissolved in dry EtOH (33 mL). Sodium ethoxide (21 wt % in EtOH solution, 10.70 mL, 22.80 mmol)) was added and the reaction was stirred for 1 h at room temperature under an atmosphere of dry argon. To the light yellow solution was added solid NH4Cl (2.94 g, 55 mmol) followed by 7 M NH3 in MeOH (8.08 mL, 56.60 mmol). The reaction was capped and allowed to stir for 16 h. The turbid suspension was filtered using MeOH to rinse. The filtrate was concentrated in vacuo and the solid residue was re-suspended in dry EtOH. The solids were filtered off, rinsing with EtOH. The filtrate was concentrated to give 2.91 g of (1-Carbamimidoyl-cyclopropyl)-carbamic acid tert-butyl ester as a light yellow solid. m/z 200.48 [M+1]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](O)=[O:14])[N:10]=[CH:9]2)=[CH:4][CH:3]=1.CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)cn1
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cn(-c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Fluoro-phenyl)-1H-imidazole-4-carboxylic acid is dissolved in THF. Borane tetrahydrofuran complex in THF is added dropwise. The reaction is refluxed for 2 h and stirred at room temperature overnight. The reaction mixture is then cooled to 0° C. and methanol is added dropwise. The solvents are evaporated and the residue is taken up in HCl and refluxed for 2 h. The reaction mixture is then cooled to 0° C. and sodium hydroxide solution is added dropwise. The desired compound [1-(4-fluoro-phenyl)-1H-imidazol-4-yl]-methanol is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]=[O:19])[CH2:14][CH2:13]1>CN(C)C=O>[N:1]1([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH:18]=[O:19])[CH2:16][CH2:17]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=CN1CCC(CCCBr)CC1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=CN1CCC(CCCn2ccnc2)CC1
Temperature: 50 °C
Yield: 93.2 %

Procedure:
The mixture of imidazole (0.7 g, 0.01M) and NaH (50% by weight in mineral oil, 0.9 g, 0.018M) in dimethylformamide (60 ml) was heated at 50° C. for 1/2 hr. and 4-(3-bromopropyl)-1-piperidinecarboxaldehyde (2.93 g, 0.0125M) in dimethylformamide (20 ml) was added. The reaction was heated at 50° C. for 4 hrs. After the reaction, the solvent was removed in vacuo, water was added and the product was extracted with CH2Cl2 (3×50 ml). The combined extracts, dried over Na2SO4, were stripped to dryness and purified on silica gel column eluted with 10% by volume methanol-90% by volume methylenechloride to give 4[3-(1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde as an oil (2.12 g, 96%).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[N:6][N:7]=1.[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28]([N:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][C:31]2=[O:37])=[N:27][C:26]=1[CH3:38])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28]([N:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:2][C:3]3[O:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=4)=[N:6][N:7]=3)=[CH:32][C:31]2=[O:37])=[N:27][C:26]=1[CH3:38])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: ClCc1nnc(-c2ccc(Cl)cc2)o1
Product: Cc1nc(-n2ccc(OCc3nnc(-c4ccc(Cl)cc4)o3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 32 %

Procedure:
Following the procedure as described in Example 21, making variation only as required to use 2-(chloromethyl)-5-(4-chlorophenyl)-1,3,4-oxadiazole in place of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 32% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.80 (t, J=5.8 Hz, 1H), 8.65 (d, J=7.8 Hz, 1H), 8.0 (d, J=8.6 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 7.32-7.19 (m, 5H), 6.46-6.39 (m, 2H), 5.60 (s, 2H), 4.38 (d, J=5.8 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 534.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:15]#[N:16])[C:9]=2[C:11]([F:14])([F:13])[F:12])[NH:4][C:3]=1[CH3:17].Cl[CH2:19][C:20]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[O:22][N:21]=1>>[F:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:15]#[N:16])[C:9]=2[C:11]([F:13])([F:12])[F:14])[N:4]([CH2:19][C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)[O:22][N:21]=2)[C:3]=1[CH3:17]
Reactant: Cc1[nH]c2ccc(C#N)c(C(F)(F)F)c2c1F
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Product: Cc1c(F)c2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 23 from 3-fluoro-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: MS (ES) m/z 469 (M+1).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=2)[O:11][CH2:12][CH:13]([OH:25])[CH2:14][NH:15][C:16]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][N:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C>[N:18]1[N:17]=[C:16]([NH:15][CH2:14][CH:13]([OH:25])[CH2:12][O:11][C:10]2[CH:26]=[CH:27][CH:28]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)[N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=12
Reactant: OC(CNc1nnc2ccccn12)COc1cccc(CN2CCCCC2)c1
Solvent: CCO
Product: OC(CNc1nnc2n1CCCC2)COc1cccc(CN2CCCCC2)c1
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A solution of 1-[3-(1-piperidinylmethyl)phenoxy]-3-[(1,2,4-triazolo[4,3-a]pyridin-3-yl)amino]-2-propanol (252 mg) in absolute ethanol (25 ml) was hydrogenated over a 5% platinium on carbon catalyst (150 mg). After 8 h, additional catalyst (200 mg) was added and the mixture was hydrogenated for a further 8 h. The mixture was filtered through hyflo and the filtrate was evaporated to give a white solid which was recrystallised from ethyl acetate-methanol to give the title compound (182 mg) as white microcrystals, m.p. 141°-2°.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[C:39]3[CH2:38][N:37]([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:36][C:35](=[O:44])[NH:34][C:33]=3[CH:32]=[CH:31][C:30]=2[O:45][CH3:46])[C:25]([Cl:47])=[CH:24][N:23]=1>>[Cl:47][C:25]1[C:26]([NH:28][C:29]2[C:39]3[CH2:38][N:37]([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:36][C:35](=[O:44])[NH:34][C:33]=3[CH:32]=[CH:31][C:30]=2[O:45][CH3:46])=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: COc1ccc2c(c1Nc1nc(Cl)ncc1Cl)CN(S(C)(=O)=O)CC(=O)N2
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3c(OC)ccc4c3CN(S(C)(=O)=O)CC(=O)N4)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and 6-(2,5-Dichloro-pyrimidin-4-ylamino)-4-methanesulfonyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one in an analogous manner to example 730 (0.022 g, 12%). Mp118-121° C.; LCMS (m/e) 673 (M); 1H-NMR (DMSO, 400 MHz) δ 10.25 (s, 1H), 8.57 (s, 1H), 8.05 (s, 1H), 7.95 (s, 1H), 7.43 (s, 1H), 7.30 (s, 1H), 7.19-7.11 (q, 2H, J=9.00 Hz), 6.70 (s, 1H), 5.75 (s, 1H), 4.42-4.40 (br, 2H), 4.40-4.25 (br, 2H), 3.74 (s, 3H), 3.70 (s, 3H), 3.70-3.63 (br, 2H), 3.24 (s, 2H), 3.06-3.05 (d, 3H, J=4.29 Hz), 2.89 (s, 2H), 2.83-2.81 (d, 3H, J=7.83 Hz), 2.78 (s, 2H), 2.73 (s, 2H), 2.73-2.60 (br, 2H), 2.40-2.30 (br, 2H).