Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:7][CH:6]=1)(=O)C>C(O)C>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([NH2:4])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: CCO
Product: Nc1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
A suspension of N-acetyl-4-(quinolin-2-yl-methoxy)aniline (Step A, 108.9 g) in 1 L of 95% ethanol containing 10M KOH (120 mL) was heated at reflux under nitrogen in a heating mantle. When the hydrolysis was complete (approx. 36 h), the reaction mixture was cooled and ethanol was partially removed under vacuum. The mixture was then diluted with water (200 mL) and the fine off-white crystals were collected and thoroughly rinsed with water. The material, after air-drying, yielded the title compound which was used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C@@H:19]([CH3:22])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.N1C=CC=CC=1>>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C@@H:19]([CH3:22])[CH:20]=[O:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)N[C@@H](C)CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccncc1
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)N[C@@H](C)C=O

Procedure:
Analogously to Example 194A, 500 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[(2S)-1-hydroxypropan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (Example 178A, 1.33 mmol, 1 equivalent) were oxidized with Dess-Martin periodinane with addition of 0.11 ml of pyridine (105 mg, 1.33 mmol, 1 equivalent) and worked up. This gave 439 mg (53% of theory; purity 60%) of the title compound which was reacted further without purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2=[CH:11][N:12]=[CH:13][N:8]2[CH:7]=1)=O)C.[NH3:14].CO>>[C:4]([C:6]1[S:10][C:9]2=[CH:11][N:12]=[CH:13][N:8]2[CH:7]=1)(=[O:3])[NH2:14]
Reactant: CCOC(=O)c1cn2cncc2s1
Reactant: N
Solvent: CO
Product: NC(=O)c1cn2cncc2s1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A 294 mg potion of 2-ethoxycarbonylimidazo[5,1-b]thiazole was dissolved in 8 ml of a 2M ammonia/methanol solution, and the mixture was then stirred at room temperature for 4 days. After concentration under reduced pressure, 3 ml of dichloromethane was added to the resulting residue, and the precipitate was collected by filtration, washed with dichloromethane, and then dried under reduced pressure to obtain 226 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=3)[NH:22][N:21]=2)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[N:7]=[C:6]2[C:8](=[CH:29][C:25]3[CH:24]=[C:23]4[C:28]([C:20](/[CH:19]=[CH:18]/[C:15]5[CH:14]=[CH:13][N:12]=[CH:17][CH:16]=5)=[N:21][NH:22]4)=[CH:27][CH:26]=3)[C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C1Cc2nc(Cl)ccc2N1
Reactant: O=Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Product: O=C1Nc2ccc(Cl)nc2C1=Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Yield: 78.8 %

Procedure:
The title compound (E/Z=3:1, 63 mg, 84%) was synthesized as an orange solid according to the method described for Example A67 (oil temp 70° C., reflux 60 min) using 5-chloro-1H-pyrrolo[3,2-b]pyridin-2(3H)-one (33.7 mg, 0.2 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) E isomer: δ 13.83 (s, 1H), 10.92 (s, 1H), 8.91 (s, 1H), 8.57 (d, J=6.0 Hz, 3H), 8.37 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 7.90 (d, J=16.4 Hz, 1H), 7.75-7.70 (m, 2H), 7.57 (d, J=16.8 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H); Z isomer: δ 13.80 (s, 1H), 11.03 (s, 1H), 9.15 (s, 1H), 8.57 (d, J=6.0 Hz, 2H, buried under the doublet at 8.57), 8.34 (d, J=8.4 Hz, 1H, partially overlapping with the doublet at 8.37), 8.25 (d, J=9.2 Hz, 1H), 8.20 (s, 1H), 7.86 (d, J=14.4 Hz, 1H, partially overlapping with the doublet at 7.90), 7.75-7.70 (m, buried under the multiplet 7.75-7.70), 7.56 (d, J=16.8 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H); MS ESI 400.0 [M+H]+, calcd for [C22H14ClN5O+H]+ 400.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:13]#[N:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(=O)(=O)(O)[OH:23]>>[C:13]([CH:12]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1)[C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)(=[O:23])[NH2:14]
Reactant: N#CC(c1ccc(Cl)cc1)c1ncc(C(F)(F)F)cc1Cl
Reactant: O=S(=O)(O)O
Product: NC(=O)C(c1ccc(Cl)cc1)c1ncc(C(F)(F)F)cc1Cl
Temperature: 0 °C

Procedure:
At 23° C., 6.0 g of 3-chloro-2-[1-(4-chlorophenyl)-1-cyanomethyl]-5-trifluoromethylpyridine (prepared by the method of Example 1) were stirred in 30 ml of 96% strength sulfuric acid for 16 hours. The reaction mixture was then carefully stirred into 200 ml of ice water during which the product crystallized out. The solid was separated off, washed successively with water and n-hexane and dried. Yield: 5.5 g (87%) of colorless crystals; mp.: 135-136° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:6]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[C:8]([CH3:14])[N:7]=1)[CH3:5]>CO>[CH2:4]([C:6]1[CH:11]=[C:10]([CH:9]=[C:8]([CH3:14])[N:7]=1)[C:12]([NH:2][OH:3])=[NH:13])[CH3:5]
Reactant: NO
Reactant: CCc1cc(C#N)cc(C)n1
Agent: Cl
Solvent: CO
Product: CCc1cc(C(=N)NO)cc(C)n1
Temperature: 0 °C
Yield: 105.7 %

Procedure:
To an ice-cooled solution of potassium tert.-butylate (7.11 g, 63.4 mmol) in methanol (50 mL), hydroxylamine hydrochloride (3.78 g, 54.4 mmol) is added. The suspension is stirred for 30 min before 2-ethyl-4-cyano-6-methyl-pyridine (2.65 g, 18.1 mmol) is added. The mixture is refluxed for 3 h before it is filtered. The filtrate is evaporated to dryness and the resulting solid is dissolved in water (30 mL) and extracted with EA (3×150 mL). The combined org. extracts are concentrated and dried under HV to give 2-ethyl-N-hydroxy-6-methyl-isonicotinamidine (3.43 g) as a white powder; LC-MS: tR=0.31 min, [M+1]+=180.07; 1H NMR (D6-DMSO) δ 1.22 (t, J=7.5 Hz, 3H), 2.44 (s, 3H), 2.71 (q, J=7.5 Hz, 2H), 5.89 (s, 2H), 7.31 (s, 2H), 9.87 (m, 1H).
Reaction SMILES: [S:1]1[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]2=[N:3][CH:2]1[NH:13][C:14](=[O:20])[C:15]([O:17]CC)=[O:16].C([O-])(O)=O.[Na+]>O>[S:1]1[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]2=[N:3][CH:2]1[NH:13][C:14](=[O:20])[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C(=O)NC1N=C2C(=Cc3ccccc32)S1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=O)NC1N=C2C(=Cc3ccccc32)S1
Yield: 92.9 %

Procedure:
3.5 g (0.012 mole) of ethyl N-(indeno[1,2-d]thiazol-2-yl)-oxamate were suspended in a solution of 1.1 g (0.013 mole) of NaHCO3 in 200 ml of water, and the suspension was refluxed for 4 hours. The reaction mixture was filtered, the filtrate was brought to pH 1 with dilute HCl, and the precipitate was filtered off under suction and dried, giving 2.9 g (93%) of a product of melting point 229°-231° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][C:11]#[C:12][CH3:13].C(N(CC)CC)C>C(O)C>[CH2:9]([NH:8][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:10][CH2:11][C:12]#[CH:13]
Reactant: Clc1ncccn1
Reactant: CC#CCCN
Solvent: CCN(CC)CC
Solvent: CCO
Product: C#CCCCNc1ncccn1
Temperature: 90 °C

Procedure:
A mixture of 2-chloropyrimidine (4.0 g, 35 mmol), 5-aminopent-2-yne (10.5 g, 88 mmol), triethylamine (12.3 mL, 88 mmol) in ethanol (50 mL) was heated in a sealed tube at 90° C. for 16 h. The mixture was cooled and evaporated in vaciio. The residue was taken up in ethyl acetate and was filtered through a plug of silica gel, eluting with ethyl acetate, and evaporated in vacuo to give the title compound:
Reaction SMILES: [Cl-].[NH4+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([NH:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([Cl:30])[CH:28]=5)[O:23][C:22](=[O:31])[C:21]=4[N+:32]([O-])=O)[CH2:15][CH2:14]3)=[CH:11][C:6]=2[O:5][CH2:4]1.[CH2:35]([OH:37])[CH3:36]>O.[Fe]>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([NH:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([Cl:30])[CH:28]=5)[O:23][C:22](=[O:31])[C:21]=4[NH:32][C:35](=[O:37])[CH3:36])[CH2:15][CH2:14]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: CCO
Reactant: O=c1oc2ccc(Cl)cc2c(NC2CCN(Cc3ccc4c(c3)OCO4)CC2)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(=O)Nc1c(NC2CCN(Cc3ccc4c(c3)OCO4)CC2)c2cc(Cl)ccc2oc1=O

Procedure:
Iron powder (0.067 g, 1.2 mmol) was added to a suspension of ammonium chloride (0.006 g, 0.12 mmol) and 4-(1-Benzo[1.3]dioxol-5-ylmethyl-piperidin-4-ylamino)-6-chloro-3-nitro-chromen-2-one (0.055 g, 0.12 mmol) in ethanol (5 mL) and water (2 mL) at room temperature. The reaction was heated at reflux for 1 d and then filtered through a pad of wet celite. The filtrate was treated with saturated NaHCO3 (10 mL), extracted with dichloromethane (3×25 mL), dried (Na2SO4), concentrated, purified by RP-HPLC and the amine carried forward to the next step. MS (ESI) m/e 428.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.N1C=CN=C1.[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(Br)cn1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1ccc(Br)cn1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (5-bromo-pyridin-2-yl)-methanol (300 mg) in dichloromethane (20 mL) was added imidazole (217 mg) and tert-butyldiphenylsilyl chloride (0.41 mL) and the reaction stirred at room temperature for 16 h. the reaction was quenched with water (20 mL) and extracted into dichloromethane (2×30 mL). The organic layers were dried (MgSO4) and reduced in vacuo to give 5-bromo-2-(tert-butyl-diphenylsilanyloxymethyl)-pyridine as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[N:34]1([CH2:39][CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[N:50]2[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:38]=[CH:37][N:36]=[CH:35]1.C(N(CC)C(C)C)(C)C.CO.ClCCl>C(#N)C.ClCCl>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][CH2:39][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: c1ccc2c(c1)nc(N1CCCNCC1)n2CCn1ccnc1
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Agent: I
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4CCn4ccnc4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.34 g, 0.60 mmol), 4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.27 g, 0.60 mmol), and N,N-diisopropylethylamine (0.31 g, 2.39 mmol) in acetonitrile (10 mL). Heat to reflux. After 12 hours, cool to ambient temperature and dilute the reaction mixture with dichloromethane and extract with twice water. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 10% methanol/dichloromethane/0.5% concentrated aqueous ammonia) to give the title compound: Rf=0.32 (silica gel, 10% methanol/dichloromethane/0.5% concentrated aqueous ammonia).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[CH3:12].O>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccccc1
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=N[C@H](C)c1ccc(Cl)cc1)c1ccccc1
Yield: 47.2 %

Procedure:
0.3 g of zinc chloride is added to a solution of 20 g (0.128 mol) of (R)-1-(4-chlorophenyl)-ethylamine (97% ee) and 15.6 g (0.13 mol) of acetophenone in 70 ml of toluene at room temperature with stirring, and the mixture is then refluxed for 74 hours at the water separator. The reaction mixture is then filtered. The filtrate is evaporated under reduced pressure to give 15.56 g (47% of theory) of (R)-[1-(4-chlorophenyl)-ethyl]-[1-phenyl-ethylidene]-amine.
Reaction SMILES: [OH2:1].[N:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].OO>C(O)(=O)C.O>[N+:2]1([O-:1])[C:3]([C:11]([OH:13])=[O:12])=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O
Reactant: O=C(O)c1ccnc(C(=O)O)c1
Agent: OO
Solvent: CC(=O)O
Product: O=C(O)c1cc[n+]([O-])c(C(=O)O)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A suspension of 2,4-pyridinedicarboxylic acid monohydrate (92.6 g, 0.5 mol) in acetic acid (700 ml) was treated with hydrogen peroxide (300 ml of a 35 wt % solution in water) and then heated at reflux for 16 h. The mixture was allowed to cool to 80° C., water (200 ml) was added and the mixture refrigerated at 4° C. for 16 h. The resulting solid was collected by filtration, washed with cold water (3×100 ml) and dried to give 2,4-pyridinedicarboxylic acid N-oxide (91.5 g, 91%) as a white crystalline solid. 1H NMR (360 MHz, d6-DMSO) δH 8.17 (1H, dd, J 3 and 7), 8.51 (1H, d, J 3), 8.76 (1H, d, J 7).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[ClH:4].[CH2:5]([O:12][C:13]([NH:15][C@H:16]([C:24]([N:26]1[CH2:34][CH2:33][CH2:32][C@H:27]1[C:28](OC)=[O:29])=[O:25])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:23])[NH2:22])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[ClH:4].[CH2:5]([O:12][C:13]([NH:15][C@H:16]([C:24]([N:26]1[CH2:34][CH2:33][CH2:32][C@H:27]1[C:28]([N-:3][CH2:1][CH3:2])=[O:29])=[O:25])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:23])[NH2:22])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCN
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Product: CC[N-]C(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1

Procedure:
Nα -Benzyloxycarbonyl-L-arginyl-L-prolyl-N-ethylamide, hydrochloride is prepared according to the following method. To a cold solution of 9.7 g. ethylamine in 50 ml. of methanol is added 2 g. of Nα -benzyloxycarbonyl-L-arginyl-L-proline, methyl ester, hydrochloride. The reaction is let stand in a sealed pressure bottle at room temperature and then warmed occasionally to 40°-45° C. during 8 days. It is then evaporated to small volume under reduced pressure. The residual solution is dropped into stirred ethyl ether to precipitate a somewhat sticky white solid which is dried under reduced pressure; [α]D25 -53° (c. 1.02, methanol).
Reaction SMILES: [Br:1][C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36][CH2:37][CH3:38])=[O:35])CC[CH2:31][CH2:30]2)=[CH:4][CH:3]=1.[CH3:41]C1(C)[C@@H]2[C@H]1C(=O)OC2=O>>[Br:1][C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:28]2[C@H:29]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:30]2([CH3:41])[CH3:31])=[CH:4][CH:3]=1
Reactant: CC1(C)[C@@H]2C(=O)OC(=O)[C@@H]21
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Product: CCOC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)C1(C)C

Procedure:
The title compound was prepared using analogous conditions to those described for ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate using racemic cis-6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione. MS (ESI): mass calcd. for C32H30BrN3O3, 583.15; m/z found, 584.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:11][O:12][CH2:13][CH2:14]Br>CC(C)=O.O>[CH3:11][O:12][CH2:13][CH2:14][O:10][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=1
Reactant: COCCBr
Reactant: O=[N+]([O-])c1cccc(O)c1
Solvent: O
Solvent: CC(C)=O
Product: COCCOc1cccc([N+](=O)[O-])c1
Yield: 98.9 %

Procedure:
3-Nitrophenol (25 g, 0.18 mol), 2-bromoethyl methyl ether (17 ml, 25 g, 0.18 mol) potassium carbonate (25.0 g, 0.18 mol) in acetone (150 ml) were heated under reflux for 72 h. The suspension was dissolved in water and extracted with ether. The extracts were washed with 2N sodium carbonate, water and saturated brine, dried (K2CO3), and concentrated, to give the title compound (Intermediate 50) as a brown oil (35.12 g, 99%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([NH:15][C:16](=[O:19])[O:17][CH3:18])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[N:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:26]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:27])[CH2:12][CH:11]([NH:15][C:16](=[O:19])[O:17][CH3:18])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCc1ccc(C2CNCC(NC(=O)OC)C2)cc1
Product: CCc1ccc(C2CC(NC(=O)OC)CN(C(=O)N3CCOCC3)C2)cc1
Yield: 32.1 %

Procedure:
170 mg (0.58 mmol) of methyl [5-(4-ethylphenyl)piperidin-3-yl]carbamate (Example 21A) and 113 mg (0.76 mmol, 1.3 eq.) of morpholine-4-carbonyl chloride were reacted according to General Method 3. Diastereomer separation of the cis/trans isomer mixture according to Method 7C gave 70 mg of the compound from Example 102.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][N:9]([CH3:20])[CH2:10][C:11]3[N:12]([C:13](=O)[NH:14][C:15]=3/[CH:16]=[CH:17]\Cl)[C:6]=2[CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[OH2:32]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:32])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[CH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(Cl)cccc2-n2c(c(/C=C\Cl)[nH]c2=O)C1
Reactant: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2

Procedure:
20.2 g (65.5 mmol) of 7-chloro-3-[(Z)-2-chlorovinyl]-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine--one was heated to boiling under reflux for 5 hours together with 11.7 ml (78.5 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 200 ml of N,N-dimethylformamide. The reaction mixture was subsequently poured into 800 ml of water and extracted four time with methylene chloride. The organic extracts were washed four times with water, dried over magnesium sulphate and evaporated. After chromatography of the residue on silica gel while eluting with ethyl acetate and two successive crystallizations from acetonitrile and from ethyl acetate there was obtained 7-chloro-3-ethynyl-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 201°-202°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.[Li]CCCC.[F:35]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:11]1[N:10]=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][N:8]2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)=[O:18])=[CH:3][C:2]=1[F:35]
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Nc1ccc(C(F)(F)F)cn1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1F)CCCN2C(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of 6-bromo-7-(dimethoxymethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2D, 50 mg, 0.105 mmol) in THF (1 ml) at −78° C. under argon was treated drop wise with n-BuLi (1.5 M in hexane, 0.154 ml, 0.231 mmol). The resulting brown solution was stirred for 2 min, then a solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (80 mg, 0.254 mmol) in THF (0.5 ml) was added. The resulting yellow solution was stirred at −78° C. for 10 min. The reaction mixture was quenched by addition of sat. aq. NH4Cl, warmed to room temperature and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 60:40) the product containing fractions were concentrated to give the title compound as a white solid. (UPLC-MS 1) tR 1.25 min; ESI-MS 415.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=O)=[CH:5][CH:4]=1.C(NC(C)C)(C)C.C([Li])CCC.Cl.[CH2:30]([O:32]P(Cl)(=O)OCC)[CH3:31]>CCCCCC.C(N=CC)(C)(C)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6](/[C:7](/[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:31]/[CH:30]=[O:32])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2cccnc2)cc1
Reactant: CCOP(=O)(Cl)OCC
Agent: CC=NC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COc1ccc(/C(=C/C=O)c2cccnc2)cc1
Reaction time: 17 h

Procedure:
The compounds were prepared according to the procedure described in Example 84 except that the reaction was worked up after 17 hours. The following reagents were used: 3-(4-methoxybenzoyl)pyridine (22 g), diisopropylamine (32.2 mL), 1.55M n-butyl lithium in hexane (148 mL), acetaldehyde N-tert-butylimine (14.75 mL), diethylchlorophosphonate (16.6 mL) and tetrahydrofuran (200 mL). The work up, varied only in that the hydrolysis step was done by treating the intermediate imine with 2N HCl (300 ml) for 9 hours at 70° C. furnished, after basification and extraction, 24 g of crude material made up of a mixture of (E)-3-(4-methoxyphenyl)-3-(3-pyridinyl)-2-propenal and (Z)-3-(4-methoxyphenyl)-3-(3-pyridinyl)-2-propenal. purification of the crude by HPLC (ether; 3 recycles) provided 5.45 g of the less polar aldehyde, (E)-3-(4-methoxyphenyl)-3-(3-pyridinyl)-2-propenal along with 11 g of the isomer (Z)-3-(4-methoxyphenyl)-3-(3-pyridinyl)-2-propenal as oils.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:14]3[N:15]=[C:16]([Cl:26])[CH:17]=[C:18]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:13]3=[N:12][C:11]=2[CH3:27])O)=[C:4]([F:28])[CH:3]=1.ClCCCl.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>CO>[Cl:26][C:16]1[CH:17]=[C:18]([CH2:19][N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[C:13]2[N:14]([C:10]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[F:28])=[C:11]([CH3:27])[N:12]=2)[N:15]=1
Reactant: Cc1nc2c(CN3CCOCC3)cc(Cl)nn2c1C(O)c1ccc(Cl)cc1F
Agent: CC[SiH](CC)CC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Cc1nc2c(CN3CCOCC3)cc(Cl)nn2c1Cc1ccc(Cl)cc1F
Temperature: 70 °C
Yield: 93.6 %

Procedure:
Combine (4-chloro-2-fluorophenyl)(6-chloro-2-methyl-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-3-yl)methanol (0.4 g, 0.94 mmol), 1,2-dichloroethane (25 mL), triethylsilane (0.45 mL, 3 equiv.), and trifluoroacetic acid (0.57 mL, 8 equiv.) in a round bottom flask and place under nitrogen. Heat at 70° C. overnight. Concentrate reaction in vacuo. Load onto a Varian MegaElut® 10 gram SCX ion exchange cartridge (prewashed with methanol). Elute with methanol to remove non-basic impurities. Elute with 2 M ammonia in methanol. Concentrate in vacuo to give the title compound (0.36 g, 94%). LCMS (4 min)=409.0, 411.0, M+1.