Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[N:15]([CH3:26])[N:16]=[N:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=2)=[CH:10][CH:11]=1)=[O:5])C.C(OC(C1N=NC(OCC2N(C)N=NC=2C2C=CC=CN=2)=CC=1)=O)C>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[N:17]=[N:16][N:15]([CH3:26])[C:14]=2[CH2:13][O:12][C:9]2[N:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=2)=[N:20][CH:21]=1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cn3)nnn2C)nn1
Agent: CCOC(=O)c1ccc(OCc2c(-c3ccccn3)nnn2C)nn1
Product: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nn1
Yield: 91.7 %

Procedure:
As described for example 48a, 6-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (500 mg, 1.40 mmol), instead of 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester, was converted to the title compound (424 mg, 92%) which was obtained as an off white solid. MS: m/e=329.1 [M−H]−.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>N1C=CC=CC=1.[Cu]Br>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[C:22]#[N:23])=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: N#Cc1ccccc1I
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: N#Cc1ccccc1Oc1ccc2c(c1)CCN(C1CCC1)CC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (300 mg, 1.38 mmol) was dissolved in pyridine (10 ml), cooled in an ice bath and treated with sodium hydride (60% in mineral oil) (66 mg, 1.66 mmol) under argon. The resulting mixture was stirred for 5 minutes, treated with copper (I) bromide (277 mg, 1.93 mmol) and allowed to warm to room temperature over 30 minutes. A solution of 2-iodobenzonitrile (948 mg, 4.14 mmol) in pyridine (2 ml) was added and the mixture heated under reflux for 2.5 hours. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the title compound (180 mg); MS (ES+) m/e 319 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][C@H:9]([NH2:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].[CH2:19]([O:26][C:27](ON1C(=O)CCC1=O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[CH3:18][O:17][C:13](=[O:16])[CH2:14][CH2:15][N:11]([C:27]([O:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:28])[C@H:9]([CH3:10])[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:12]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: C[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCN(C(=O)OCc1ccccc1)[C@H](C)CNC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 165.7 %

Procedure:
72 g (413 mmol) ((R)-2-amino-propyl)-carbamic acid tert-butyl ester were dissolved in MeOH (350 ml) in a jacketed reactor. A solution of 40 ml (438 mmol) methyl acrylate in MeOH (50 ml) was added over 10 min. After 15 h reaction at RT, 108 g (413 mmol) of N-benzyloxycarbonyloxy-succinimide were added in one portion. After 18 h, the reaction mixture was concentrated under reduced pressure affording a yellow oil (ca 270 g). The oil was re-dissolved in 300 mL MeOH and concentrated under reduced pressure (45° C./160-200 mbar) until constant weight to give 219 g of crude titled product as a yellow oil used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]1[S:20][C:14]2[C:15](=O)[NH:16][N:17]=[CH:18][C:13]=2[CH:12]=1.P(Cl)(Cl)([Cl:23])=O.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>OS([O-])(=O)=O.[K+]>[Cl:23][C:15]1[N:16]=[N:17][CH:18]=[C:13]2[CH:12]=[C:11]([C:3]3[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=3[CH3:1])[C:6]([NH:29][CH:26]3[CH2:28][CH2:27]3)=[O:8])[S:20][C:14]=12
Reactant: NC1CC1
Reactant: Cc1ccc(C(=O)O)cc1-c1cc2cn[nH]c(=O)c2s1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnnc(Cl)c2s1
Temperature: 105 °C

Procedure:
A mixture of 4-methyl-3-(7-oxo-6,7-dihydrothieno[2,3-d]pyridazin-2-yl)benzoic acid (1.01 g, 3.53 mmol) and phosphorus oxychloride (30.0 ml, 322 mmol) was heated to 105° C. for 4 hrs. After cooling to RT, the volatiles were removed in vacuo. The residue was re-dissolved in DCM (50 ml) and treated with TEA (1.49 ml, 10.6 mmol) and dropwise with cyclopropylamine (0.746 ml, 10.6 mmol). The mixture was diluted with 1 M KHSO4 and extracted with CH2Cl2 (3×). The combined organics were dried over Na2SO4, filtered and concentrated over SiO2. Column chromatography (MeOH/CH2Cl2=0→2%) afforded the desired product. Yield: 0.92 g. MS (ESI, pos. ion) m/z: 344 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)#[N:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:31]([C:29]#[N:30])=[CH:32][CH:33]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1CN(C(=O)c2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 98.2 %

Procedure:
In a manner similar to the method described in Example 11, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (84.6 mg, 0.20 mmol) was reacted with 4-cyano-benzoic acid (Aldrich, 35.3 mg, 0.24 mmol), in the presence of HATU (72.0 mg, 0.20 mmol) and iPr2NEt (0.1 mL) in CH2Cl2 (2 mL) at rt for 2 hrs to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-1-(4-cyano-benzoyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (108.5 mg, 98.2%). HRMS (ES+) m/z Calcd for C30H25Cl2F2N3O+H [(M+H)+]: 552.1417, found: 552.1416.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=3)[N:6]=2)[CH2:2]1.C(N(CC)CC)C.[CH:24]([NH:27][C:28]1[N:33]2[N:34]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:36]=[C:32]2[N:31]=[C:30]([C:43]2[CH:50]=[CH:49][C:46]([CH:47]=O)=[CH:45][CH:44]=2)[C:29]=1[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([CH3:26])[CH3:25].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[CH:24]([NH:27][C:28]1[N:33]2[N:34]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:36]=[C:32]2[N:31]=[C:30]([C:43]2[CH:44]=[CH:45][C:46]([CH2:47][N:1]3[CH2:4][CH:3]([C:5]4[N:6]=[C:7]([C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=5)[NH:8][N:9]=4)[CH2:2]3)=[CH:49][CH:50]=2)[C:29]=1[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([CH3:26])[CH3:25]
Reactant: CC(C)Nc1c(-c2ccccc2)c(-c2ccc(C=O)cc2)nc2nc(-c3ccccn3)nn12
Reactant: Cc1cccc(-c2n[nH]c(C3CNC3)n2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: Cc1cccc(-c2nc(C3CN(Cc4ccc(-c5nc6nc(-c7ccccn7)nn6c(NC(C)C)c5-c5ccccc5)cc4)C3)n[nH]2)n1
Reaction time: 1 h
Yield: 2.5 %

Procedure:
138.8 mg (0.51 mmol) 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-6-methylpyridine×2HCl (60% pure) are dissolved in 3.9 mL NMP. 0.15 mL (1.08 mmol) triethylamine are added and the reaction mixture is stirred for one hour. 200 mg (0.46 mmol) 4-(7-Isopropylamino-6-phenyl-2-pyridine-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde and 0.05 mL (0.83 mmol) acetic acid are added. The reaction mixture is stirred over night at room temperature. 107 mg (0.51 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature over night. The reaction mixture is treated with NaHCO3 and the formed precipitate has been filtered off. The filtrate is extracted with methyl-tert.butylether. The organic phase is washed with water, dried (Na2SO4) and the solvent removed. This residue and the precipitate are combined and purified by column chromatography (silicagel, eluents: dichloromethane/methanol) and additionally by HPLC yielding 7.4 mg (2.54%) of the desired compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[CH:7][C:8]([O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:22](=[O:25])([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:22]([C:2]1[CH:11]=[CH:10][CH:5]=[CH:4][C:3]=1[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[CH:7][C:8]([O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1)=[O:25]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Oc2ccc(C#N)cc2)nc2cc(Br)ccc12
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(Oc2ccc(C#N)cc2)nc2cc(-c3ccccc3C=O)ccc12

Procedure:
Prepared analogously to Example 27e from 4-[(7-bromo-4-methyl-quinolin-2-yl)oxy]-benzonitrile, 2-formylbenzeneboric acid, sodium carbonate and tetrakis-(triphenylphosphine)-palladium (0) in toluene/water.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:20][O:21][CH2:22]Cl>C(Cl)Cl.O>[CH:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:20][O:21][CH3:22])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(O)c1
Reactant: COCCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(C(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.5 %

Procedure:
Into methylene chloride (300 mL) was dissolved 3-isopropylphenol (27.24 g, 200 mmol). After cooling the solution in an ice bath, diisopropylethyl amine (69.7 mL, 400 mmol) was added in one portion, followed by the dropwise addition of chloromethyl methyl ether (18.9 mL, 236 mmol) in methylene chloride (50 mL). The reaction mixture was gradually allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with cold water (500 mL) and methylene chloride. The mixture was shaken in a separatory funnel and the layers were separated. The organic layer was extracted with cold water (2×500 mL), dried (MgSO4), and concentrated under vacuum. The product was dissolved in ether (200 mL) and stirred with 5 N NaOH (200 mL) at room temperature for 5 min. The ether layer was separated and extracted with cold 1 N HCl (200 mL), dried (MgSO4), and concentrated under vacuum. The product was chromatographed over silica (0 to 30% EtOAc in hexane gradient), giving 20.0 g (56%) of the title compound.
Reaction SMILES: [N:1]1[C:2](=[O:10])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.Br[C:12]1[CH:20]=[C:19]2[C:15]([C:16](=O)[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1.Cl>C(O)(=O)C>[CH:13]1[CH:12]=[CH:20][C:19]2[NH:18][C:17](=[O:21])/[C:16](=[C:3]3\[C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=4[NH:1][C:2]\3=[O:10])/[C:15]=2[CH:14]=1
Reactant: O=C1C=c2ccccc2=N1
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2/C1=C1\C(=O)Nc2ccccc21
Temperature: 25 °C
Yield: 95 %

Procedure:
Separately adding 6-brome indolone (500 mg, 2.36 mmol), 6-bromoisatin (533 mg, 2.36 mmol of isatin), 15 mL glacial acetic acid and 0.1 mL HCl into a flask, heating and refluxing for 24 hours. Stop the reaction and cooling to room temperature, filtering to obtain a solid, and then washing the solid by water, ethanol, and ethyl acetate. Drying the final product in a vacuum drying box, get brown 6,6′-bidromo isoindigo, the yield was 95%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][CH2:4][C:5]1[N:10]=[CH:9]C(C#N)=[CH:7][CH:6]=1.[OH-:15].[K+].[CH3:17][CH2:18][OH:19]>>[F:1][C:2]([F:14])([F:13])[CH2:3][CH2:4][C:5]1[N:10]=[CH:9][C:17]([C:18]([OH:15])=[O:19])=[CH:7][CH:6]=1
Reactant: CCO
Reactant: N#Cc1ccc(CCC(F)(F)F)nc1
Reactant: [OH-]
Agent: [K+]
Product: O=C(O)c1ccc(CCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a solution of 6-(3,3,3-trifluoropropyl)pyridine-3-carbonitrile (Intermediate 208, 189 mg, 0.945 mmol) in EtOH (20 mL) was added potassium hydroxide (265 mg, 4.72 mmol). The solution was heated at 100 C for 6 h and then additional potassium hydroxide (53 mg, 0.94 mmol) added. After stirring for a further 3 h at 105 C, the reaction mixture was cooled to room temperature, evaporated to dryness and re-dissolved in water (20 mL). The solution was acidified to pH 3 with a 1M aq. HCl solution and extracted with EtOAc (3×25 mL). Combined organics were dried over magnesium sulfate and evaporated to dryness to afford the title compound as a light brown solid (183 mg, 89%). Method C HPLC-MS: MH+ requires m/z=220. Found: m/z=220, Rt=1.12 min (91%).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([OH:13])=O)[C:4]=2[CH:3]=1.[Br:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[C:22]=1[NH2:23]>>[Br:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[C:22]=1[NH:23][C:11]([CH:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:7][O:6][C:5]2[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][C:4]1=2)=[O:13]
Reactant: Nc1c(Br)cccc1Br
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Product: Cc1ccc2c(c1)C(C(=O)Nc1c(Br)cccc1Br)c1ccccc1CO2
Yield: 58.7 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.40 g of Compound A and 1.28 g of 2,6-dibromoaniline in place of aniline to obtain 1.46 g of Compound 7.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:25])[CH2:22][O:23][CH3:24])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:32])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:25])[CH2:22][O:23][CH3:24])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COCC(=O)N1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: COCC(=O)N1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(methoxyacetyl)piperazin-1-yl]quinolin-7-yl}ethanone (0.023 g, 0.064 mmol) and ammonium acetate (0.0490 g, 0.636 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.16 mL, 0.16 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C18H24ClN4O2 (M+H)+: m/z=363.2; Found: 363.1.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[F:22][C:23]([F:27])([F:26])[CH2:24][NH2:25]>>[F:22][C:23]([F:27])([F:26])[CH2:24][NH:25][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Reactant: NCC(F)(F)F
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NCC(F)(F)F)s1
Yield: 68 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using 2,2,2-trifluoroethylamine instead of rac-2-amino-1-butanol, to the title compound (131 mg, 68%) which was obtained as a white solid after purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) and recrystallization from ethyl acetate/heptane. MS: m/e=388.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:19])[C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:20](Br)[CH:21]=[CH2:22].C(=O)([O-])[O-].[K+].[K+].CN1C(=O)[CH2:34][CH2:33][CH2:32]1>>[CH2:20]([N:19]([CH2:34][CH:33]=[CH2:32])[C:6]1[C:7]([C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH:21]=[CH2:22]
Reactant: CN1CCCC1=O
Reactant: Nc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCN(CC=C)c1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 4,4′-dinitro-2-biphenylamine (10.0 g), allyl bromide (20 mL), potassium carbonate (16 g) and NMP (100 mL) was heated to 90–95° C. for 90 hr. The mixture was extracted with tetrahydrofuran (THF)-ethyl acetate-water and purified by crystallization from ethyl acetate to give N,N-diallyl-4,4′-dinitro-2-biphenylamine (7.0 g).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](ON)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.20 g, 0.72 mmol) in dry DCM (20 mL) were added tert-butyl (3R)-3-(aminooxy)piperidine-1-carboxylate 11 (0.19 g, 0.86 mmol, J. Med. Chem. 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.14 g, 1.03 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g, 1.03 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl (3R)-3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate 12 (0.28 g, 82%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH2:14][CH2:13][C:12]3[S:11][C:10]([C:16]([NH2:18])=[O:17])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[C:19]([C:21]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]1)#[CH:20]>>[OH:26][C:21]1([C:19]#[C:20][C:2]2[CH:3]=[CH:4][C:5]3[O:15][CH2:14][CH2:13][C:12]4[S:11][C:10]([C:16]([NH2:18])=[O:17])=[N:9][C:8]=4[C:6]=3[CH:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C#CC1(O)CCCC1
Reactant: NC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: NC(=O)c1nc2c(s1)CCOc1ccc(C#CC3(O)CCCC3)cc1-2

Procedure:
9-Bromo-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxamide (0.15 g) was reacted with 1-ethynylcyclopentanol similar to as described in Procedure E to afford 46.2 mg of 9-[2-(1-hydroxycyclopentyl)ethynyl]-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxamide following reverse phase hplc purification. MS (Q1) 355 (M)+. 1H NMR (400 MHz, DMSO) δ 8.58 (d, J=2.1 Hz, 1H), 8.40 (s, 1H), 7.84 (s, 1H), 7.27 (dd, J=8.3, 2.1 Hz, 1H), 7.01 (t, J=7.6 Hz, 1H), 5.26 (s, 1H), 4.34 (t, J=4.9 Hz, 2H), 3.41 (t, J=4.9 Hz, 2H), 2.00-1.82 (m, 4H), 1.82-1.59 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[C:42](Cl)(=[O:44])[CH3:43].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:42](=[O:44])[CH3:43])[C:5]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(N)c12
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(NC(C)=O)c12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-amine (115 mg, 0.261 mmol) was taken up in THF (2.6 ml) and cooled to 0° C. DIPEA (228 μl, 1.304 mmol) followed by acetyl chloride (93 μl, 1.304 mmol) was added. The mixture was allowed to stir, reaching room temperature overnight. EtOAc and saturated NH4Cl were added. The products were extracted into EtOAc (3×). The combined organic layers were washed with brine, dried over Mg SO4, and concentrated in vacuo to give N-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)acetamide (48B). Reaction products were carrried forward without purification. MS: [M+H]+ m/z 483.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][CH2:10][CH2:11][N:12]1[C:16]3[C:17]([C:21]([O-])=[O:22])=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[CH:13]1)[CH2:2]2.[Li+].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C)C=O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([N:9]1[C:21](=[O:22])[C:17]3[CH:18]=[CH:19][CH:20]=[C:15]4[N:14]=[CH:13][N:12]([C:16]=34)[CH2:11][CH2:10]1)[CH2:2]2
Reactant: O=C([O-])c1cccc2ncn(CCN[C@@H]3CN4CCC3CC4)c12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2cccc3ncn(c23)CCN1[C@@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of lithium (S)-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-benzo[d]imidazole-7-carboxylate (0.2 g, 0.7 mmol) from Step G above, N,N-diisopropylethylamine (0.7 mL, 4.1 mmol), and 1-propanephosphonic acid cyclic anhydride (T3P) (2.1 mL, 3.4 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 7 h. The crude reaction was concentrated under reduced pressure and then purified by SCX column and preparative thin layer chromatography (90:9:1 methylene chloride/methanol/ammonium hydroxide) to afford 6-((S)-quinuclidin-3-yl)-5,6-dihydroimidazo[4,5,1-jk][1,4]benzodiazepin-7(4H)-one: 1H NMR (500 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.86 (dd, J=8.0, 1.0 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 4.85-4.50 (m, 2H), 4.48-4.39 (m, 2H), 3.91-3.33 (m, 1H), 3.31-3.11 (m, 1H), 3.08-3.02 (m, 1H), 2.99-2.89 (m, 1H), 2.81-2.71 (m, 3H), 1.97-1.95 (m, 1H), 1.71-1.56 (m, 3H), 1.49-1.39 (m, 1H).