Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Cl[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10].[Cl:11][C:12]1[C:13]([F:33])=[C:14]([CH:30]=[CH:31][CH:32]=1)[C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16]>C1COCC1>[Cl:11][C:12]1[C:13]([F:33])=[C:14]([C@:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:18]2)([OH:16])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])[CH:30]=[CH:31][CH:32]=1
Reactant: COCCCCCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2F)C1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
A flame dried 250 mL three-necked flask was charged with magnesium turnings (7.02 g, 0.293 mol), a small crystal of iodine and THF (30 mL). The flask was evacuated and refilled with N2. A solution of 1-chloro-4-methoxybutane (28.69 g, 0.234 mol) in THF (120 mL) was added dropwise slowly to the mixture. The reaction mixture was stirred under reflux for 2.5 h and most of magnesium was consumed. The resulting Grignard reagent was used as follows To another 100 mL three-necked flask was added (R)-tert-butyl 3-(3-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (10 g, 0.0293 mol) and THF (100 mL). The flask was evacuated and refilled with N2. The mixture was cooled with dry ice-acetone bath and the Grignard reagent (250 mL) was added. The reaction mixture was allowed to warm slowly to rt while stirring overnight. The mixture was quenched with satd aq NH4Cl (50 mL), extracted with EtOAc (3×), and the combined organic layers were dried over Na2SO4. Evaporation of the solvent gave the crude product. The LC-MS analysis of the crude product indicated the presence of two isomers (95:5). Flash column chromatography, eluting with 10% EtOAc/PE afforded (R)-tert-butyl 3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (9.4 g, 75% yield). 1H NMR (400 MHz, DMSO): 0.68 (m, 1H), 1.50-1.01 (m, 7 H), 1.37 (s, 9H), 1.75 (m, 2H), 2.01 (m, 1H), 3.11 (s, 3H), 3.17 (m, 2H), 3.85 (m, 1H), 7.2 (t, 1H), 7.45 (m, 2H). MS (E/Z): 430 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[N+:17]([O-:19])=[O:18].N1CCCCC1.CN(C=O)C>CC(O)C>[N+:17]([C:16]1[NH:15][CH:14]=[N:13][C:12]=1/[CH:11]=[CH:7]/[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([O-:19])=[O:18]
Reactant: Cc1nc[nH]c1[N+](=O)[O-]
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(/C=C/c2nc[nH]c2[N+](=O)[O-])cc1
Reaction time: 24 h
Yield: 47.9 %

Procedure:
4-Cyanobenzaldehyde (75 g, 0.57 mol) was heated to 110° C. Once melted, 4-methyl-5-nitroimidazole (15 g, 0.12 mol) and piperidine (5 g, 0.06 mol) were added and heating continued for a further 24 hours. DMF (15 mL) and IPA (150 mL) were then added and the precipitate filtered from solution and washed with IPA (50 mL) to leave the product as a yellow solid (13.8 g, 49%). mp>300° C. δH (DMSO-d6) 7.95 (1H, s), 7.88 (2H, d, J=6.8), 7.78 (2H, d, J=6.8), 7.78 (1H, d, J=16.8), 7.50 (1H, d, J=16.8); IR (cm−1) 2239 (C≡N), 1502, 1348 (NO2); MS (m/z) 241.1 (C12H9N4O2 (M+1)).
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([CH3:21])[CH3:20])[CH:13]=2)([CH2:9][CH2:10][CH3:11])[CH2:5][CH2:4]1)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24].[OH-].[Na+]>C1(C)C=CC=CC=1>[NH3:3].[C:26]1([O:25][C:23]([N:3]2[CH2:4][CH2:5][C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([CH3:21])[CH3:20])[CH:13]=3)([CH2:9][CH2:10][CH3:11])[CH2:7][CH2:8]2)=[O:24])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCC1(c2cccc(OC(C)C)c2)CCN(CC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCC1(c2cccc(OC(C)C)c2)CCN(C(=O)Oc2ccccc2)CC1
Product: N
Temperature: 50 °C
Yield: 96.1 %

Procedure:
To N-ethyl-4-(3-(1-methylethoxy)phenyl)-4-n-propylpiperidine (Preparation 65, 10.9 g) in toluene (80 ml) under nitrogen at 85° C. was slowly added phenyl chloroformate (5.63 ml, 44.88 mmol) over 20 min. The mixture was then heated under reflux for 4 h. The solution was cooled to 50° C. and 5M aqueous sodium hydroxide (10 ml) was added. Once the solution had cooled to room temperature the layers were separated and the organic extract was washed with methanol:1N aqueous hydrochloric acid (1:1, 2×10 ml), methanol 1N aqueous sodium hydroxide solution (1:1, 20 ml) and water (20 ml). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give the crude product. This was purified by silica column chromatography using ethyl acetate:hexane:0.880 ammonia (15:85:1) to give the title compound as a pale yellow oil (6.9 g, 42% over three steps).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][C@H:40]1[CH2:45][O:46][CH3:47])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:31])([F:29])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:41][C@H:40]1[CH2:45][O:46][CH3:47])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: COC[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COC[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CCN1C(=O)OC(C)(C)C

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-(S)-Methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[NH:15][CH:16]=2)=[CH:6][CH:5]=1.O>C(O)(=O)C.CCOC(C)=O>[Br:1][C:16]1[NH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]=1[CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: O=C(O)c1cc(CCc2ccc(Cl)cc2)c[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(CCc2ccc(Cl)cc2)c(Br)[nH]1
Yield: 57.7 %

Procedure:
Bromine (0.049 mL, 0.962 mmol) was added dropwise over 5 minutes to a stirring solution of 39 (0.200 g, 0.802 mmol) in acetic acid (2.5 mL). When the reaction was judged complete by HPLC (30 min), H2O was added, and the solid that precipitated was filtered off and washed with H2O. The light purple solid that was obtained was dissolved in EtOAc, washed with Na2SO3 and H2O, then dried with Na2SO4, filtered, and concentrated. The product was purified by preparative reverse phase HPLC with 40:60 H2O:CH3CN (w/0.05% TFA); 20 mL/min.; λ=214 nM. 0.1520 g (57.7%) of 70 was obtained as a fluffy white solid. 1H (CD3OD, 400 MHz): δ 7.22 (2H, d, J=8.8 Hz), 7.12 (2H, d, J=8.8 Hz), 6.65 (1H, s), 2.81 (2H, t, J=7.3 Hz), 2.67 (2H, t, J=7.3 Hz) ppm. Partial 13C (CD3OD, 100 MHz): δ 163.33, 141.42, 132.54, 131.03, 129.18, 124.73, 117.15, 105.84, 36.72, 29.04 ppm. DEPT (CD3OD, 100 MHz): CH2 carbons: 36.72, 29.04; CH carbons: 131.03, 129.18, 117.15 ppm. HPLC: 10.484 min.
Reaction SMILES: O.NN.[CH2:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=1)[CH3:5]>C(O)C.[Pd]>[CH2:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[N:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=1)[CH3:5]
Reactant: CCc1ccccc1Oc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCc1ccccc1Oc1ccc(N)cn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 208.7 %

Procedure:
In a 50 mL round-bottomed flask 2-[(2-ethylphenyl)oxy]-5-nitropyridine (Intermediate 45, 623 mg) was dissolved in ethanol (10 mL) to give a pale orange solution. Palladium on carbon (244 mg, 0.230 mmol) and hydrazine hydrate (0.442 mL, 4.59 mmol) were added. The reaction mixture was stirred at 90° C. After 3 hours the reaction was completed. The reaction mixture was filtered and the organic phase was evaporated under vacuum affording 1.1408 g of a dark orange solid that was charged on a 10 g SCX cartridge. It was then flushed with 200 mL of ethanol followed by 50 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as dark orange solid (456.1 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[C:19]2[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:18]=2[O:17][CH2:16][CH2:15]1)[C:6]([O:8][CH3:9])=[O:7].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]2[O:17][CH2:16][CH2:15][N:14]([CH2:13][C:12]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])[C:19]=2[CH:20]=1
Reactant: COC(=O)c1ccc(CN2CCOc3ccc([N+](=O)[O-])cc32)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN2CCOc3ccc(N)cc32)c(OC)c1
Yield: 98.9 %

Procedure:
Palladium-on-carbon (10% w/w, 0.2 g.) was added to a solution of (G) (0.69 g.) in ethyl acetate (50 ml.) in a hydrogenation bottle and the mixture hydrogenated at a pressure of 3.17 bars of hydrogen. When the uptake of hydrogen had ceased, catalyst was removed by filtration through diatomaceous earth. The filter pad was washed with ethyl acetate and the filtrate and washings were evaporated to give methyl 4-(6-amino-2,3-dihydrobenz-1,4-oxazin4-ylmethyl)-3-methoxybenzoate (0.625 g., 91%) as a foam; NMR: 3.1(br s,2H, NH2), 3.3(t,2H, OCH2CH2N), 3.85(m,6H, OCH3 +CO2CH3), 4.2(t,2H, OCH2CH2N), 4.45(s, 2H, CH2 -Ar), 6.0(m,2H), 6.55(d,1H), 7.3(d,1H), 7.55(m, 2H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O-:21])=[O:20])=[C:8]([C:11]3[N:12]=[CH:13][N:14]4[CH:18]=[CH:17][S:16][C:15]=34)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].C(=O)([O-])O.[Na+].[C:30]([O:36][CH2:37]I)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O:21][CH2:37][O:36][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:20])=[C:8]([C:11]3[N:12]=[CH:13][N:14]4[CH:18]=[CH:17][S:16][C:15]=34)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(C)(C)C(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3ncn4ccsc34)[C@H](C)[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3ncn4ccsc34)[C@H](C)[C@H]12
Temperature: -30 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 27 mg of sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 0.5 ml of DMF was added 4.0 mg of sodium hydrogen carbonate, and the mixture was cooled to −30° C. under the atmosphere of argon. Pivaloyloxymethyl iodide (30 mg) was added, and the reaction mixture was stirred at −20-−30° C. for 1 hour. The reaction mixture was diluted with 20 ml of ethyl acetate and 10 ml of semi-saturated aqueous saline, and the mixture was stirred and separated. The organic layer was washed with semi-saturated aqueous saline, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to a volume of about 1 ml. It was purified by column chromatography on silica gel (ethyl acetate-ethyl acetate:methanol=97:3), and the solvent was concentrated under reduced pressure to a volume of about 0.5 ml and added dropwise to isopropyl ether. The resulting precipitate was collected by filtration, and desiccated under reduced pressure to give 17 mg of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[N:26]([CH2:29][C:30]([C:32]1[CH:33]=[CH:34][C:35]2[N:39]=[C:38]([C@@H:40]3[CH2:44][CH2:43][CH2:42][NH:41]3)[NH:37][C:36]=2[CH:45]=1)=[O:31])=[N+:27]=[N-:28].Cl.[CH3:47][N:48]([CH3:59])[C@H:49]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:50](O)=[O:51].CCN(C(C)C)C(C)C>CN(C)C=O>[N:26]([CH2:29][C:30]([C:32]1[CH:33]=[CH:34][C:35]2[N:39]=[C:38]([C@@H:40]3[CH2:44][CH2:43][CH2:42][N:41]3[C:50](=[O:51])[C@H:49]([N:48]([CH3:47])[CH3:59])[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[NH:37][C:36]=2[CH:45]=1)=[O:31])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=NCC(=O)c1ccc2nc([C@@H]3CCCN3)[nH]c2c1
Reactant: CN(C)[C@@H](C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@@H](C(=O)N1CCC[C@H]1c1nc2ccc(C(=O)CN=[N+]=[N-])cc2[nH]1)c1ccccc1
Reaction time: 6 h
Yield: 50.1 %

Procedure:
To a solution of J.31 (1.8 g, 4.86 mmol) in ethyl acetate (5 mL) was added HCl/dioxane (10 mL of 4N), and the reaction was stirred 4 hr. The solvents were removed in vacuo, and the HCl salt was exposed to high vacuum for 18 h to give (S)-2-azido-1-(2-(pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)ethanone.2HCl a yellow solid. HATU (1.94 g, 5.10 mmol) was added to the HCl salt of (S)-2-azido-1-(2-(pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)ethanone (1.8 g, 4.86 mmol), (R)-2-(dimethylamino)-2-phenylacetic acid HCl salt (1.05 g, 4.86 mmol), and Hunig's base (3.4 mL, 19.4 mmol) in dimethylformamide (50 mL) while being rapidly stirred 6 h. The solvent was removed in vacuo and the reside was partitioned into two lots and separately pre-absorbed onto SiO2 (dichloromethane), and subjected to flash chromatography on a 40 M Biotage silica gel column pre-equilibrated 2% B, and eluted with 2% B (150 mL); Segment 2: 2-40% B (1200 mL); Segment 3: 40-80% (600 mL). A=dichloromethane; B=25% methanol/dichloromethane to give J.31a (R)-1-((S)-2-(6-(2-azidoacetyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-(dimethylamino)-2-phenylethanone (combined lots: 1.05 g (50%)) as a yellow foam. 1H NMR (500 MHz, DMSO-d6) δ: 8.16 (s, 1H), 7.82 (dd, J=8.8, 1.5 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.60-7.56 (m, 5H), 5.51 (s, 1H), 5.22 (dd, J=8.2, 2.8, 1H), 4.95 (m, 2H), 4.09-4.05 (m, 1H), 3.17-3.12 (m, 1H), 2.90/2.84 (br. s, 6H), 2.23-2.19 (m, 1H), 2.21-1.89 (m, 3H). LC (D-Cond. 1): RT=1.5 min; LC/MS: Anal. Calcd. for [M+H]+ C23H26N7O2: 432.22; found: 431.93. HRMS: Anal. Calcd. for [M+H]+ C23H26N7O2: 432.2148; found: 432.2127.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[CH:18]1([NH:21][C:22](=[O:36])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:20][CH2:19]1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH:18]1([NH:21][C:22](=[O:36])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH2:2][C:3]4[CH:12]=[N:11][C:10]5[N:9]6[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]6[C:7](=[O:17])[NH:6][C:5]=5[CH:4]=4)[CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:19][CH2:20]1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)c(F)c1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)c(F)c1
Temperature: 100 °C
Yield: 86.2 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (150 mg, 0.643 mmol), N-cyclopropyl-3-fluoro-4-(piperazin-1-yl)benzamide (203 mg, 0.772 mmol), (cyanomethyl)trimethylphosphonium iodide (250 mg, 1.029 mmol) and N,N-diisopropylethylamine (562 μl, 3.22 mmol) were suspended in Propiononitrile (Volume: 1931 μl) and heated in a closed vial at 100° C. for 4 h. The reaction mixture became a dark brown solution with precipitate. It was cooled to room temperature and the precipitate was filtered off, washed with MeCN (2 mL) and suspended in MeCN with heating and sonication. The suspension was cooled to ambient temperature, and the precipitate was filtered off, washed with MeCN (2 mL) and dried in vacuum to afford (S)—N-cyclopropyl-3-fluoro-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (265 mg, 0.554 mmol, 86% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.48 (s, 1H), 8.31 (d, J=4.3 Hz, 1H), 7.53-7.69 (m, 4H), 7.02 (t, J=8.8 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 4.50 (br. d, J=12.9 Hz, 1H), 3.84 (dd, J=11.2, 2.7 Hz, 1H), 3.37 (s, 2H), 3.01-3.13 (m, 4H), 2.80 (tq, J=7.4, 3.9 Hz, 1H), 2.60 (td, J=12.6, 2.5 Hz, 1H), 2.44-2.51 (m, 4H), 2.04 (br. d, J=12.9 Hz, 1H), 1.85 (br. d, J=12.4 Hz, 1H), 1.64 (br. d, J=12.6 Hz, 1H), 1.33-1.56 (m, 3H), 0.61-0.71 (m, 2H), 0.50-0.60 (m, 2H); [M+H] calc'd for C26H31FN6O2, 479; found, 479.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([O:13]C)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:15][C@H:16]([C:18]([NH:20][C@H:21]([C:23]([OH:25])=[O:24])[CH3:22])=[O:19])[CH3:17].[OH-].[Na+]>>[NH2:1][C@H:2]([C:11]([NH:15][C@H:16]([C:18]([NH:20][C@H:21]([C:23]([OH:25])=[O:24])[CH3:22])=[O:19])[CH3:17])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O

Procedure:
0.2 ml of aqueous solution containing 2 mM Mal-Tyr-OMe, 50 mM H-Ala-Ala-OH, 25 mM NaOH and 0.3 M α-chymotrypsin are deep-frozen. Subsequently the reaction mixture is kept at -25° C. until the Mal-Tyr-OMe is consumed. Following thawing, the yield is determined analytically by RP-HPLC and amounts to 94% of theory.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[C:24]([F:31])[CH:23]=1.[CH3:32][PH:33](=[O:35])[CH3:34]>>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([P:33]([CH3:34])([CH3:32])=[O:35])=[CH:23][C:24]=2[F:31])[CH:3]=1)[CH3:11]
Reactant: CC(Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: C[PH](C)=O
Reactant: OB(O)c1ccc(Br)cc1F
Product: CC(Oc1cc(-c2ccc(P(C)(C)=O)cc2F)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared from 5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine, 4-bromo-2-fluoro-phenyl boronic acid, and dimethylphosphine oxide following the same procedures as Example 1 Step 1 and Step 3; ESMS: m/z 471 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[CH2:12][CH:11]([C:25](O)=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:28][C:29]1[CH:30]=[C:31]([C:35](=[N:37]O)[NH2:36])[CH:32]=[CH:33][CH:34]=1>>[F:28][C:29]1[CH:30]=[C:31]([C:35]2[N:37]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:26][N:36]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)C1CC(c2cccc(C(F)(F)F)c2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1cccc(F)c1
Product: O=C(N1CCOCC1)N1CC(c2cccc(C(F)(F)F)c2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
100 mg (0.26 mmol) of the compound from Example 147A and 60 mg (0.39 mmol) of the compound from Example 73A were reacted according to the General Method 2. Yield: 75 mg (57% of theory)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1.O>CN(C)C=O>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[CH:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: Oc1ccc(-c2nncn2-c2ccncc2)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2nc(COc3ccc(-c4nncn4-c4ccncc4)cc3)ccc2c1
Temperature: 60 °C
Yield: 64.2 %

Procedure:
To a solution of 4-(4-Pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-phenol (44 mg) in dimethyl formamide (1 ml) in a 7 ml Teflon capped vial was added cesium carbonate (185 mg) and 2-Chloromethyl-quinoline (37 mg) and the reaction mixture heated on a shaker plate at 60° C. for 18 h. The reaction mixture was poured into water and extracted with methylene chloride, dried magnesium sulfate, filtered and concentrated to provide the title compound (45 mg). 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.65 (d, J=6.0 Hz, 2 H), 8.37 (d, J=8.3 Hz, 1 H), 8.03 (d, J=8.7 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.78 (m, 1 H), 7.70 (d, J=8.3 Hz, 1 H), 7.61 (t, J=5.8 Hz, 1 H), 7.40 (m, 4H), 7.14 (d, J=9.1 Hz, 2 H), 5.38 (s, 2H); MS: (M+H m/z=380.2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[C:5]2[CH3:18].O1CCCC1.[F:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>C(N(CC)CC)C>[C:14]([O:13][C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=3)(=[O:33])=[O:32])=[CH:10][CH:9]=2)[C:5]([CH3:18])=[N:6]1)=[O:12])([CH3:15])([CH3:17])[CH3:16]
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc(N)cc12
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nn(C(=O)OC(C)(C)C)c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Yield: 6.8 %

Procedure:
N-(N-tert-Butoxycarbonyl-3-methyl-1H-indazol-5-yl)-3-fluorobenzenesulfonamide can be obtained as described in Example 1 from 0.9 g of 5-amino-N-tert-butoxycarbonyl-3-methyl-1H-indazole, 40 ml of tetrahydrofuran, 1 ml of triethylamine and 0.78 g of 3-fluorobenzenesulfonyl chloride. 0.1 g of N-(N-tert-butoxycarbonyl-3-methyl-1H-indazol-5-yl)-3-fluorobenzenesulfonamide is thus obtained in the form of a cream solid melting at 195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][CH2:22][CH2:23]O>CC(=O)CC>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:23][CH2:22][Cl:21])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: ClCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 32 %

Procedure:
A mixture of 1-(4-chlorobenzyl)piperazine (21.05 g; 0.1 mole), anhydrous potassium carbonate (20.7 g; 0.15 mole) and 2-chloroethanol (8.85 g; 0.11 mole) in butanone (270 ml) was stirred at reflux for 61/2 hr, cooled, and the solvent removed in vacuo. Chromatography of the residue on silica eluting with chloroform gave 8.74 g (34%) of the title compound as an oil, νmax (film) 3350, 2910, 2800, 1595 cm-1 ; (Found; C, 61.48; H, 7.96; N, 10.13; C13H19N2ClO requires; C, 61.28; H, 7.52; N, 11.00%).