Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.C(O[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[CH:12]=[N:11][CH:10]=1)C.[CH3:25][NH:26][O:27][CH3:28].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:23][C:19]1[CH:18]=[C:17]([C:16]#[C:15][C:13]2[CH:12]=[N:11][CH:10]=[C:9]([CH:14]=2)[C:8]([N:26]([O:27][CH3:28])[CH3:25])=[O:24])[CH:22]=[CH:21][CH:20]=1
Reactant: CNOC
Reactant: CCOC(=O)c1cncc(C#Cc2cccc(F)c2)c1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cncc(C#Cc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
Sequentially add a 2 M solution of trimethylaluminum in toluene (0.64 g, 8.91 mmol) and 5-(3-fluorophenylethynyl)-nicotinic acid ethyl ester (0.24 g, 0.89 mmol), (prepared essentially as described in PREPARATION 17), to a solution of N,O-dimethylhydroxylamine (0.435 g, 4.46 mmol) in anhydrous toluene (4.0 mL) at 0° C. After 30 min, warm to room temperature and stir overnight. Dilute the reaction with ethyl acetate and an aqueous saturated solution of Rochelle salt (potassium sodium tartrate) and stir vigorously for 1 h. Separate the organic layer; dry (magnesium sulfate), filter and concentrate. Purify the resulting residue by silica gel chromatography, eluting with a linear gradient of 100:0 to 60:40 tetrahydrofuran:hexanes, to give the title compound as a pale yellow oil (0.084 g, 33%).
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([C:21]#[C:22][Si](C)(C)C)[C:10]([NH2:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Cl.[OH-].[Na+]>C(O)(C)(C)C.O>[C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:21]=[CH:22][NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2nc(N)c(C#C[Si](C)(C)C)nc2-c2ccc(C)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccc(-c2nc3cc[nH]c3nc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5,6-Di-p-tolyl-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (step 4)(170 mg, 0.458 mmol) in tert-BuOH (5 ml) at RT was treated with potassium tert-butoxide (205 mg, 1.830 mmol) and heated at reflux for 3 hours. After cooling to RT, conc. HCl (0.5 ml, 16.46 mmol) was added and the mixture was heated at reflux for 3 hours and stirred at RT overnight. The mixture was added to water (100 ml) and the pH was adjusted to pH 10 using 2M NaOH. The aqueous portion was extracted with DCM (×3) and the combined organic extracts were passed through a phase separating column. The solvent was removed under reduced pressure and purification of the crude product by chromatography on silica eluting with 0-20% EtOAc in iso-hexane afforded the titled compound;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Reactant: C1CCNCC1
Solvent: CCO
Product: N#Cc1c(-c2ccco2)nc(N)nc1N1CCCCC1

Procedure:
From 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and piperidine in ethanol. EI-MS m/e (%): 269 (M+, 36), 268 ([M—H]+, 100), 240 (38).
Reaction SMILES: [NH2:1][C@@H:2]([C:20]([NH:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH2:34]([S:41](Cl)(=[O:43])=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[CH2:34]([S:41]([NH:1][C@@H:2]([C:20]([NH:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:11])=[O:10])(=[O:43])=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](N)C(=O)NCC(=O)OCc2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)NCC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
The oily residue of the compound of Example 9 was dissolved in 5 mL of DMF, cooled to 0° C. and neutralized with 1 mL of TEA. To the solution was added BnSO2Cl (397 mg, 2.0 mmol) and the solution was stirred at 0° C. for 3 h and 25° C. for 3 h. DMF was removed and residue was dissolved in 100 mL of EtOAc and 20 mL of water. The organic layer was separated, washed with sat. NaHCO3 (10 mL), water (10 mL), 1N HCl (10 mL) and sat. NaCl (3×10 mL), dried with MgSO4, filtered and evaporated. The solid residue was purified by column chromatography on silica gel (EtOAc) to give the title compound (328 mg, 30% yield) as a powder. ES-MS (M+H)+630.5
Reaction SMILES: F[B-](F)(F)F.[N:6]1(OC(N(C)C)=[N+](C)C)[C:10]2C=CC=CC=2N=N1.[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[C:37]([S:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=O)=[C:38]([Cl:41])[CH:39]=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CN.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[C:37]([S:42][CH2:43][CH2:44][CH2:45][C:46](=[O:48])[NH:6][CH3:10])=[C:38]([Cl:41])[CH:39]=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCC(=O)O)c2CC1
Agent: CN
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)CCCSc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.1 %

Procedure:
Add O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (123 mg, 0383 mmol) portion wise to a solution of 3-tert-butoxycarbonyl-7-chloro-6-(3-carboxy-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (146 mg, 0365 mmol) and methylamine (182 μL, 0.365 mmol) in anhydrous DMF (5 mL) under nitrogen at 0° C. Stir for 15 min then add diisopropylethylamine (127 μL, 0.73 mmol) in anhydrous DMF (1 mL) and continue to stir at, 0° C. for 1 h. Warm to room temperature and continue to stir overnight Pour into water (50 mL) and extract with EtOAc (3×20 mL). Wash the combined organic extracts with saturated aqueous NaHCO3 (50 mL) and brine (50 mL). Dry over MgSO4, filtrate and concentrate in vacuo to give a pale yellow oil (74 mg). MS (ES+) m/z: 398 (M+H)+. Purify using Mass-guided reverse phase HPLC [Supelco Discovery C18 column (21.2×100 mm, 5 μm packing), 25 mL/min flow rate, eluting with water/acetonitrile/acetic acid gradient over 12 min, fraction collection triggered by Electrospray MS]. Concentrate in vacuo to give the desired intermediate as a colourless oil (30 mg, 20%). MS (ES+) m/z: 435 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[N-:10]([C:13]#[N:14])[C:11]#[N:12].[Na+]>>[C:11]([N:10]=[C:13]([NH2:14])[NH:4][C:3]1[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=1[F:9])#[N:12]
Reactant: N#C[N-]C#N
Reactant: Nc1c(F)cccc1F
Agent: [Na+]
Product: N#CN=C(N)Nc1c(F)cccc1F

Procedure:
2,6-Difluoroaniline and sodium dicyanamide were procesed as described in Example 71A to provide the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Mn]([O-])(=O)(=O)=[O:17].[K+].[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:17])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=S([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C1COCCN1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 10 g 4-(4-Nitro-phenyl)-morpholine in 200 mL DCM, 32 g Benzyl-triethyl-ammonium chloride and 22.7 g potassium permanganate (325 mesh) were cautiously added at RT. After stirring for 1 h at RT the reaction mixture was heated to reflux for 10 h. Then a solution of 95 g Na2SO3 in 450 mL water were added under ice cooling and vigourous stirring. The mixture was filtered trough a pad of celite and the filtrate was concentrated under reduced pressure. The yellow solid was stirred with 250 mL water and the precipitated product was collected by filtration. This crude product was purified by chromatography on silica gel eluting with a gradient of DCM/MeOH 100%->50%. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 2.6 g.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)N)=[CH:4][CH:3]=1.Cl.O1CCOCC1.C(O[CH:29](OCC)[CH2:30][CH2:31][CH2:32][NH:33][CH3:34])C.Cl>C(OCC)(=O)C.C(O)C.O>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:30]([CH2:31][CH2:32][NH:33][CH3:34])=[CH:29]2)=[CH:4][CH:3]=1
Reactant: NN(CCc1ccc(F)cc1)c1ccc(Cl)cc1
Reactant: CCOC(CCCNC)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CNCCc1cn(CCc2ccc(F)cc2)c2ccc(Cl)cc12
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
The title compound was prepared by General Method 3. 1-(4-fluorophenethyl)-1-(4-chlorophenyl)hydrazine (500 mg) was converted into its hydrochloride salt by dissolving in ethyl acetate and treatment of dioxane-HCl. The salt was dissolved in ethanol/water (1/1; 4 mL)) and was heated to 60° C. 4,4-diethoxy-N-methylbutan-1-amine (0.35 g) was added and the temperature was raised to 70-80° C. 28% aqueous HCl (0.24 mL) was added and the heating was continued for 40 min. Additional amount of 4,4-diethoxy-N-methylbutan-1-amine (0.3 g) and % aqueous HCl (0.3 mL) was added and heating was continued for additional 3 h after which the reaction mixture was cooled and stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (eluent EtOAc/EtOH/NH3: 7/3/1) to obtain 600 mg of product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[C:20]([NH:22][C:23]3[CH:28]=[N:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=3)[N:19]=[CH:18][C:17]=2[N:31]2[CH:35]=[CH:34][C:33]([C:36](O)=[O:37])=[CH:32]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:39]([O:46][CH2:47][CH2:48][NH2:49])([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].C(N(C(C)C)C(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C=O)C>[Si:39]([O:46][CH2:47][CH2:48][NH:49][C:36]([C:33]1[CH:34]=[CH:35][N:31]([C:17]2[C:16]([NH:15][CH2:14][CH:10]3[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]3)=[CH:21][C:20]([NH:22][C:23]3[CH:28]=[N:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=3)=[N:19][CH:18]=2)[CH:32]=1)=[O:37])([C:42]([CH3:44])([CH3:45])[CH3:43])([CH3:41])[CH3:40]
Reactant: CC(C)(C)[Si](C)(C)OCCN
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2-n2ccc(C(=O)O)c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2-n2ccc(C(=O)NCCO[Si](C)(C)C(C)(C)C)c2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.9 %

Procedure:
1-(4-((1-(tert-Butoxycarbonyl)piperidin-3-yl)methylamino)-6-(5-cyanopyrazin-2-ylamino)pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (80 mg, 0.154 mmol) was dissolved in DMF (1.5 mL). 2-(tert-Butyldimethylsilyloxy)ethanamine (41 mg, 0.230 mmol), N-ethyldiisopropylamine (30 mg, 0.230 mmol), 1-hydroxy benzotriazole hydrate (31 mg, 0.230 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (44 mg, 0.23 mmol) were added to the solution and the reaction mixture was stirred for 14 h at room temperature. The solution was partitioned between dichloromethane and water. The two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and evaporated to give tert-butyl 3-((5-(3-(2-(tert-butyldimethylsilyloxy)ethylcarbamoyl)-1H-pyrrol-1-yl)-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (80 mg, 78%) which was used in the next step without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:12]1[N:17]=[C:16]([Cl:18])[CH:15]=[CH:14][N:13]=1.[OH-].[Na+]>O.CC(C)=O>[Cl:18][C:16]1[CH:15]=[C:14]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:13]=[CH:12][N:17]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Temperature: 62.5 °C
Reaction time: 1 h

Procedure:
4-Nitrophenol (2.8 g, 20.1 mmol), 2,4-dichloro-pyrimidine (3 g, 20.1 mmol), NaOH (0.8 g, 20.1 mmol) dissolved in H2O/acetone (80 ml; 1:1) are stirred at 60-65° C. for 1 h. The reaction solution is concentrated under reduced pressure and flash chromatographed (silica gel, 4.5×22 cm, AcOEt/hexane=1:4) to give the title compound of Stage 21.2 as a colorless solid: M+H=252/254; 1H-NMR (400 MHz, DMSO-d6): 8.67 (s, 1H, pyrimidinyl), 8.34 (d, 9 Hz, 2H, phenyl), 7.58 (d, 9 Hz, 2H, phenyl), 7.53 (s, 1H, pyrimidinyl); Rf (AcOEt/hexane=1:1): 0.16; m.p.=125.4-126.6° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:35]/[O:36][C:37]2([C:40]([O:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[CH2:39][CH2:38]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[N:28]=[C:27]([CH2:29]OS(C)(=O)=O)[CH:26]=[N:25]2)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:64]1[CH2:69][CH2:68][CH:67]([NH:70][C:71](=[O:77])[O:72][C:73]([CH3:76])([CH3:75])[CH3:74])[CH2:66][CH2:65]1>CN(C=O)C.CCOC(C)=O.[Li+].[Cl-]>[C:73]([O:72][C:71]([NH:70][CH:67]1[CH2:66][CH2:65][N:64]([CH2:29][C:27]2[CH:26]=[N:25][N:24]([CH2:23][C@@H:19]3[C@H:18]([NH:17][C:15](=[O:16])/[C:14](=[N:35]\[O:36][C:37]4([C:40]([O:42][CH:43]([C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)[C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)=[O:41])[CH2:38][CH2:39]4)/[C:12]4[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[S:10][CH:11]=4)[C:21](=[O:22])[NH:20]3)[N:28]=2)[CH2:69][CH2:68]1)=[O:77])([CH3:74])([CH3:76])[CH3:75]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(COS(C)(=O)=O)n2)cs1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(CN3CCC(NC(=O)OC(C)(C)C)CC3)n2)cs1
Reaction time: 3 h
Yield: 72.2 %

Procedure:
Benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((4-(((methylsulfonyl)oxy)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (64 mg, 0.081 mmol) and sodium iodide (18.1 mg, 0.121 mmol) were stirred in DMF (700 μL) for 14 h, whereupon cesium carbonate (33.4 mg, 0.103 mmol) and tert-butyl piperidin-4-ylcarbamate (17.7 mg, 0.089 mmol) were added. After 3 h of additional stirring the mixture was diluted with EtOAc and LiCl (5% aq) solution. The aqueous layer was extracted with EtOAc (2×) and the combined organic layers were washed with LiCl (5% aq) solution, brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (1-8% MeOH-DCM), affording the title compound (52.6 mg, 73%) as an off-white solid. LCMS: Rt=0.98 min, m/z=899.7 (M+1) Method 2m_acidic.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12]C(C)=O)[C:9]([S:16]([CH2:18][CH3:19])=[O:17])=[CH:8][C:4]=1[C:5]([OH:7])=O.O.ClC(OCC)=O.[CH:27]1([N:32]2[CH2:36][CH2:35][CH2:34][CH:33]2[CH2:37][NH2:38])[CH2:31][CH2:30][CH2:29][CH2:28]1>C(N(CC)CC)C.CC(C)=O>[CH:27]1([N:32]2[CH2:36][CH2:35][CH2:34][CH:33]2[CH2:37][NH:38][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:16]([CH2:18][CH3:19])=[O:17])[C:10]([NH2:12])=[CH:11][C:3]=2[O:2][CH3:1])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCS(=O)c1cc(C(=O)O)c(OC)cc1NC(C)=O
Reactant: NCC1CCCN1C1CCCC1
Agent: CCOC(=O)Cl
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCS(=O)c1cc(C(=O)NCC2CCCN2C2CCCC2)c(OC)cc1N
Reaction time: 2 h

Procedure:
85.5 g of 2-methoxy-4-acetamino-5-ethylsulphinyl benzoic acid, 85 ml of water, 342 ml of acetone and 31 g of triethylamine are placed in a 1 liter flask fitted with an agitator, a thermometer and a dropping funnel. The mixture is agitated until the solids dissolve, then 32.5 g of ethyl chloroformate is added drop by drop while the temperature is kept at about 10° C. The reaction medium is agitated for 30 minutes at room temperature then cooled to 5°-10° C. and 50.4 g of 1-cyclopentyl-2-aminomethylpyrrolidine is added drop by drop in the course of 1 hour. Agitation is continued for 2 hours at room temperature, then the reaction mixture is evaporated to dryness under vacuum. The residue is dissolved in 300 ml of water and the suspension is extracted with 500 ml then twice with 300 ml of methylene chloride. The organic phase is washed twice with 200 ml of water and evaporated under vacuum. The oily residue is dissolved hot in 300 ml of water. 90 ml of soda lye is added and the medium is heated to reflux for 2 hours 30. An oil appears rapidly. It is cooled, the suspension is extracted twice with 250 ml methylene chloride, and the organic solution is washed three times with 200 ml of water. It is dried over magnesium sulphate, filtered and evaporated to dryness under vacuum. The residue is dissolved in 320 ml of ethyl acetate, then the product is left to crystallise in a refrigerator. The crystals are filtered off and dried in an oven at 50° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[O:17][CH3:18].Br[C:20]1[N:24]2[N:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[N:28][C:23]2=[N:22][CH:21]=1.C([O-])(O)=O.[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]2[N:24]3[N:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[N:28][C:23]3=[N:22][CH:21]=2)=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1F
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(-c2cnc3nc(C(F)(F)F)cnn23)ccc1F
Temperature: 95 °C
Reaction time: 17 h
Yield: 47 %

Procedure:
A mixture of 2-(4-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.637 g, 2.528 mmol), 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.5 g, 1.873 mmol) and saturated aqueous NaHCO3 (10 ml) in 1,2-dimethoxyethane (25 ml) was degassed by evacuation and refilling with nitrogen three times. Tetrakis(triphenylphosphine)palladium(0) (0.169 g, 0.078 mmol) was added and the mixture was stirred under nitrogen at 95° C. for 17 h. After allowing to cool to ambient temperature, the mixture was diluted with ethyl acetate then filtered through glass fibre paper. The combined filtrates were partitioned between water (100 ml) and ethyl acetate (100 ml). The organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 25% EtOAc/isohexane), to give 275 mg (47%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 4.00 (3H, s), 7.26 (1H, dd, J 10.9, 8.4 Hz), 7.61-7.64 (1H, m), 7.76 (1H, dd, J 2.1, 8.1 Hz), 8.58 (1H, s), 8.81 (1H, s).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=C(C)O[N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:33](O)=[O:34]>>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:38]([CH3:39])=[C:30]([O:29][CH3:28])[CH:31]=2)=[C:5]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=1)(=[NH:11])[NH2:14]
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Reactant: COc1cc(C(=O)O)ccc1C
Agent: Cl
Product: COc1cc(C(=O)NCc2ccc(C(=N)N)cc2NCC(=O)O)ccc1C

Procedure:
Compound 58d was reacted with 3-methoxy-4-methylbenzoic acid and subsequently hydrogenated according to the procedure described in Example 58, to give example 68. ESI-MS m/e 371.5 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[CH3:12]>[Pd].C(O)(=O)C>[F:1][C:2]1[C:3]([CH3:12])=[C:4]([F:11])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1F
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1c(F)ccc(N)c1F
Yield: 69.9 %

Procedure:
To acetic acid (1.2 l) are added 5% Pd-C (24 g) and 2,6-difluoro-3-nitrotoluene (238.7 g) and the mixture is subjected to catalytic reduction at room temperature under 4.5 atoms. The 5% Pd-C is filtered off and the acetic acid is distilled off under reduced pressure. The residue is poured into ice-water, neutralized, extracted with dichloromethane, and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is distilled under reduced pressure to give 2,4-difluoro-3-methylaniline (138 g), colorless oils, b.p.: 75° C./11 mmHg.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[C:11]1([CH3:24])[CH2:15][CH2:14][CH2:13][CH:12]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>ClCCl>[F:7][C:11]1([CH3:24])[CH2:15][CH2:14][CH2:13][CH:12]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCCC1(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCC1(C)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
(Diethylamino)sulphur trifluoride (2.75 mL, 20.84 mmol) was added to a solution of tert-butyl 2-hydroxy-2-methylcyclopentylcarbamate (2.243 g, 10.42 mmol, from Step 3) in dichloromethane (40 mL) at −78° C. under nitrogen. After 4 h at −78° C., the mixture was quenched with saturated sodium bicarbonate, allowed to warm to room temperature, and extracted with dichloromethane. The dichloromethane phase was concentrated and purified by silica gel chromatography, eluting with 0 to 50% ethyl acetate in hexanes, to give tert-butyl 2-fluoro-2-methylcyclopentylcarbamate as brown oil (1.095 g, 48% yield). 1H NMR analysis indicated approximately 3.5:1 mixture of two diastereomers.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:7]([CH2:14][CH3:15])[CH2:8][CH2:9][O:10][CH2:11][CH2:12]O)[CH3:6]>C1C=CC=CC=1>[CH2:5]([N:7]([CH2:14][CH3:15])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][Cl:3])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCN(CC)CCOCCO
Solvent: c1ccccc1
Product: CCN(CC)CCOCCCl

Procedure:
A modification of the procedure described in J. Am. Chem. Soc. 76:3163 (1954) was used to obtain this compound, beginning with the dropwise addition of thionyl chloride (17.02 mL, 233.42 mmol) to a solution of 2-(2-di-ethylaminoethoxy)-ethanol in benzene (100 mL). The reaction mixture was stirred at reflux for 1.5 hours and the volatiles were removedunder diminished pressure. The oily residue crystallized in ether, was nearly homogeneous by TLC, and was used without further purification. The HCl salt obtained in this reaction was very hygroscopic. Attempts at purification of the free base via distillation resulted in decomposition. CIMS 180 m/z (M+1), 183 m/z (M+3).