Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].[O:8]([CH2:15][CH2:16][OH:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[Cl:1][CH2:2][C:3]([NH:5][C:6](=[O:7])[O:17][CH2:16][CH2:15][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: OCCOc1ccccc1
Reactant: O=C=NC(=O)CCl
Solvent: c1ccccc1
Product: O=C(CCl)NC(=O)OCCOc1ccccc1

Procedure:
Chloroacetylisocyanate (12g) was added slowly to the solution of β-phenoxyethylalcohol (13.8g) and benzene (100ml) at room temperature.
Reaction SMILES: [C:1]([O:10][CH:11]([CH3:13])[CH3:12])(=[O:9])[CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[H-].[Na+].[Na+].[I-].CC1C=CC(S(O[CH2:29][C:30]2([C:33]([F:36])([F:35])[F:34])[CH2:32][CH2:31]2)(=O)=O)=CC=1>CN(C=O)C>[F:34][C:33]([F:36])([F:35])[C:30]1([CH2:29][CH:2]([C:3]([O:5][CH:6]([CH3:7])[CH3:8])=[O:4])[C:1]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH2:32][CH2:31]1
Reactant: CC(C)OC(=O)CC(=O)OC(C)C
Reactant: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CC2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C(CC1(C(F)(F)F)CC1)C(=O)OC(C)C
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A 0° C. solution of diisopropyl malonate (4.10 mL, 21.58 mmol) in DMF (30 mL) was treated with NaH (60% in mineral oil, 1.036 g, 25.9 mmol), warmed to RT, treated with NaI (0.647 g, 4.32 mmol) followed by the drop-wise addition of a solution of (1-(trifluoromethyl)cyclopropyl)methyl 4-methylbenzenesulfonate (2.54 g, 8.63 mmol) in DMF (30 mL) and heated at 80° C. overnight. The mixture was cooled to RT, quenched with satd. NH4Cl, extracted with hexane (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MTBE/Hex) to afford diisopropyl 2-((1-(trifluoromethyl)cyclopropyl)methyl)malonate (1.53 g, 57.1%). 1H NMR (400 MHz, DMSO-d6): δ 4.91 (m, 2H), 3.47 (t, J=7.2 Hz, 1H), 2.10 (d, J=7.2 Hz, 2H), 1.17 (dd, J=7.3, 6.3 Hz, 12H), 0.89 (m, 2H), 0.76 (m, 2H).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=C(C2C=CC=CC=2)C(C2C=CC=CC=2)=[N:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([C:50]([C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=2)=O)=O)=[CH:44][CH:43]=1>>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:48]([C:45]2[CH:46]=[CH:47][C:42]([CH3:41])=[CH:43][CH:44]=2)[C:50]([C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=2)=[N:22]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)c(-c4ccccc4)nc3c1)n2C1CCCCC1
Product: Cc1ccc(-c2nc3ccc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)cc3nc2-c2ccc(C)cc2)cc1

Procedure:
Prepared as described for Compound 406 using 4,4′-dimethylbenzil in place of benzil.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][CH2:11][CH:12](OCC)[O:13]CC)=[CH:5][CH:4]=1>C(OCC)C.[Cl-].[Na+].O>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][CH2:11][CH:12]=[O:13])=[CH:7][CH:8]=1
Reactant: CCOC(COCc1ccc(Br)cc1)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=CCOCc1ccc(Br)cc1
Reaction time: 16 h

Procedure:
5 N HCl (20 mL) is added to a stirred solution of 1-bromo 4-(2,2-diethoxy-ethoxymethyl)-benzene (1.86 g, 6.13 mmol) in diethyl ether (20 mL) at ambient temperature. The resultant two-layered mixture is stirred vigorously under nitrogen for 16 hours. Diethyl ether (30 mL) and brine (20 mL) are added to the mixture. The organic layer is separated, washed with half-saturated brine, dried, filter and concentrated into a ˜50 mL solution (35 mg/mL). 1H NMR (CDCl3): δ9.72 (s, 1H), 7.49 (d, J=7.49 Hz, 2H), 7.24 (d, J=7.9 Hz, 2H), 4.57 (s, 2H), 4.11 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.[C:33]([C:35]1[CH:36]=[C:37]([NH:41][C:42]2[C:51]3[C:46](=[CH:47][CH:48]=[C:49]([NH2:52])[CH:50]=3)[N:45]=[CH:44][N:43]=2)[CH:38]=[CH:39][CH:40]=1)#[CH:34]>N1C=CC=CC=1.C1COCC1>[C:33]([C:35]1[CH:36]=[C:37]([NH:41][C:42]2[C:51]3[C:46](=[CH:47][CH:48]=[C:49]([NH:52][C:15]([CH:14]=[C:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]4)=[O:17])[CH:50]=3)[N:45]=[CH:44][N:43]=2)[CH:38]=[CH:39][CH:40]=1)#[CH:34]
Reactant: CC(C)(C)OC(=O)N1CCC(=CC(=O)O)CC1
Reactant: C#Cc1cccc(Nc2ncnc3ccc(N)cc23)c1
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C#Cc1cccc(Nc2ncnc3ccc(NC(=O)C=C4CCN(C(=O)OC(C)(C)C)CC4)cc23)c1

Procedure:
1 g of 2-(1-(tert-butyloxycarbonyl)piperidine-4-ylidene)acetic acid was added to 20 mL of anhydrous THF in a one-neck flask (100 mL). The solution was stirred and cooled on salt-ice bath. Then, 0.6 mL of isobutyl chloroformate and 0.5 mL of N-methylmorpholine were added, and the reaction mixture was let stir for 20 min 1.046 g of N4-(3-ethynylphenyl)quinazoline-4,6-diamine dissolved in 10 mL of pyridine (dried over molecular sieves) and 0.4 mL of N-methylmorpholine were added to the reaction mixture on an ice bath with stirring. After reaction completion, the solvent was evaporated in vacuo and the remaining residue was partitioned with chloroform and water. The chloroform layer was washed once with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product. The crude product was recrystallized from isopropanol. MS (EI) 482 M+.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH2:6]([OH:12])[CH2:7][O:8][CH2:9][CH2:10][OH:11]>>[P:1]([O:12][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][P:1]([Cl:5])([Cl:3])=[O:2])([Cl:5])([Cl:3])=[O:2]
Reactant: OCCOCCO
Reactant: O=P(Cl)(Cl)Cl
Product: O=P(Cl)(Cl)OCCOCCOP(=O)(Cl)Cl
Temperature: 30 °C

Procedure:
In a one liter flask, fitted with a mechanical stirrer, thermometer and reflux condenser are placed 307 gms. (2.0 moles) phosphorus oxychloride. The phosphorus oxychloride is cooled to 14° to 15°C. and 106 gms. (1.0 moles) of diethylene glycol is added over a period of 2 to 3 hours. Residual phosphorus oxychloride is removed. The product recovered is diethylene glycol bis-phosphorodichloridate. The temperature of the reaction mixture is then raised to 30°C. for about one hour.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:15](=[O:16])[N:7]2[CH2:8][CH:9]=[CH:10][CH:11]([C:12]([OH:14])=[O:13])[N:6]2[C:5]1=[O:17].[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>[OH-].[Na+]>[CH2:18]([S:25][CH2:2][CH2:3][N:4]1[C:15](=[O:16])[N:7]2[CH2:8][CH:9]=[CH:10][CH:11]([C:12]([OH:14])=[O:13])[N:6]2[C:5]1=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)C1C=CCn2c(=O)n(CCCl)c(=O)n21
Reactant: SCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1C=CCn2c(=O)n(CCSCc3ccccc3)c(=O)n21
Temperature: 100 °C
Reaction time: 3 h

Procedure:
1.2 g (0.005 mol) of 2-(2-chloroethyl)-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylic acid were dissolved in 10 ml (0.10 mol) of 1-M sodium hydroxide solution. The solution was treated with 1 ml (0.008 mol) of benzyl mercaptan and the mixture was stirred at 100° C. for 3 hours. The mixture was acidified with concentrated hydrochloric acid and extracted with two 20 ml portions of ethyl acetate. The organic layer was extracted with 50 ml of saturated sodium bicarbonate solution. The aqueous extract was acidified with concentrated hydrochloric acid and re-extracted with two 25 ml portions of ethyl acetate. The organic extracts were dried over magnesium sulphate and evaporated to give 2-(2-benzylthioethyl)-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylic acid in the form of a colourless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[OH:17][C:18]1[C:19]([CH3:24])=[N:20][CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:24][C:19]1[C:18]([O:17][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=3)=[CH:5][CH:4]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: Cc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ncccc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 36.3 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 3-hydroxy-2-methylpyridine (20 mg, 0.18 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. overnight and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2-methyl-pyridin-3-yloxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (12 mg, 36%) as a white powder. 1H NMR (DMSO-d6) δ ppm 8.37 (br. s., 1H), 8.00 (dd, J=4.7, 1.1 Hz, 2H), 7.93 (d, J=8.5 Hz, 2H), 7.54-7.65 (m, 3H), 7.34-7.43 (m, 1H), 7.17 (dd, J=8.5, 4.8 Hz, 1H), 5.23 (s, 2H), 2.41 (s, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:8]=[C:7]3[C:20]4[CH:26]=[C:25]([O:27]C)[CH:24]=[CH:23][C:21]=4[S:22][C:5]=1[C:6]=23.B(Br)(Br)[Br:30].ClCCl.Br>ClCCCl.CO>[BrH:30].[NH2:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:8]=[C:7]3[C:20]4[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:21]=4[S:22][C:5]=1[C:6]=23
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1ccc(OC)cc1-2
Reactant: BrB(Br)Br
Agent: Br
Agent: Cl
Solvent: ClCCCl
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1ccc(O)cc1-2

Procedure:
A solution of 98 g (0.222 mol) of 5-amino-N,N-diethyl-9-methoxy-2H-[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine dihydrochloride (Compound 1A), in 900 ml 1,2-dichloroethane, was treated with 444 ml of a 1M solution of boron tribromide in dichloromethane (0.444 mol). The mixture was heated to 50° C. for 24 hours at which time 200 ml of the boron tribromide solution (0.200 mol) were added, and the reaction maintained at 50° for an additional 24 hours. The mixture was cooled, and methanol (600 ml) was carefully added. The mixture was heated under reflux for three hours, then cooled at 0° for 48 hours. The yellow precipitate was collected by suction filtration, washed with cold methanol, then dried at 60°, 200 mm Hg, affording 110.4 g of 5-amino-2-[2-(diethylamino)ethyl]-2H-[1]benzothiopyrano[4,3,2-cd]indazol-9-ol, hydrobromide with 1.8 equivalents of hydrogen bromide, mp 305° (decomposition), 98.36% pure by HPLC.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Mg].O1C2C=CC=CC=2C=C1[Mg]Br.CN(OC)[C:25]([C:27]1([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:28]1)=[O:26]>>[C:34]([O:33][C:31]([NH:30][C:27]1([C:25]([C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[CH:6]=2)=[O:26])[CH2:29][CH2:28]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: Brc1cc2ccccc2o1
Reactant: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CC1
Agent: Br[Mg]c1cc2ccccc2o1
Agent: [Mg]
Product: CC(C)(C)OC(=O)NC1(C(=O)c2cc3ccccc3o2)CC1

Procedure:
Alternatively, the starting bromobenzofuran may be reacted with magnesium metal under standard conditions to prepare the corresponding Grignard reagent, benzofurylmagnesium bromide. This Grignard reagent is then reacted with the Weinreb amide, N-methyl N-methoxy 1-(tert-butoxycarbonylamino)cyclopropane-1-carboxamide, to provide 1-(tert-butoxycarbonylamino)-1-(benzofurylcarbonyl)cyclopropane. This ketone is then reduced under standard conditions, typically with sodium borohydride in methanol or ethanol, to provide 1-(tert-butoxycarbonylamino)-1-(benzofuryl(hydroxymethyl))cyclopropane. This alcohol is then converted to the corresponding acetate and reduced to the corresponding methylene by treatment with samarium iodide as previously described. The resulting 1-(tert-butoxycarbon-yl)-1-(benzofurylmethyl)cyclopropane is treated with acid under standard conditions to provide the compounds of the present invention. If necessary or desired, the Weinreb amide may be reduced by reaction with lithium aluminum hydride to provide the corresponding aldehyde essentially as described by Fehrentz and Castro (Synthesis, 676 (1983)). This aldehyde is then reacted with the Grignard reagent previously described to prepare 1-(tert-butoxycarbonylamino)-1-(benzofuryl(hydroxymethyl))cyclopropane, which is then subjected to the reaction conditions previously described to prepare the compounds of the present invention. The requisite Weinreb amide, N-methyl N-methoxy 1-(tert-butoxycarbonylamino)cyclopropane-1-carboxamide, may be prepared from the commercially available 1-amino-1-carboxycyclopropane by standard methods well known in the art.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[CH3:41][CH:42]([CH3:52])[C@H:43]([NH:50][CH3:51])[CH2:44][N:45]1[CH2:48][CH:47]([OH:49])[CH2:46]1.[OH-].[Na+]>CN(C=O)C.CS(C)=O.O.O1CCOCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:50]([C@@H:43]([CH:42]([CH3:52])[CH3:41])[CH2:44][N:45]2[CH2:46][CH:47]([OH:49])[CH2:48]2)[CH3:51])=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: CN[C@H](CN1CC(O)C1)C(C)C
Reactant: Cc1cc(C(=O)O)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)N(C)[C@H](CN2CC(O)C2)C(C)C)ccc1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 67.6 %

Procedure:
4-Fluoro-3-methylbenzoic acid (0.089 g, 0.58 mmol) and TBTU (0.196 g, 0.61 mmol) was mixed in DMF (1.5 mL). The mixture was cooled to 0° C. and NMM (0.070 mL, 0.64 mmol) was dropwise added. After 40 min at 0° C. was (S)-1-(3-methyl-2-(methylamino)butyl)azetidin-3-ol (Compound K2) (0.1 g, 0.58 mmol) added. The resultant mixture was stirred at 0° C. for 30 min and at rt for 16 h. NaOH (aq., 3.8 M, 0.5 mL), water (0.5 mL) and dioxane (1 mL) was added and the resultant mixture was stirred at rt overnight. To the mixture was water (2 mL) and DMSO (4 mL) added. The residue was purified by preparative HPLC to give the title compound (121 mg, 68%). Mixture of rotamers: 1H NMR (400 MHz, CD3OD) δ 0.80-0.87, 0.94, 1.05, 1.68-1.93, 2.25-2.34, 2.54-3.00, 3.26-3.34, 3.39-3.46, 3.55-3.61, 3.62-3.75, 4.19-4.43, 7.02-7.49. Ratio major:minor:1:0.5. Total no of protons: 24. HRMS (M+H)+: calculated 309.1978. found 309.1949. XRPD pattern d (Å) 9.3 (vw), 7.8 (w), 7.6 (w), 6.5 (med), 5.7 (vs), 5.3 (str), 4.71 (str), 4.52 (str), 4.40 (med), 4.31 (med), 3.83 (med), 3.30 (med), 3.22 (med). The compound was found to be a hydrate (most likely a monohydrate).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:28]=[CH:27][C:9]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([NH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19]3)[CH2:14][CH2:13]2)=[CH:27][CH:28]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(=O)NCc1ccc(CCN2CCC(n3ccc4ccccc43)CC2)cc1
Yield: 80.4 %

Procedure:
A suspension of 1-[1-(4-acetamidomethylphenethyl)piperidin-4-yl]indoline (0.80 g) obtained in Example 36 and active manganese dioxide (1.32 g) in chloroform (30 ml) was heated under reflux for 6 hr with vigorous stirring. Then the reaction mixtures were filtered through celite and the residue was washed with chloroform. The filtrate was concentrated under reduced pressure and the obtained residue was crystallized from a solvent mixture of ethyl acetate with hexane to give the title compound (0.64 g) as a white powder (yield: 80.4%).
Reaction SMILES: [OH:1][CH:2]([C:4]1[NH:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3]>C(O)(=O)C.O.[O-2].[O-2].[O-2].[Cr+6]>[C:2]([C:4]1[NH:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)(=[O:1])[CH3:3]
Reactant: COc1cccc2nc(C(C)O)[nH]c12
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc2nc(C(C)=O)[nH]c12
Yield: 64.9 %

Procedure:
A solution of 2-(1-hydroxyethyl)-4-methoxybenzimidazole (2.18 g) in acetic acid (8.5 ml) was heated at 100° C. and treated with a solution of chromium trioxide (0.85 g) in water (3 ml). After 10 minutes the reaction was poured into water (110 ml), the precipitate was removed by filtration through a plug of Celite and the product extracted with dichloromethane (3×100 ml). The combined organic layers were dried over magnesium sulphate, filtered, and evaporated in vacuo and to yield the desired product as a light-brown solid (1.4 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[C:22]([O:24]C)=[O:23])(=[O:10])=[O:9].C(N(CC)CC)C.[CH2:33]([N:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][NH2:39])[CH3:34].Cl>C(#N)C>[CH2:33]([N:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][NH:39][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[C:22]([OH:24])=[O:23])(=[O:10])=[O:9])[CH3:34]
Reactant: CCN(CC)CCCN
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1CCCC2
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCCC2
Temperature: 200 °C

Procedure:
A mixture of Example 229A (143 mg, 0.393 mmol), triethylamine (0.165 mL), acetonitrile (1.2 mL), and N,N-diethyl-1,3-propanediamine (0.37 mL, 2.36 mmol) was sealed and heated in microwave for fifteen hundred seconds at 200° C. The solution was cooled and adjusted to pH 5 with 1N HCl. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic fractions were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by preparative HPLC to provide the desired product. MS (ESI(+)) m/e 460 (M+H)+; (ESI(−)) m/e 458 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 13.15 (br s, 1H), 9.54 (s, 1H), 9.02 (br s, 1H), 7.51 (dd, 1H), 7.41 (dt, 1H), 6.96 (2, 1H), 6.86 (d, 1H), 6.64 (m, 2H), 6.00 (t, 1H), 3.29 (q, 2H), 3.09 (m, 7H), 2.65 (br s, 4H), 1.89 (m, 2H), 1.67 (br s, 4H), 1.14 (t, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:50]3[O:49][C:48]([NH2:51])=[N:47][C:46]=3[C:45]([O:52][CH3:53])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[F:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[C:50]3[O:49][C:48]([NH:51][C:6](=[O:8])[C:5]4[CH:9]=[CH:10][C:2]([CH3:1])=[N:3][CH:4]=4)=[N:47][C:46]=3[C:45]([O:52][CH3:53])=[CH:44][CH:43]=2)=[CH:40][CH:41]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(F)cc2)c2oc(NC(=O)c3ccc(C)nc3)nc12

Procedure:
From 6-methyl-nicotinic acid, HATU and N-diethylisopropylamine in THF, then treatment with 7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 378 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:4]([CH2:34][CH2:35][CH3:36])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:18][N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])[CH:15]=2)[CH:10]1[O:30][CH2:31]OC)[CH2:2][CH3:3].Cl.CO>CO>[CH2:34]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:18][N:19]3[C:20](=[O:29])[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]3=[O:28])[CH:15]=2)[CH:10]1[O:30][CH3:31])[CH2:35][CH3:36]
Reactant: CCCN(CCC)CCCCC1Cc2cc(CN3C(=O)c4ccccc4C3=O)ccc2C1OCOC
Agent: Cl
Solvent: CO
Product: CCCN(CCC)CCCCC1Cc2cc(CN3C(=O)c4ccccc4C3=O)ccc2C1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.1 %

Procedure:
The compound (253.9 mg) obtained in Example 127-11 was dissolved in methanol (10.2 ml), added with a 10% hydrogen chloride/methanol solution (5.08 ml), and stirred for 16 hours at room temperature. Then, the reaction solution was concentrated under reduced pressure and dried under vacuum. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (95.7 mg) as a yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][CH3:11].C1C(=O)N([Br:19])C(=O)C1>CC#N>[Br:19][C:6]1[CH:7]=[C:2]([F:1])[C:3]([O:10][CH3:11])=[CH:4][C:5]=1[CH2:8][OH:9]
Reactant: COc1cc(CO)ccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1cc(CO)c(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
To a solution of (4-fluoro-3-methoxy-phenyl)-methanol (10.0 g, 64.04 mmol) in MeCN (160 mL) was added a solution of NBS (11.4 g, 64.04 mmol) in MeCN (50 mL) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was suspended in diethyl ether (200 mL). Solid material was removed by filtration and washed with further diethyl ether. The filtrate was washed with water (200 mL) and brine (100 mL), dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid (14.4 g) in a 96% yield.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=[C:6]1SC.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1>>[Br:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=[C:6]1[N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CSc1nnc(C)c(=O)n1Cc1cc(F)ccc1Br
Product: Cc1nnc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2cc(F)ccc2Br)c1=O
Temperature: 135 °C
Reaction time: 0.08 h

Procedure:
The mixture of 4-(2-bromo-5-fluorobenzyl)-6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (17, 180 mg, 0.523 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (208 mg, 1.04 mmol) was ground for 5 min and then heated in a tube under nitrogen atmosphere at 135° C. for 13 h. The mixture was separated by silica gel column, and eluted with 10-50% ethyl acetate in petroleum ether to give (R)-tert-butyl 1-(4-(2-bromo-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate (18). MS: m/z, 496 (100%, M+1), 498 (100%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1nc(Br)cnc1N
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1

Procedure:
Prepared by method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine and benzenesulphonyl chloride
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])N.[OH:11]S(O)(=O)=O.NC(N)=O>O.[O-]S([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([OH:11])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)c(C)c1Cl
Reactant: O=S(=O)(O)O
Agent: [Cu+2]
Agent: NC(N)=O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Cc1ccc(O)c(C)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-chloro-2,4-dimethyl-aniline (0.47 g, 3.0 mmol), in a mixture of water (3 mL) and conc. H2SO4 (2 ml), a solution of Na2NO2 (0.22 g) in H2O (5 ml) was added dropwise at 0° C. The mixture was stirred 1 h at 0° C., than treated with urea (0.2 g), stirred for 10 min at 0° C. A solution of CuSO4 (1.0 g) in water (6 mL) was added and the mixture was stirred for 60 h at RT. The reaction mixture was extracted with CH2Cl2 (2×20 ml), extracts were dried over Na2SO4 and evaporated. The residue was separated on SiO2 (4.0 g) column, hexane-EtOAc (0 to 10%). Brown crystals, 45 mg (0.29 mmol, 10%).