Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:37]=[CH:36][C:25]([O:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=2)=[CH:24][C:23]=1[F:38]>O1CCCC1.C(N(CC)CC)C>[F:38][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][C:22]=1[NH:21][C:14]([C:11]1([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:12][CH2:13]1)=[O:16])[O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: NC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.2 %

Procedure:
To a solution of 1-(4-fluorophenylaminocarbonyl)cyclopropanecarboxylic acid (1.45 g) in tetrahydrofuran (14.5 ml) was added dropwise triethylamine (1.13 ml) under a nitrogen atmosphere while cooling in an ice water bath, followed by stirring for 15 min. To the reaction mixture was added thionyl chloride (0.473 ml), followed by stirring at the same temperature for 1.5 hr. To the reaction mixture were added a solution of 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxamide (1.0 g) in tetrahydrofuran (10.5 ml) and triethylamine (1.13 ml) in this order at the same temperature under a nitrogen atmosphere, followed by stirring. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The reaction mixture was partitioned after addition of ethyl acetate (50 ml) and a 2N aqueous solution of sodium hydroxide (10 ml). The organic layer was washed with a 2N aqueous solution of sodium hydroxide (10 ml, twice), 1N hydrochloric acid (10 ml, three times) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml), and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was filtered (eluent; ethyl acetate) through silica gel column (Fuji Silysia NH). The filtrate was concentrated under reduced pressure, and to the resultant residue (1.28 g) were added ethyl acetate (4 ml) and heptane (4 ml) to suspend. The solid was collected by filtration and dried under aeration to provide the titled compound as a pale pink solid (991.1 mg, 54.1%). The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:heptane=3:1). Fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as a white solid (24.3 mg, 1.33%).
Reaction SMILES: [Mg].[CH2:2](Br)[CH:3]([CH3:5])[CH3:4].[N:7]1([C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH:15]=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>CCOCC>[CH3:4][CH:3]([CH3:5])[CH2:2][CH:15]([OH:16])[C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=Cc1ccccc1N1CCCCC1
Reactant: CC(C)CBr
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)CC(O)c1ccccc1N1CCCCC1
Reaction time: 0.33 h
Yield: 54.2 %

Procedure:
In a 3 necked round bottom flask (25 ml), equipped with a dropping funnel, reflux condenser and thermometer pocket, placed magnesium turnings (0.254 gm, 10.47 mmol) and flame dried the apparatus. Dry diethyl ether (10 ml.) was added to Mg. Turning, Isobutyl bromide (1.13 ml, 1.45 gm, 10.58 mmol) was taken in 2 ml of dry ether and added drop wise to the Mg turnings. As soon as ether starts boiling (in a few minutes) the reaction was cooled using ice-salt and continued the addition of isobutyl bromide. After complete addition of isobutyl bromide continued for another 20 minutes. o-piperidino benzaldehyde 8 (1.0 gm, 5.29 mmol) in 2 ml of ether was added drop wise at −10° C. After the completion of addition of 8 continued the stirring for 1 hr and the reaction was quenched with ice-cooled saturated ammonium chloride solution (5 ml), the solid separated is filtered off, the filtrate is extracted with ethyl acetate (10×2 ml) dried over sodium sulphate and concentrated to yield 1.36 gm of crude product. The crude product was chromatographed and obtained pure 9 (54.2%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:42])[NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:13][C:12]([C:21]3[CH:22]=[N:23][C:24]([N:27]4[CH2:32][CH2:31][C:30]([C:38]([F:41])([F:40])[F:39])([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]4)=[N:25][CH:26]=3)=[CH:11][C:9]=2[N:10]=1)[CH3:2].CC(C)([O-])C.[K+].O>CS(C)=O>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:13][C:12]([C:21]3[CH:22]=[N:23][C:24]([N:27]4[CH2:28][CH2:29][C:30]([C:38]([F:41])([F:40])[F:39])([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]4)=[N:25][CH:26]=3)=[CH:11][C:9]=2[N:10]=1)=[O:42])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C(=O)OCC)(C(F)(F)F)CC4)nc3)cc(-c3ccccn3)c2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C(=O)O)(C(F)(F)F)CC4)nc3)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To an ice-cold solution of ethyl 1-(5-(2-(3-ethylureido)-7-(pyridin-2-yl)benzothiazol-5-yl)pyrimidin-2-yl)-4-(trifluoromethyl)piperidine-4-carboxylate (0.05 g, 0.08 mmol) in DMSO (2.0 mL) was added potassium tert-butoxide (0.046 g, 0.41 mmol) and the mixture stirred at rt for 2 h. After completion of reaction (by TLC), water (10 mL) was added followed by extraction with EtOAc (2×50 mL) and the organic layer discarded. The pH of the aqueous layer was adjusted up to 4-5 then extracted with hot EtOAc (3×75 mL) and the combined organic layer dried over Na2SO4, filtered and evaporated under reduced pressure. The residue thus obtained was triturated with ether to afford Compound 142 as off-white solid (0.04 g, 84% yield). 1H NMR (DMSO-d6): δ 1.09 (t, J=7.20 Hz, 3H), 1.65 (m, 2H), 2.31 (m, 2H), 3.01 (m, 2H), 3.20 (q, J=7.20 Hz, 2H), 4.75 (m, 2H), 6.87 (br s, 1H, D2O exchangeable), 7.43 (m, 1H), 7.99 (m, 2H), 8.23 (s, 1H), 8.48 (d, J=7.20 Hz, 1H), 8.80 (d, J=3.60 Hz, 1H), 8.92 (s, 2H), 10.57 (br s, 1H, D2O exchangeable) and 14.06 (br s, 1H, D2O exchangeable). MS: 572.10 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].O>N1C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([NH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:18]
Reactant: O=C(Cl)CCCCl
Reactant: CCOC(=O)c1ccccc1N
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1ccccc1NC(=O)CCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-aminobenzoate (5 g) in pyridine (50 mL) was added 4-chlorobutanoyl chloride (3.6 mL) at 0° C., and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into water, and the mixture was partitioned twice with ethyl acetate. The organic layers were combined, and the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.03 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[C:12](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:12][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2c(O)cccc21
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc2c1CCC2=O
Temperature: 50 °C
Reaction time: 72 h
Yield: 98.8 %

Procedure:
4-Hydroxy-1-indanone (5.0 g, 33.7 mmol) was dissolved in acetone (170 mL) and then potassium carbonate (9.0 g, 138.21 mmol) and Mel (9.6 g, 67.5 mmol) were added. The resulting suspension was heated to 50° C. and stirred for 3 days at which time the reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (5.4 g, 98%) as a yellow solid. GC-MS m/z [M+H]+ 163.
Reaction SMILES: [Na].Br[C:3]1[C:8]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)=[C:7]([C:17](=[O:19])[CH3:18])[CH:6]=[C:5]([Cl:20])[C:4]=1[CH3:21].[CH2:22]([O:24][CH:25]([N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1)[CH3:26])[CH3:23]>O.C1(C)C=CC=CC=1.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>[Cl:20][C:5]1[C:4]([CH3:21])=[C:3]([C:30]2[CH:29]=[N:28][N:27]([CH:25]([O:24][CH2:22][CH3:23])[CH3:26])[CH:31]=2)[C:8]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)=[C:7]([C:17](=[O:19])[CH3:18])[CH:6]=1
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1-c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)=O)c2-c2cc(F)cc(F)c2)cn1
Temperature: 90 °C
Yield: 40.1 %

Procedure:
To a solution of sodium hydrogenecarbonate (0.093 g, 1.1 mmol) in water (2 mL) was added a solution of 1-(6-bromo-4-chloro-3′,5′-difluoro-5-methylbiphenyl-2-yl)ethanone (0.20 g, 0.56 mmol) in toluene (2 mL) followed by 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.18 g, 0.67 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.064 g, 0.056 mmol). The mixture was bubbled with N2 for 5 min and then heated at 90° C. overnight. The organic layer was concentrated and flashed on silica gel (eluting with 0-20% of ethyl acetate in hexanes) to afford the desired product (94 mg, 40%). LCMS calculated for C22H22ClF2N2O2 (M+H)+: m/z=419.1. found: 419.1.
Reaction SMILES: [CH:1]1([N:4]([CH3:12])[C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)=O)[CH2:3][CH2:2]1.B.Cl>C1COCC1>[CH:1]1([N:4]([CH3:12])[CH2:5][C@@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH2:3][CH2:2]1
Reactant: CN(C(=O)[C@@H]1CCCN1)C1CC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CN(C[C@@H]1CCCN1)C1CC1
Temperature: 25 °C

Procedure:
To a solution of (S)-pyrrolidine-2-carboxylic acid cyclopropyl-methyl-amide in THF at 0° C. was added borane (2 eq., 1 M in THF) dropwise. The mixture was allowed to warm up to rt then heated to reflux for 24 hours. The cooled reaction was acidified with HCl and heated at 75° C. for 10 mins. The mixture was concentrated, basified with 2N NaOH and extracted with 10% methanol in DCM. The combined DCM was dried and concentrated to give cyclopropyl-methyl-(S)-1-pyrrolidin-2-ylmethyl-amine.
Reaction SMILES: [Cl-].[C:2]([CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]([NH3+:17])[CH2:7]1)(O)=[O:3].COS(C1C=CC(C)=CC=1)(=O)=O.C1(N=C=NCCN2CCOCC2)CCCCC1>N1C=CC=CC=1>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]1[CH2:7][CH:6]2[CH2:5][C:2](=[O:3])[NH:17]1
Reactant: COc1ccc2c(c1)C(CC(=O)O)CC2[NH3+]
Agent: C(=NCCN1CCOCC1)=NC1CCCCC1
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C1CC(=O)NC2C1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
3-Carboxymethyl-5-methoxy-indan-1-yl-ammonium chloride (13.2 g) and 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulfonate (21.7 g) dissolved in pyridine (500 mL) are stirred at room temperature for 7 d. Then, the pyridine is removed under reduced pressure and the residue is taken up in water (200 mL) and dichloromethane (200 mL). The organic phase is separated and the aqueous phase is extracted twice with dichloromethane. The combined organic phases are washed with 1 M hydrochloric acid, 1 M NaOH solution, and water. After drying (MgSO4), the solvent is evaporated under reduced pressure to yield the product as a beige solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][CH:30]=1)[O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH:24]=[CH2:25])=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][CH:30]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH2:34][C:33]2[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:32]=2[F:31])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH:24]=[CH2:25])=[CH:26][CH:27]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C=C)cc2)c1
Reactant: Fc1ccc(CBr)c(F)c1
Product: C=CCOc1cccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C=C)cc2)c1

Procedure:
The product from Example 87A and 2,4-difluorobenzyl bromide were processed as described in Example 6B to provide the title compound. MS (ESI+) m/z 529 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][N:18]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH3:23])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[S:54](Cl)([C:57]1[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=1)(=[O:56])=[O:55]>C(Cl)Cl>[S:54]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:16][CH2:17][N:18]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH3:23])([C:57]1[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=1)(=[O:56])=[O:55]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CCN(CCN(CCCCCCO)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CCN(CCN(CCCCCCOS(=O)(=O)c1ccc(C)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 6.1 g amount of 7,10,13-tri (t-butoxycarbonyl)-7,10,13-triazapentadecanol, 100 mg of dimethylaminopyridine, and 4 ml of triethylamine in 100 ml of CH2Cl2 was stirred at 0° C. Dropwise, 2.64 of tosyl chloride in 20 ml of CH2Cl2 was added at 0° to 5° C. The reaction was then stirred overnight at room temperature and then 100 ml of CH2Cl2 was added. The reaction mixture was washed with 30 ml of 2N HCl, 30 ml of water and 30 ml of brine. The organic layer was dried over MgSO4 and was filtered. The solvent was evaporated and the residue from the filtrate was purified using a silica gel column and eluted with ethyl acetate/hexane (1:2 v/v). About 7.8 g of 7,10,13-tri(t-butoxycarbonyl)-7,10,13-triazapentadecanol tosylate was collected. The reaction is shown below:
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]([NH:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH:5]([CH3:8])[CH2:6][CH3:7].C1COCC1.[Li+].[OH-].Cl>CO.O>[CH3:8][CH:5]([CH2:6][CH3:7])[CH:4]([NH:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[C:3]([OH:18])=[O:2]
Reactant: CCC(C)C(NC(=O)c1cccnc1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCC(C)C(NC(=O)c1cccnc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.2 %

Procedure:
To a solution of 3-methyl-2-[pyridine-3-carbonyl-amino]-pentanoic acid methyl ester (1.5 g, 5.9 mmol), in methanol (10 mL), THF (9 mL), was added LiOH (1.25 g, 29.9 mmol) dissolved in water (3 mL). The mixture was allowed to stir at room temperature (25° C.) over 3 h. Methanol and THF was stripped off from the reaction mass, acidified the reaction mass using 1.5N HCl (pH=2-3). Extracted the reaction mass with ethyl acetate (100 mL) thrice and dried over sodium sulphate and concentrated to obtain product as pale yellow solid (0.7 g, 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][CH2:25][CH3:26])[CH:23]=3)[S:18][C:11]=12)[NH2:5].FC1C=CC=CC=1NC(=O)CC(O)=O.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH:49][C:50](=[O:55])[CH2:51][C:52](O)=[O:53]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:52](=[O:53])[CH2:51][C:50]([NH:49][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[O:42][CH3:41])=[O:55])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][CH2:25][CH3:26])[CH:23]=3)[S:18][C:11]=12
Reactant: CCCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Agent: O=C(O)CC(=O)Nc1ccccc1F
Product: CCCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5OC)cc4F)c3s2)c1

Procedure:
Title compound 134 (scheme 38) was obtained similarly to the compound 130 (example 49, scheme 38) starting from the amine 133 and replacing the acid 29 with the acid 27. 1H NMR (DMSO-d6). δ (ppm): 10.58 (s, 1H), 9.64 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.07 (dd, J=1.2 and 8.8 Hz, 1H), 7.94 (d, J=1.2 Hz, 1H), 7.87 (dd, J=1.6 and 12.8 Hz, 1H), 7.77 (d, J=1.2 Hz, 1H), 7.68 (s, 1H), 7.49 (t, J=8.8 Hz, 1H), 7.43 (dd, J=2.0 and 8.8 Hz, 1H), 7.11-7.04 (m, 2H), 6.92 (ddd, J=2.4, 6.4 and 8.0 Hz, 1H), 6.58 (d, J=5.6 Hz, 1H), 3.98 (t, J=7.2 Hz, 2H), 3.86 (s, 3H), 3.64 (s, 2H), 1.78 (sex, J=7.2 Hz, 2H), 0.87 (t, J=7.2 Hz, 3H). MS (m/z): 559.2 (M+H).
Reaction SMILES: [I:1]Cl.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([S:12]([Cl:15])(=[O:14])=[O:13])=[CH:11][C:6]=2[CH2:5][CH2:4]1.C(#N)C>C(Cl)Cl>[I:1][C:8]1[C:7]2[O:3][CH2:4][CH2:5][C:6]=2[CH:11]=[C:10]([S:12]([Cl:15])(=[O:13])=[O:14])[CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)CCO2
Reactant: ClI
Solvent: ClCCl
Solvent: CC#N
Product: O=S(=O)(Cl)c1cc(I)c2c(c1)CCO2
Temperature: 25 °C
Yield: 100.9 %

Procedure:
A solution of ICl (7.7 g, 47 mmol) in DCM (100 mL) was added dropwise to a solution of 2,3-dihydro-benzofuran-5-sulfonyl chloride (5 g, 23 mmol; Intermediate 54) in DCM (100 mL) at reflux temperature under nitrogen atmosphere. The reaction was heated at reflux overnight. The reaction mixture was cooled at room temperature and acetonitrile (50 mL) was added. The resultant mixture was washed with a saturated solution of NaHCO3 and the organic phase was separated followed by elimination of the volatiles under vacuum to give 8 g of brown oil which was used to the next step without further purification. 1H NMR 270 MHz (CDCl3) δ ppm 3.45 (t, J=8.91 Hz, 2H) 4.82 (t, J=8.91 Hz, 2H) 7.79 (d, J=1.48 Hz, 1H) 8.16 (d, J=1.98 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43]>O1CCOCC1>[C:42]([NH:46][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])([CH3:45])([CH3:44])[CH3:43]
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.3 %

Procedure:
5-Bromopicolinic acid (200 mg, 0.99 mmol) was dissolved in dioxane (2 ml) and Hunig's Base (520 μl, 2.97 mmol, 3 equiv.), TBTU (350 mg, 1.09 mmol, 1.1 equiv.) and tert-butyl amine (124 μl, 1.19 mmol, 1.2 equiv.) were added at room temperature. The mixture was stirred for 16 hours at room temperature. The reaction mixture was evaporated and extracted saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 50:50. The desired 5-bromo-pyridine-2-carboxylic acid tert-butylamide (235 mg, 92% yield) was obtained as a colorless oil, MS: m/e=257.0/259.0 (M+H+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Product: Cc1cccc(C)c1-c1cc(Cl)cc2c1OC(CN1CCOCC1)C2

Procedure:
The title compound was prepared (0.09 g, 68%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and morpholine (0.58 g, 6.76 mmol). mp 228-230° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH3:15])=[C:10]([C:12]([OH:14])=[O:13])[N:11]=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Na].[CH2:17](I)[CH3:18]>C(O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH3:15])=[C:10]([C:12]([O:14][CH2:17][CH3:18])=[O:13])[N:11]=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCI
Reactant: CCn1ncc2nc(C(=O)O)c(C)nc21
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1nc2cnn(CC)c2nc1C

Procedure:
12.1 g. of 1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid (0.059 mol.) are added to a solution of 1.36 of sodium (0.059 mol.) in 250 ml. of absolute ethanol and is stirred for 30 minutes at room temperature. The alcohol is distilled off in vacuo and the sodium salt is dissolved in 350 ml. of dry dimethylformamide. Then, 14 g. of ethyl iodide (0.88 mol.) are added and the solution is heated in an autoclave at 120° for 10 hours. After the dimethylformamide has been removed in vacuo, the residual 1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid ethyl ester is treated with water, dried at 50° and recrystallized from hexane, yield 9.4 g. (68%), m.p. 64°-65°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1)(=[O:27])=[O:26]>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:30]5[CH:31]=[N:32][CH:33]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:29]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CS(=O)(=O)c1cncc(B(O)O)c1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cncc(S(C)(=O)=O)c3)cc1-2
Yield: 30 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 5-(methylsulfonyl)pyridin-3-ylboronic acid were reacted to give 237 (0.053 g, 30%). 1H NMR (400 MHz, DMSO) δ 9.28 (d, J=2.0, 1H), 9.07 (d, J=1.8, 1H), 8.82 (d, J=2.2, 1H), 8.56 (s, 1H), 8.11 (s, 1H), 7.87 (dd, J=8.4, 2.3, 1H), 7.27 (d, J=8.4, 1H), 5.87 (dt, J=13.0, 6.5, 1H), 4.45 (t, J=4.8, 2H), 3.50 (t, J=4.8, 2H), 3.41 (s, 3H), 1.59 (d, J=6.6, 6H). MS (ESI(+)): m/z 468.1 (M+H)
Reaction SMILES: [C:1]1([C:7](SCC(OC)=O)=[S:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[C:17]([C:23]([NH:25][NH2:26])=O)=[N:18][C:19]([Br:22])=[CH:20][N:21]=1.Cl>C(O)C>[Br:22][C:19]1[N:18]=[C:17]([C:23]2[S:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:26][N:25]=2)[C:16]([NH2:15])=[N:21][CH:20]=1
Reactant: NNC(=O)c1nc(Br)cnc1N
Reactant: COC(=O)CSC(=S)c1ccccc1
Agent: Cl
Solvent: CCO
Product: Nc1ncc(Br)nc1-c1nnc(-c2ccccc2)s1
Yield: 35.9 %

Procedure:
Methyl 2-((phenylcarbonothioyl)thio)acetate (3.6 g, 15.9 mmol) and 3-amino-6-bromopyrazine-2-carbohydrazide (2.9 g, 12.5 mmol) were suspended in 200 mL of ethanol and refluxed for 2 days. To the mixture, 50 mL of sat. ethanolic HCl was added and the mixture was refluxed overnight. A precipitate formed. The formed solid was filtered and dried to afford 5-Bromo-3-(5-phenyl-1,3,4-thiadiazol-2-yl)pyrazin-2-amine 5 (1.5 g, 36%).