Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:4][N:3]=1.[CH:28](=O)[CH3:29]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]([CH2:28][CH3:29])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC=O
Reactant: O=C(NCCCNCc1cccc(-c2ccnc(Cl)n2)c1)c1ccccc1
Product: CCN(CCCNC(=O)c1ccccc1)Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 43 was coupled with acetaldehyde following procedure E. LC-MS showed the product had the expected M+H+ of 409.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][CH2:35]O)/[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:43])CC)C>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][CH2:35][F:43])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)/C(=N\OCCO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: O=C(O)/C(=N\OCCF)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
N.m.r. in solvent C: 2.9 (s, 3H), 3.5 (t, 2H), 4.5 t, 2H , 6.65 s, 1H , 7.3 (s, 15H). 6. N.m.r. in solvent C: 3 0 (s, 3H), 3.5-3.7 (m, 4H), 4.3 (m, 2H), 4.7 (m, 2H), 5.1 (d, 1H), 5.9 (d, 1H) 6.8 (s, 1H), 7.4 (s, 15H). 7. N.m.r. in solvent A: 3.4 (s, 2H), 3.9 (d, 1H), 4.4 (d, 1H), 4.8 (s, 2H , 4.9 (d, 1H), 5.7 (d, 1H), 6.8 (s, 1H), 7.2 (s, 15H). 8. The starting material may be prepared as follows. Reaction of ethyl 2-(2-tritylaminothiazol-4-yl)-2-[(Z)-2-hydroxyethoxyimino]acetate with diethylamino sulphur trifluoride and hydrolysis of the resulting ester gave 2-(2-tritylaminothiazol-4-yl)-2[(Z)-2-fluoroethoxyimino]acetic acid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.[OH-].[Li+].[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1>C(O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:32][CH:29]2[CH2:31][CH2:30]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Sc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Reactant: BrCC1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2c(NCC3CC3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The starting material is prepared as follows: To the mixture of 3.8 g of 4-(4-acetamidophenylmercapto)-3-amino-5-sulfamoylbenzoic acid, 20 ml of water, 15 ml of ethanol and 2 ml of 4 N aqueous lithium hydroxide, 2.2 g of cyclopropylmethyl bromide are added while stirring and the pH of the mixture adjusted with lithium hydroxide to 7.0 during 24 hours. Thereupon,it is filtered, the filtrate diluted with water, washed with diethyl ether and acidified with concentrated hydrochloric acid. The precipitate formed is filtered off and recrystallized from aqueous ethanol, to yield the 4-(4-acetamidophenylmercapto)-3-cyclopropylmethylamino-5-sulfamoylbenzoic acid melting at 200°-204°.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([O:14][CH3:15])=[C:9]([CH3:16])[CH:8]=1.[Br:17][C:18]1[CH:19]=[C:20](/[C:24](/[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[C:39]#[N:40])=[N:25]\S(C(C)(C)C)=O)[CH:21]=[CH:22][CH:23]=1.Cl.CO>C1COCC1>[Br:17][C:18]1[CH:19]=[C:20]([C:24]2([C:7]3[CH:8]=[C:9]([CH3:16])[C:10]([O:14][CH3:15])=[C:11]([CH3:13])[N:12]=3)[C:32]3[C:33](=[C:34]([F:38])[CH:35]=[CH:36][CH:37]=3)[C:39]([NH2:40])=[N:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccc(F)c1C#N
Reactant: COc1c(C)cc(Br)nc1C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C)cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
tert-Butyllithium (1.040 mL, 1.77 mmol) was added dropwise to THF (5 mL) at −100° C. under an argon atmosphere. A solution of 6-bromo-3-methoxy-2,4-dimethylpyridine (191 mg, 0.88 mmol) in THF (3 ml) was added dropwise followed by the addition of (E)-N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 0.74 mmol) in THF (7 ml). The resulting reaction mixture was left on the thawing cooling bath for 30 min then the cooling bath was removed and the mixture was stirred at r.t. for 1 h. Hydrogen chloride-methanol solution (3.54 mL, 4.42 mmol) was added and the resulting mixture was stirred at r.t. for 1 h. The mixture was concentrated under reduced pressure and the residue was purified on a silica gel column eluted with 0-10% 0.1 M NH3 in MeOH in DCM to give the title compound (272 mg, 84%). MS (ES+) m/z 440, 442 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:27]=1[C:28](Cl)=[O:29].O=C1CC(=O)N(C2C=CC(C(O)=O)=CC=2)C2C=CC3C(C=2N1)=CC=CC=3>>[Br:25][C:26]1[C:27]([C:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:29])=[C:31]([O:35][CH3:36])[CH:32]=[CH:33][CH:34]=1
Reactant: COc1cccc(Br)c1C(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Product: COc1cccc(Br)c1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 76 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 2-bromo-6-methoxybenzoyl chloride, the title compound (yield 76%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[Ca+2].[Br-:24].[Br-:25].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>CO.ClCCl>[NH2:1][C:2]1[C:7]([Br:24])=[CH:6][C:5]([Br:25])=[CH:4][C:3]=1[N:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)N(CCN(C)C)c1ccccc1N
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N(CCN(C)C)c1cc(Br)cc(Br)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.4 %

Procedure:
To a solution of N-(2-aminophenyl)-N-ethoxycarbonyl-N',N'-dimethylethylenediamine (1.60 g) in methanol (20 ml) and dichloromethane (30 ml) were added calcium carbonate (1.29 g) and benzyltrimethylammonium tribromide (5.05 g), and the reaction mixture was stirred at room temperature for 24 hours. The insoluble matter was filtered off and the solvent was distilled off under reduced pressure. To the residue were added 5% aqueous sodium hydrogen sulfite solution and 1N aqueous sodium hydroxide solution to make the solution alkaline and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: chloroform:methanol=30:1) to give 0.87 g of N-(2-amino-3,5-dibromophenyl)-N-ethoxycarbonyl-N',N'-dimethylethylenediamine.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[OH:28][NH:29][C:30](=N)[CH:31]([CH3:33])[CH3:32]>>[CH:31]([C:30]1[N:27]=[C:26]([N:23]2[CH2:24][CH2:25][CH:20]([C@H:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)[O:28][N:29]=1)([CH3:33])[CH3:32]
Reactant: CC(C)C(=N)NO
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@H](C2CCN(C#N)CC2)C3)CC1
Product: CC(C)c1noc(N2CCC([C@@H]3Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from (S)-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridine-2-yl]-piperidine-1-carbonitrile (Intermediate 46; the configuration of the stereocenter is arbitrarily assigned) and N-hydroxy-isobutyramidine following a procedure analogous to that described in Example 2. LC (method 6): tR=1.40 min; Mass spectrum (ESI+): m/z=474 [M+H]+.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:24][CH2:23][C:16]3[N:17]=[CH:18][N:19]=[C:20](OC)[C:15]=3[CH2:14]2)=[N:11][CH:12]=1.C1(OC)C=CC=CC=1.[OH-].[K+]>C(#N)C>[Br:3][C:20]1[C:15]2[CH2:14][N:13]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][N:11]=3)[CH2:24][CH2:23][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: O=P(Br)(Br)Br
Reactant: COc1ncnc2c1CN(c1ccc(Cl)cn1)CC2
Agent: [K+]
Agent: [OH-]
Solvent: COc1ccccc1
Solvent: CC#N
Product: Clc1ccc(N2CCc3ncnc(Br)c3C2)nc1
Temperature: 0 °C
Yield: 37.6 %

Procedure:
Phosphorus oxybromide (14 g, 49 mmol) was added portionwise over 2 min to a stirred suspension of 6-(5-chloropyridin-2-yl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (3.36 g, 12.1 mmol), anisole (50 mL), and acetonitrile (50 mL) in a 250 mL flask. The stirred mixture clarified briefly and was then heated at reflux. The mixture was removed from the heat after 4.5 h. The cooled mixture was diluted with CH2Cl2 (100 mL), and poured onto a mixture of crushed ice (250 g) and 50% aqueous KOH (20 mL; 0.18 mol). The pH of the mixture was then adjusted to 12 with 2M aq. KOH, and extracted with CH2Cl2 (300 mL). The aqueous phase was diluted with brine (200 mL) and extracted with CH2Cl2 (2×100 mL). The combined CH2Cl2 layers were washed with saturated NaHCO3 (200 mL), dried (Na2SO4), filtered and concentrated to a brown oil which was purified by silica gel column (0-50% ethyl acetate/hexane) to give a yellow solid (1.48 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:10][CH2:11]Cl)=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1.[S-:13][C:14]#[N:15].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([S:10][CH2:11][S:13][C:14]#[N:15])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1
Reactant: ClCSc1nc(Cl)c(Cl)nc1Cl
Reactant: N#C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CSCSc1nc(Cl)c(Cl)nc1Cl
Temperature: 75 °C

Procedure:
To a solution of 4.0 grams (0.015 mole) of 3,5,6-trichloro-2-(chloromethylthio)pyrazine in 75 milliliters of dimethylformamide was added 1.6 grams (0.02 mole) of sodium thiocyanate. The reaction mixture was heated to 75° C and monitored by nuclear magnetic resonance spectroscopy. An additional 4.8 grams (0.06 mole) of sodium thiocyanate was incrementally added until the reaction was complete (5 days). The solvent was removed by evaporation under reduced pressure and the residue remaining was dissolved in a mixture of water and chloroform. Two phases formed and the aqueous phase was extracted with chloroform. The organic fractions were combined and washed with a saturated sodium bicarbonate solution followed by washing with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation and the crude 3,5,6-trichloro-2-(thiocyanatomethylthio)pyrazine product was purified by elution with chloroform from a silica gel column. The product was recovered in a yield of 0.32 grams (7.5 percent of theoretical) and melted at 90°-93° C. Upon analysis, the product was found to have carbon, hydrogen, nitrogen and sulfur contents of 25.60, 1.01, 14.29 and 22.60 percent, respectively, as compared with the theoretical contents of 25.13, 0.70, 14.66 and 22.34 percent, respectively, calculated for the above-named structure.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([OH:14])=O)=[CH:2]1.[N:21]1(OC(N(C)C)=[N+](C)C)[C:25]2C=C[CH:28]=[CH:29][C:24]=2N=N1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(N)CCC>>[CH2:25]([NH:21][C:12](=[O:14])[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)[CH2:24][CH2:29][CH3:28]
Reactant: O=C(O)C(=Cc1c[nH]c2ncccc12)c1ccccc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCN
Product: CCCCNC(=O)C(=Cc1c[nH]c2ncccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a solution of 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenyl-2-propenoic acid (100 mg, 0.3784 mmol.) in 2 ml of DMFd were added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoborate (121.5 mg, 0.3784 mmol.), N-hydroxybenzotriazole (51.1 mg, 0.3784 mmol) and N,N-diisopropylethylamine (129.2 μl, 0.7568 mmol). After stirring at room temperature for 30 min., 34.5 μl (0.3784 mmol.) of n-butylamine were added and the obtained solution was stirred at room temperature, for 24 hours. The resulting mixture was concentrated by evaporation of the solvent in vacuo, the residue was diluted with dichloromethane washed with 1 N NaOH, 1 N HCl, brine, dried over sodium sulphate and evaporated. The residual solid was triturated with Et2O to afford 49 mg of the title compound as a white solid (yield 41%) m.p. 177-179° C. (dec.)
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4].[Cl-:16].[Ca+2].[Cl-]>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C>[Cl:16][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4]
Reactant: CCCCCCCCCCC(Br)C(=O)O
Reactant: [Cl-]
Agent: CC[N+](CC)(CC)CC
Agent: [Ca+2]
Solvent: CC#N
Product: CCCCCCCCCCC(Cl)C(=O)O

Procedure:
To 2-bromododecanoic acid (1 g), after having been dissolved in acetonitrile (50 ml), were added calcium chloride (2 g) and tetraethylammonium chloride (1 g), and the mixture was heated under reflux for 4 hours. The reaction mixture was filtered, concentrated and distributed into ethyl acetate and water, and the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give 2-chlorododecanoic acid.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[C:12](\[CH2:27][O:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)/[CH2:13][NH:14][CH:15]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]2)=[CH:7][CH:6]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[OH:1][NH:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[C:12](/[CH2:13][NH:14][CH:15]2[CH2:19][CH2:18][NH:17][CH2:16]2)\[CH2:27][O:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC/C(=C/c2ccc(C(=O)NO)cc2)COc2cccc3ccccc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NO)c1ccc(/C=C(/CNC2CCNC2)COc2cccc3ccccc23)cc1
Yield: 46.6 %

Procedure:
The compound of formula 4d (103 mg, 0.19 mmol) obtained in Example 4-4 was dissolved in dichloromethane (1.5 ml), and trifluoroacetic acid (0.07 ml, 0.95 mmol) was added dropwise thereto at room temperature. The resulting mixture was reacted at room temperature for 8 hours. After the completion of reaction, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was purified by a preparative HPLC, to obtain 37 mg of the title compound as pale orange foam, which was used in the subsequent analysis.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[S:11][CH:10]=[N:9][CH:8]=1.[CH2:12]([O:19][C:20]1[N:25]=[C:24]([C:26](OC)=[O:27])[CH:23]=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C1COCC1>[CH2:12]([O:19][C:20]1[N:25]=[C:24]([C:26]([C:10]2[S:11][C:7]([CH3:6])=[CH:8][N:9]=2)=[O:27])[CH:23]=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1cccc(OCc2ccccc2)n1
Reactant: Cc1cncs1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cnc(C(=O)c2cccc(OCc3ccccc3)n2)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of n-BuLi (2.5 M in hexane, 16 mL, 40 mmol) in dry THF (120 mL) at −78° C. was added 5-methylthiazole (4.17 g, 40 mmol) drop wise over 20 minutes under nitrogen atmosphere. The mixture was stirred at −78° C. for 2 hrs and a solution of methyl 6-(benzyloxy)picolinate (4.7 g, 20 mmol) in THF (30 mL) was added drop wise over 20 minutes. After being stirred at −78° C. for 1 hr, the mixture was acidified with HCl (1N) to pH around 6 and extracted with ethyl acetate. The organic layer was concentrated and then diluted with MTBE. The white precipitate was collected by filtration to give A030-4. The remaining filtrate was concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (10/1) to afford A030-4. Total 6.2 g of (6-(benzyloxy)pyridin-2-yl)(5-methylthiazol-2-yl)methanone (85% yield) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([O:10][CH2:11][CH:12]([O:16][CH3:17])[CH2:13][O:14][CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[B:19]1([OH:29])[C:23]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=2[CH2:21][O:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:28][C:26]2[CH:25]=[CH:24][C:23]3[B:19]([OH:29])[O:20][CH2:21][C:22]=3[CH:27]=2)=[N:4][C:5]([O:10][CH2:11][CH:12]([O:16][CH3:17])[CH2:13][O:14][CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: COCC(COc1nc(Cl)c(Cl)cc1C#N)OC
Reactant: OB1OCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COCC(COc1nc(Oc2ccc3c(c2)COB3O)c(Cl)cc1C#N)OC
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL 3-neck-bottle purged and maintained with an inert atmosphere of nitrogen were placed a solution of 5,6-dichloro-2-(2,3-dimethoxypropoxy)nicotinonitrile (1.40 g, 4.59 mmol, 1.00 equiv, 95%) in DMSO (20 mL), benzo[c][1,2]oxaborole-1,5(3H)-diol (800 mg, 5.07 mmol, 1.10 equiv, 95%) and Cs2CO3 (1.88 g, 5.78 mmol, 1.20 equiv). The resulting solution was stirred for 2 h at 50° C. in an oil bath. The reaction mixture was then cooled and quenched by the addition of 20 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate. The organic layers were combined, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/petroleum ether (1:5). This resulted in 1.09 g (57%) of 5-chloro-2-(2,3-dimethoxypropoxy)-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinonitrile as a white solid. LC-MS (ES, m/z): 405 [M+H]+. 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.27 (1H, m); 8.61 (1H, m); 7.82 (1H, d, J=8.1 Hz); 7.34 (1H, m); 7.26 (1H, m); 5.00 (2H, s); 4.12-4.17 (1H, m); 3.97-4.03 (1H, m); 3.25-3.30 (1H, m); 3.17 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>CN(C=O)C>[O:20]([C:18]([NH:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1)=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1nc2cnccc2s1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cnccc2s1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 71.1 %

Procedure:
To a mixture of 2-aminothiazolo[4,5-c]pyridine (302 mg, 2 mmoles) and pyridine (0.2 ml) in 5 ml of DMF was added phenyl chloroformate (400 mg, 2.5 mmoles), and the mixture was stirred at room temperature for 1.5 days. The crystalline precipitate was collected by filtration to afford 386 mg (71%) of the title compound. Mp. >290° C.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=O>CC(O)C>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CN1CCNCC1
Reactant: BrCCCCOc1ccccc1
Solvent: CC(C)O
Product: c1ccc(OCCCCN2CCNCC2)cc1
Yield: 71.3 %

Procedure:
A mixture of 45.8 g (0.2 moles) of 4-phenoxybutyl bromide and 45.6 g (0.4 moles) of 1-formylpiperazine in 500 ml of 2-propanol was heated at reflux for 18 hours. The mixture was cooled and filtered. The filter was washed with 2-propanol and the filtrate was evaporated to a paste in vacuo. Water was added and the mixture was extracted three times with 200 ml portions of chloroform. The extracts were combined and evaporated to dryness. Then 250 ml of 5N sodium hydroxide was added to the residue. The mixture was refluxed for 18 hours with stirring, cooled and extracted twice with 250 ml portions of chloroform. The extracts were combined, dried over magnisium sulfate and evaporated to an oil. The oil was distilled bp 153°-156° C./0.05 mm of mercury and gave 33.4 g of 1-(4-phenoxybutyl)piperazine as a colorless liquid which crystallized on standing, mp 35°-36° C.
Reaction SMILES: O1CCCOB1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[O:22][CH3:23].N1C=CC(B(O)O)=CC=1>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:16]([O:22][CH3:23])[CH:17]=1
Reactant: COc1cc(Cl)ccc1CBr
Reactant: c1cncc(B2OCCCO2)c1
Agent: OB(O)c1ccncc1
Product: COc1cc(Cl)ccc1Cc1cccnc1

Procedure:
The title compound was prepared by substituting 1-bromomethyl-4-chloro-2-methoxy-benzene and 3-[1,3,2]dioxaborinan-2-yl-pyridine for 1-bromomethyl-4-chloro-2-methoxy-benzene and 4-pyridyl boronic acid, respectively, in Example 700A. MS (ESI) m/e 234 (M+H)+.
Reaction SMILES: C(OCC)(=O)C.[C:7]([O:11][C:12]([NH:14][C:15]1([CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[H][H]>[C].[Pd].CO>[C:7]([O:11][C:12]([NH:14][C:15]1([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: [H][H]
Reactant: CCOC(=O)C=CC1(NC(=O)OC(C)(C)C)CCOCC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC1(NC(=O)OC(C)(C)C)CCOCC1

Procedure:
In the ethyl acetate (30 mL) and methanol (12 mL) mixed solution of ethyl 3-(4-t-butoxycarbonylamino-tetrahydro-pyran-4-yl)-acrylate which had been obtained in 3), 5% palladium carbon catalyst was added at room temperature. The reaction mixture was stirred under the hydrogen gas stream at room temperature for 75 minutes. The palladium catalyst was removed by filtration with Celite, and the filtrate was concentrated and dried up to give colorless oily matter (2.69 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1C=C[CH:11]=[CH:10][C:9]=1O.C(OCC)C>N1C=CC=CC=1>[O:4]1[C:5]2[CH:6]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:7][C:2]1=[O:3]
Reactant: Nc1ccccc1O
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=c1[nH]c2ccccc2o1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
38.4 cc (0.4 mol) of ethyl chloroformate are added, at a temperature between 0° and 10° C., to a solution of 38.4 g (0.35 mol) of o-aminophenol in 150 cc of pyridine. When the addition has ended, the reaction mixture is stirred for a further 2 hours and then poured into 1.5 liters of diethyl ether. The precipitate is filtered off. The ether in the filtrate is evaporated off on a rotary evaporator. The residue is heated to 180° C. in order to distill off the pyridine. After cooling, the residue is recrystallized from ethyl acetate. The melting point of the obtained compound is 136° C.