Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[O:10][C:9]([C:14]3[C:15](F)=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:8][C:7]=2[CH:6]=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2].C(N(CC)CC)C.[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1>O1CCOCC1>[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][N:34]([C:15]2[C:14]([C:9]3[O:10][C:11](=[O:13])[C:12]4[C:3]([CH2:1][CH3:2])=[CH:4][C:5]([O:21][CH3:22])=[CH:6][C:7]=4[N:8]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:33]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: CCc1cc(OC)cc2nc(-c3cccnc3F)oc(=O)c12
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCc1cc(OC)cc2nc(-c3cccnc3N3CC[C@H](N(C)C)C3)oc(=O)c12
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a solution of compound S (37.60 g, 125 mmol) and triethylamine (42 mL, 301 mmol) in anhydrous 1,4-dioxane (800 mL) was added dropwise (S)-(−)-3-(dimethylamino)-pyrrolidine (17.1 g, 150 mmol) at room temperature under Ar. The resulting mixture was stirred for 8 hours. The solution was concentrated, and diluted with water (200 mL) and EtOAc (50 mL). The resulting solution was basified to pH 9 with saturated sodium bicarbonate and then extracted with ethyl acetate (3×300 mL). The organic layers were combined and washed with water, brine, and dried over anhydrous Na2SO4 followed by the removal of EtOAc in vacuo. The crude product was purified by column chromatography (Chromatrex NH-DM2035, Fuji Sislysia Chemical Co. Ltd.) using a gradient of 20-25% ethyl acetate/hexanes to yield compound 132 (37.03 g, 73%) as a yellow amorphous solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:21]1[N:22]=[C:23]([C:30]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]([CH3:42])[C:37](=[O:43])[N:36]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)[C:35]3=[O:52])=[O:31])[N:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=12>O.CN(C=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:51][C:48]1[CH:49]=[CH:50][C:45]([CH2:44][N:36]2[C:35](=[O:52])[C:34]3[C:39](=[CH:40][CH:41]=[C:32]([C:30]([C:23]4[N:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]5=[C:21]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[N:22]=4)=[O:31])[CH:33]=3)[N:38]([CH3:42])[C:37]2=[O:43])=[CH:46][CH:47]=1
Reactant: Cn1c(=O)n(Cc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(Br)c4ccccn34)ccc21
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(Cc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(-c4cccnc4)c4ccccn34)ccc21
Temperature: 150 °C
Yield: 87.9 %

Procedure:
0.04 g (0.32 mmol) of 3-pyridylboronic acid, 0.2 g (0.81 mmol) of potassium phosphate dihydrate dissolved in 0.29 ml of water, and 6.2 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium are added to 0.15 g (0.27 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-(4-fluorobenzyl)-1-methylquinazoline-2,4(1H,3H)-dione in 3 ml of DMF under an inert argon atmosphere. The reaction medium is microwave-heated at 150° C. for 20 minutes. After filtration over talc, the reaction medium is concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/5) mixture. 0.12 g of a yellow solid is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)=[CH:4][CH:3]=1.C([NH:31][CH2:32][CH:33]([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])C1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:35]([O:34][CH:33]([O:37][CH2:38][CH3:39])[CH2:32][NH:31][C:21]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:11]=1)=[O:23])[CH3:36]
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Reactant: CCOC(CNCc1ccccc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(CNC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1)OCC
Reaction time: 23 h
Yield: 46 %

Procedure:
To a stirred solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid (prepared according to the methods described by Barth, et al. in U.S. Pat. No. 5,624,941); 740 mg, 2.01 mmol) and N-benzyl-N-(2,2-diethoxyethyl)amine (450 mg, 2.01 mmol) in methylene chloride (6.5 ml) at room temperature was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (464 mg, 2.42 mmol) and then diisopropylethylamine (0.42 ml, 2.2 mmol), dropwise. After stirring for 23 hr, the reaction was concentrated, in vacuo, and then extracted from saturated aqueous sodium bicarbonate with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), a concentrated, in vacuo. The crude material (1.05 g) was purified on a Biotage™ Flash 40S column using 0-20% ethyl acetate in hexanes as eluant to afford I-1A-1a as a foam (534 mg, 46%): +ES MS (M+1) 572.1; 1H NMR (500 MHz, CD2Cl2) 1:1 mixture of rotamers, δ 7.51 (br s, 0.5H), 7.47 (d, J=2.1 Hz, 0.5H), 7.38-7.34 (m, 2H), 7.38-7.23 (m, 9H), 7.18-7.11 (m, 2H), 7.03 (s, 0.5H), 6.95 (s, 0.5H), 5.22 (s, 1H), 4.91 (s, 1H), 4.83-4.79 (m, 1H), 3.56-3.07 (m, 6H), 1.20 (t, J=7.0 Hz, 3H). 1.07 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9](C)(C)[CH3:10])=[C:6](O)[CH:7]=1.C1C=CC=CC=1.CC(C)([O-])C.[K+].BrC1C=CC(CC)=CC=1[N+]([O-])=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(Br)cc1O
Agent: CC(C)(C)[O-]
Agent: CCc1ccc(Br)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCc1ccc(Br)cc1

Procedure:
Employing the same general procedure as for the preparation of 5-bromo-2-tert-butyl-1-[(2'-amino-4'-methyl)phenoxy]benzene (Compound I), 781 mg (3.4 mmol) of 5-bromo-2-tert-butylphenol (Compound H) was converted into crude 5-bromo-2-tert-butyl-1-[4'-ethyl-2'-nitro)phenoxy]benzene using 611 mg (5.0 mmol) of potassium t-butoxide, 1.0 g (5.25 mmol) of cuprous iodide, 770 mg (~2.78 mmol) of 1-bromo-4-ethyl-2-nitrobenzene (~80% purity, obtained from the nitration of 1-bromo-4-ethylbenzene) and 10 mL of pyridine. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) gave crude 5-bromo-2-tert-butyl-1-[(4'-methyl-2'-nitro)phenoxy]benzene as a yellow oil. 290 mg of this crude sample was converted into the title compound using a balloon filled with hydrogen, 31 mg of 10% Pd/C, 4 mL of acetonitrile and 1 mL of methanol. Purification by flash chromatography (silica, 2% ethyl acetate in hexane) gave the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:28][CH3:29])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[CH:26]=O)=[O:19])[CH3:13].N1CCCCC1>C(O)C>[CH2:28]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[CH:26]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[NH:7][C:6]1=[O:11])=[O:19])[CH3:29]
Reactant: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=O
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=C1C(=O)Nc2ccc(Br)cc21
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-oxindole (106 mg, 0.5 mmol), 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (126 mg, 1 equiv.) and piperidine (0.2 mL) in ethanol (2 mL) was heated in a sealed tube at 80° C. for 1 hr and then cooled. The precipitate was collected by vacuum filtration, washed with ethanol and ethyl acetate and dried to give the title compound as an orange solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:35][C@H:36]4[CH2:41][CH2:40][C@H:39]([CH3:42])[CH2:38][CH2:37]4)[C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[C:31]([F:34])([F:33])[F:32])=[N:25][C:21]=3[CH:20]=[C:19]([C:43]#[N:44])[N:18]=2)[CH:14]=[N:15][CH:16]=1>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:35][C@H:36]4[CH2:37][CH2:38][C@H:39]([CH3:42])[CH2:40][CH2:41]4)[C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[C:31]([F:33])([F:32])[F:34])=[N:25][C:21]=3[CH:20]=[C:19]([C:43](=[N:2][OH:3])[NH2:44])[N:18]=2)[CH:14]=[N:15][CH:16]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(F)(F)F)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(F)(F)F)nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (44.5 mg, 0.64 mmol), sodium bicarbonate (81 mg, 0.96 mmol), and water (0.64 mL) were combined in a vial and stirred for 15 minutes. This solution was added to a vial containing 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (161 mg, 0.32 mmol) dissolved in ethanol (1.5 mL). The mixture was sealed and heated at 100° C. for 1 hour. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide. MS ESI calc'd. for C25H29ClF3N7O [M+H]+ 536. found 536.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](O)[CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].[CH2:29]([N:31](CC)CC)[CH3:30].CS(Cl)(=O)=O>O1CCCC1.C(=O)(O)[O-].[Na+]>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:30][C:29]#[N:31])[CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(O)c2)c1=O
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCc1cccc(-n2cc(-c3ccccn3)cc(-c3ccccc3C#N)c2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-(2-Cyanophenyl)-5-(2-pyridyl)-1-(3-hydroxyphenyl)-1,2-dihydropyridin-2-one (53 mg) was dissolved in 2 ml of tetrahydrofuran, then 60 ml of triethylamine and 20 ml of methanesulfonyl chloride were added thereto with ice cooling and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate and the extract was dried over an hydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated in vacuo, the resulting residue was dissolved in 1 ml of dimethyl sulfoxide, 3 mg of sodium cyanide were added and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with an aqueous solution of sodium bicarbonate and a saturated saline solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated in vacuo and the resulting crude crystals were recrystallized from ethyl acetate-diethyl ether-hexane to give 12 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1.Br[C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][NH:24]2)=[CH:20][CH:19]=1.BrC1C=C2C(C=CN2)=CC=1.C(O)(C(F)(F)F)=O>CN(C=O)C>[F:31][C:28]([F:29])([F:30])[C:27]([C:22]1[C:21]2[C:25](=[CH:26][C:18]([NH:16][C:14]3[N:15]=[C:8]4[C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[N:12][CH:11]=[CH:10][N:9]4[N:13]=3)=[CH:19][CH:20]=2)[NH:24][CH:23]=1)=[O:32]
Reactant: Cn1cc(-c2nccn3nc(N)nc23)cn1
Reactant: O=C(c1c[nH]c2cc(Br)ccc12)C(F)(F)F
Agent: Brc1ccc2cc[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cn1cc(-c2nccn3nc(Nc4ccc5c(C(=O)C(F)(F)F)c[nH]c5c4)nc23)cn1

Procedure:
8-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine is reacted with 1-(6-bromo-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, available by reaction of 6-bromo-1H-indole (1 eq.) with TFA (1.6 eq) in DMF at 120° C. for 1 h, under conditions described in general procedure 2.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>CCO>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: C1CNCCNC1
Reactant: Clc1ncccn1
Solvent: CCO
Product: c1cnc(N2CCCNCC2)nc1
Reaction time: 0.5 h

Procedure:
An ice bath is used to cool a solution of 3 g of 2-chloropyrimidine in 20 ml of EtOH which is then admixed dropwise with a solution of 13 g of 1,4-diazepane in 50 ml of EtOH, left with stirring in the cold for 30 minutes and then at AT for 24 hours. It is concentrated under vacuum, the residue is taken up with 100 ml of AcOEt and 100 ml of saturated K2CO3 solution, the system is decanted, the organic phase is diluted by adding 100 ml of AcOEt, the organic phase is washed with saturated K2CO3 solution and dried over Na2SO4 and the solvent is evaporated under vacuum. This gives the expected product, which is used as it is.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][CH:31]([CH2:33]Br)[CH2:30][C:29]=2[CH:35]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][CH:31]([CH2:33][N:11]3[CH2:10][CH2:9][C:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=4)([OH:14])[CH2:13][CH2:12]3)[CH2:30][C:29]=2[CH:35]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc(CC2(O)CCNCC2)cc1
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Product: COc1ccc(CC2(O)CCN(CC3Cc4cc(OCc5ccccc5)ccc4O3)CC2)cc1

Procedure:
The title compound MS: m/e=460.2 (M+H+) was prepared from 4-(4-methoxy-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][S:17][C:18]#[N:19])=[CH:11][CH:10]=1.Cl.[NH2:22][C:23]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24]1>C(O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[C:18]([NH:22][C:23]3([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24]3)[S:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: N#CSCC(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)C1(N)CCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1(Nc2nc(-c3ccc(Br)cc3)cs2)CCC1
Temperature: 68 °C
Reaction time: 8 h
Yield: 12.1 %

Procedure:
Triethylamine (3.30 mL, 23.7 mmol) was added under nitrogen to a mixture of 2-(4-bromophenyl)-2-oxoethyl thiocyanate (5.50 g, 21.6 mmol), prepared in step 1 of Example 1, and ethyl 1-aminocyclobutanecarboxylate hydrochloride (4.24 g, 23.6 mmol) in 130 mL of absolute ethanol. The mixture was then stirred at 68° C. overnight. The reaction was concentrated under reduced pressure to remove the ethanol. The residue was partitioned between ethyl acetate and water. The aqueous layer was made basic by the addition of 2 N NaOH. The organic layer was separated, washed two times with water, dried (MgSO4), filtered and the solvent removed under reduced pressure. Purification of the residue on a Horizon™ Flash Collector (the Biotage FLASH 40+™ cartridge) using a linear gradient of 45% methylene chloride in hexane to 100% methylene chloride as the eluent gave ethyl 1-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}cyclobutane carboxylate (1.0 g, 12%) as a brown oil, MS (ESI) m/z 381 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17]CC)=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1.[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([OH:17])=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1
Reactant: CCOC(=O)c1ncn2c1CN=C(c1ccccc1)c1cc(Br)ccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ncn2c1CN=C(c1ccccc1)c1cc(Br)ccc1-2
Yield: 96.6 %

Procedure:
The ester 5 (2 g) was dissolved in EtOH (50 mL) and aq sodium hydroxide (10 mL, 2N) was added to the solution. The mixture was heated to reflux for half an hour. After the EtOH was removed under reduced pressure, the solution was allowed to cool. The pH value was adjusted to 4 by adding 10% aq HCl dropwise. The mixture was filtered and the solid was washed with water and ethyl ether. The solid was dried to provide 27 (1.8 g, 96.6%): mp>250° C.; IR (KBr) 3450 (b), 2844, 1707, 1615, 1493, 1166, 700 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 4.14 (d, 1H, J=12.6 Hz), 5.79 (d, 1H, 12.6 Hz), 7.41–7.54 (m, 6H), 7.88 (d, 1H, J=8.7 Hz), 8.03 (dd, 1H, J=8.7 Hz, J=2.1 Hz), 8.47 (s, 1H); MS (EI) m/e (rel intensity) 381 (M+, 20), 383 (19).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].C(NC1C=CC(S([N:21]=[N+:22]=[N-])(=O)=O)=CC=1)(=O)C.C(N(CC)CC)C>C(#N)C>[N+:21](=[C:4]([C:5](=[O:7])[CH3:6])[C:1](=[O:3])[CH3:2])=[N-:22]
Reactant: CC(=O)CC(C)=O
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)C(=[N+]=[N-])C(C)=O
Temperature: 0 °C

Procedure:
A 1-L round-bottomed flask was charged with acetylacetone (S1) (10.25 mL, 100 mmol, 1.0 equiv) and acetonitrile (600 mL). p-Acetamidobenzene sulfonyl azide (p-ABSA)(J. S. Baum et al., Synth. Commun. 17, 1709 (1987) (24.0 g, 100 mmol, 1.0 equiv) was added and the reaction was cooled to 0° C. Triethylamine (NEt3) (41.8 mL, 300 mmol, 3 equiv) was added dropwise and the reaction was warmed to rt for 1 hour. The resulting suspension was filtered through a fitted funnel and concentrated. The obtained residue was triturated with 1:1 ether:petroleum ether and the precipitated white solids were removed via filtration. Solvents were removed in vacuo providing analytically pure S2 as a yellow oil in quantitative yield. Spectral data matched those reported in the literature (Z.-B. Chem et al., J. Org. Chem. 74, 903 (2009)).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH3:15][NH2:16]>O1CCCC1>[CH3:15][NH:16][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: CN
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(SC)nc1NC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.0 g, 21.5 mmol) and 29% methylamine (5.75 g, 53.72 mmol, methanol (MeOH) solution) in tetrahydrofuran (THF) (100 mL) was stirred at room temperature for 2 hours. The reaction mixture was then concentrated, followed by the addition of sodium bicarbonate (NaHCO3) (aq., 20 mL), and the resulting solution was extracted with ethyl acetate (EtOAc) (3×50 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated to afford ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate (4.68 g, 96%) as a yellowish solid. MS (ES+) C9H13N3O2S requires: 227. Found: 228 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH2:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl[S:13]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14].Cl>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][S:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=3)(=[O:15])=[O:14])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: NCc1ccc2occc2c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3occc3c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
To a solution of benzofuran-5-ylmethanamine (6.5 g, 28 mmol) in DCM (100 mL) was added methyl 4-(chlorosulfonyl)benzoate (4.1 g, 28 mmol) in portion wise at 0° C., and the mixture was stirred at room temperature for 3 hrs. The mixture was added 2 M aqueous HCl (80 mL) to give a white suspension. A half volume of DCM was removed by nitrogen flow, and the precipitates were collected by filtration, washed with water, and the solid was dried in vacuo at 50° C. to give 5.3 g (55% yield) of the titled compound as a off-white solid. The filtrate formed a suspension, which was collected by filtration, washed with water, and the solid was dried in vacuo at 50° C. to give 3.4 g (35% yield) of the titled compound as a pale brown white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([O:10][CH3:11])=[C:4]([CH2:12][CH3:13])[CH:3]=1.C([Li])CCC.[C:19](=[O:21])=[O:20]>C1COCC1.CCOC(C)=O>[CH2:12]([C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH2:8][CH3:9])[C:5]=1[O:10][CH3:11])[C:19]([OH:21])=[O:20])[CH3:13]
Reactant: CCc1cc(Br)cc(CC)c1OC
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(C(=O)O)cc(CC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
At -78° C., to a stirred solution of 4-bromo-2,6-diethylanisole (12.0 g, 49.4 mmol) in THF (329 mL) was added dropwise n-butyllithium (27.2 mL, 43.5 mmol). After 3 h, the reaction was poured into crushed dry ice and allowed to warm to ambient temperature. The reaction mixture was diluted with EtOAc, concentrated, suspended in H2O, acidified (pH 1), filtered and the collected solids washed with H2O. The crude product was slurried in hexane (15 mL), collected by filtration and dried to give 6.76 g (66%) of the title compound. 1H NMR: consistent. IR (KBr) consistent. mass spectrum (EI), m/z 208 (M+). Anal. Calcd. for C12H16O3 : C, 69.21; H, 7.74; N, 0.00. Found: C, 69.28; H, 7.49; N, 0.07.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].O1CCOCC1.S(Cl)([Cl:21])=O>CN(C=O)C>[Cl:21][C:5]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[S:1](=[O:3])(=[O:2])[N:4]=1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=S1(=O)N=C(Cl)c2ccccc21

Procedure:
Saccharin (10 g) was treated sequentially with dioxane (40 mL), thionyl chloride (15 mL) and DMF (0.4 mL). The resulting suspension was heated to reflux for 24 hours. The reaction mixture was concentrated to dryness and recrystalized from 60 mL toluene to give 5.7 g of the sub-title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CN(C)[CH:16]=[O:17].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:16]=[O:17])=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a solution of 2,5-dibromopyridine (2.37 g, 10.0 mmol) in tetrahydrofuran (15 mL) was added isopropylmagnesium chloride (2 mol/L in tetrahydrofuran; 5.0 mL, 10 mmol) under nitrogen atmosphere, and the mixture was stirred at room temperature for 1 h. Dimethylformamide (1.6 mL, 20 mmol) was added, and the mixture was stirred for additional 15 min. Water was added, and the mixture was extracted with ethyl acetate twice. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (2:1 hexane/ethyl acetate) to afford 2-bromo-5-pyridinecarboxaldehyde (1.23 g, 66%).