Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15]CC3C=CC=CC=3)[C:7]2=[N:6][C:5]=1[CH3:23].[H][H]>[Pd].CO>[Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[C:7]2=[N:6][C:5]=1[CH3:23]
Reactant: [H][H]
Reactant: Cc1nc2c(OCc3ccccc3)cccn2c(=O)c1CCCl
Agent: [Pd]
Solvent: CO
Product: Cc1nc2n(c(=O)c1CCCl)CCCC2O
Yield: 99 %

Procedure:
To a stirred mixture of 84 parts of phosphoryl chloride and 540 parts of methylbenzene were added 20 parts of 3-(phenylmethoxy)-2-pyridinamine. The mixture was stirred at 50° C. and 22 parts of 3-acetyl-4,5-dihydro-2(3H)-furanone were added. The reaction mixture was stirred for 5 hours at 90° C. Another portion of 22 parts of 3-acetyl-4,5-dihydro-2(3H)-furanone was added and stirring was continued for 30 minutes at 90° C. The solution was allowed to stand overnight at 90° C. The whole was poured into crushed ice and treated with an ammonium hydroxide solution 25%. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2-propanol. The product was filtered off, washed with a mixture of 2-propanol and 1,1′-oxybisethane and dried at 50° C., yielding 20.5 parts (62.3%) of 3-(2-chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 141.1° C. (intermediate 1) b) A mixture of 3.3 parts of 3-(2-chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2.0 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated to dry, yielding 2.4 parts (99%) of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one as an oily residue. (intermediate 2)
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].C([O-])(=O)C.[Na+].[Br:18]Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O>[Br:18][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:11])[C:2]2([CH3:12])[CH3:1]
Reactant: BrBr
Reactant: CC1(C)C(=O)Nc2ccccc21
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)C(=O)Nc2ccc(Br)cc21
Reaction time: 0.83 h
Yield: 92 %

Procedure:
3,3-dimethyl-indol-2-one (0.65 g, 4.03 mmol) and sodium acetate (0.33 g, 4.07 mmol) were stirred in acetic acid (5 cm3) then bromine (0.66 g, 4.13 mmol) in acetic acid (5 cm3) was added drop-wise to the reaction mixture. The reaction was stirred for 50 min., then poured into water. The mixture was basified with sodium carbonate, extracted with ethyl acetate (×3), dried (MgSO4), filtered, and evaporated to give the subtitled compound (0.89 g, 92%) 1H NMR (DMSO-d6) δ1.21 (s, 6H), 6.76 (d, 1H, J=8.22 Hz), 7.29 (dd, 1H, J=2.12 Hz, 8.23 Hz), 7.49 (d, 1H, J=2.03 Hz), 10.4 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH2:10][C:11]#[CH:12])=[O:7])([CH3:4])[CH3:3].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:37][C@H:38]([C:43]([O:45][CH3:46])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41].Cl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:2]([O:5][C:6]([NH:8][CH:9]([CH2:10][C:11]#[CH:12])[C:13]([NH:37][CH:38]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:43]([O:45][CH3:46])=[O:44])=[O:15])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CCC(NC(=O)OC(C)(C)C)C(=O)NC(CC(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of Boc-L-propargylglycine (26.65 g; 125 mmol) in dry DMF (170 mL) was added EDCI (29.23 g; 152.5 mmol) and HOBt (23.5 g; 122.5 mmol), and the reaction mixture was stirred at room temperature for 40 min (solution A). In a separate RB flask, (L) Leu-OMe hydrochloride (22.72 g; 125 mmol) in dry DMF (82 mL) kept at 0° C. was treated with diisopropyl ethyl amine (DIEA) (64.62 g; 500 mmol) and the solution was stirred for 25 min (solution B). Solution B was added to solution A and the reaction mixture was stirred overnight at room temperature. The solvent was removed on the rotary evaporator and the residue was taken up in dichloromethane (DCM) (600 mL) and washed sequentially with saturated sodium bicarbonate (2×200 mL), 5% HCl (2×200 mL) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, leaving a crude product which was purified using flash chromatography (silica gel; hexane/ethyl acetate 75:25) to give 1 as a white solid (38.12 g; 89% yield); 1H NMR (CDCl3) δ 8.2 (s, 1H), 7.0 (s, 1H), 4.3 (m, 1H), 4.1 (m, 1H), 3.6 (s, 3H), 2.8 (s, 1H), 2.4 (m, 2H), 2.3 (m, 1H), 1.6 (m, 2H), 1.5 (m, 1H), 1.38 (s, 9H), 0.87 (d, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH:15]([O:17][CH2:18][CH2:19]Cl)=[CH2:16].CN(C)C=O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:8][C:6](=[O:7])[N:5]([CH2:19][CH2:18][O:17][CH:15]=[CH2:16])[C:3]1=[O:4]
Reactant: C=COCCCl
Reactant: CN1CC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=COCCN1C(=O)CN(C)C1=O

Procedure:
A mixture of 82.6 g (0.72 mol) of 1-methylhydantoin, 50.7 g (0.37 mol) of anhydrous potassium carbonate, 89.6 g (0.84 mol) of 2-chloroethyl vinyl ether, 700 ml of dimethylformamide and 100 ml of toluene is reacted for 2 hours and 30 minutes at 130°-138° C., whilst removing the water of reaction. The mixture is then worked up as described in Example 1, and 128.5 g of a clear, reddish brown, viscous crude product (96.9% of theory) are obtained. The crude product is distilled (boiling point 133° C.-134° C./0.2 mm Hg) and 108.5 g (81.8% of theory) of a colourless, viscous distillate are obtained; this crystallises and melts at 54°-56° C.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].IC.[C:14]([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[F:1][C:2]1[C:3]([O:11][CH3:14])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c(F)ccc(F)c1O
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(F)ccc(F)c1C=O
Temperature: 80 °C

Procedure:
A mixture of commercially available 3,6-difluoro-2-hydroxybenzaldehyde (2.450 g; 15.50 mmol), iodomethane (2.199 g; 15.50 mmol), and K2CO3 (2.570 g; 18.60 mmol) in anh. DMF (50 ml) was heated to 80° C., under nitrogen, for 4 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 3,6-difluoro-2-methoxybenzaldehyde as a colorless solid. LC-MS (conditions A): tR=0.62 min.; no ionisation.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[Cl:10].[N+]([C:14]1[CH:19]=CC=C[CH:15]=1)([O-])=O.B(O)(O)O.S(=O)(=O)(O)O>OCC(CO)O>[Cl:10][C:4]1[CH:5]=[C:6]([OH:9])[CH:7]=[C:8]2[C:3]=1[N:2]=[CH:19][CH:14]=[CH:15]2
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Nc1ccc(O)cc1Cl
Agent: Cl
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: OCC(O)CO
Product: Oc1cc(Cl)c2ncccc2c1
Temperature: 120 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
In a 500 ml 3-necked flask equipped with a mechanical stirrer, a reflux condenser, were added in order ferrous sulfate (2.0 g), 4-amino-3-chlorophenol hydrochloride (6.4 g, commercially available), nitrobenzene (2.9 mL) and a solution of boric acid (3.0 g) in glycerol (16 g). Then concentrated sulfuric acid (9 mL) was added drop by drop with cooling. The ice bath was removed and replaced by an oil bath and the mixture was heated cautiously to 120° C. for 2 hours, then at 150° C. and kept stirring under this temperature for 20 hours. After cooling, the reaction was poured on crushed ice and the resulting solution was neutralized with K2CO3. The product separated as a light brown solid that was filtered off, washed with water and hexanes and dried in a vacuum oven (35° C.) overnight giving 7 g (77%) of the desired product. MS (ES) m/z (relative intensity): 180 (M++−H, 100).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([CH:22]2[CH2:24][CH2:23]2)[C:6]2[C:12]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[C:11]([F:21])[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3].Cl[C:26]1[C:27]2[N:34]=[CH:33][S:32][C:28]=2[N:29]=[CH:30][N:31]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[CH:22]1([N:5]2[C:6]3[C:12]([C:13]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[O:14])=[C:11]([F:21])[CH:10]=[CH:9][C:7]=3[N:8]=[C:4]2[C@@H:2]([NH:1][C:26]2[C:27]3[N:34]=[CH:33][S:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH3:3])[CH2:23][CH2:24]1
Reactant: C[C@H](N)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1C1CC1
Reactant: Clc1ncnc2scnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc2scnc12)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1C1CC1
Temperature: 90 °C
Yield: 71.3 %

Procedure:
A mixture of [2-((S)-1-aminoethyl)-3-cyclopropyl-5-fluoro-3H-benzoimidazol-4-yl]-morpholin-4-yl-methanone (108 mg, 0.33 mmol), 7-chloro-thiazolo[5,4-d]pyrimidine (61 mg, 0.36 mmol) and DIPEA (170 μL, 0.98 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 17 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford 400 as a pale yellow solid (110 mg, 39%). LCMS (Method K): RT 3.16 min [M+H]+ 468.02. 1H NMR (CDCl3, 400 MHz): δ 8.82 (0.7H, s), 8.77 (0.3H, s), 8.54 (0.3H, s), 8.52 (0.7H, s), 7.73-7.65 (1H, m), 7.17 (0.7H, d, J=8.02 Hz), 7.05-6.95 (1H, m), 6.67 (0.3H, d, J=8.45 Hz), 6.31-6.23 (0.3H, m), 6.14-6.04 (0.7H, m), 4.23-4.14 (1H, m), 3.93-3.72 (4H, m), 3.68-3.51 (2H, m), 3.47-3.33 (2H, m), 1.84 (1H, d, J=6.77 Hz), 1.75 (2H, d, J=6.76 Hz), 1.54-1.46 (0.7H, m), 1.41-1.29 (1H, m), 1.20-1.10 (0.3H, m), 1.03-0.93 (1H, m), 0.86-0.71 (1H, m)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C1C(=O)N([Br:18])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:18])=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccccc1N
Solvent: ClCCl
Product: CC(=O)c1cc(Br)ccc1N
Temperature: -10 °C

Procedure:
A flask charged with 1-(2-aminophenyl)ethanone (135 mg) and DCM (2.5 mL) was cooled to −10° C. and NBS (178 mg) was added in several portions over 30 min. The reaction mixture was diluted with 10 mL DCM, washed with sat. aqueous NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure, affording the title compound. MS (ESI+): m/z 215.06 (MH+). 1H NMR (400 MHz, CDCl3): δ 7.79 (s, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 6.30 (br, 2H), 2.55 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Br.CCN(CC)CC.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([N:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][OH:20])[CH2:24][CH2:25]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCN1CCNCC1
Reactant: COC(=O)C(Br)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(c1ccccc1)N1CCN(CCO)CC1
Temperature: 25 °C

Procedure:
To a solution of racemic a-bromophenylacetic acid methyl ester, 5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) of Et3N and 8 mL (66.0 mmol) of 1-(hydroxyethyl)piperazine. The reaction mixture was refluxed for three hours, cooled to rt. and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give a quantitative yield of the desired mixture of isomers as a yellow oil. MS (ion spray) 279.1 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]2[CH2:17][CH2:16][CH2:15][NH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[CH3:19][C:20]1[N:21]=[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[S:23][C:24]=1[C:25](Cl)=[O:26]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:25]([C:24]3[S:23][C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:21][C:20]=3[CH3:19])=[O:26])[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C2=NNCCC2)ccc1OC
Reactant: Cc1nc(-c2ccccn2)sc1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C2=NN(C(=O)c3sc(-c4ccccn4)nc3C)CCC2)ccc1OC
Yield: 78.8 %

Procedure:
Analogously to Example 2, reaction of 1.1 g of 3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazine with 1.2 g of 4-methyl-2-pyridin-2-ylthiazole-5-carbonyl chloride, hydrochloride (“BB”) gives the compound 1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-pyridin-2-ylthiazol-5-yl)methanone (1.5 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[CH:7]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CS(C)=O.C[CH2:52][O:53][C:54](C)=[O:55].O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:52][O:53][C:54]([C:2]1[N:3]=[C:4]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[CH:7]=1)=[O:55]
Reactant: CC(C)Nc1nc(Br)cn2c(=O)[nH]nc12
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)c1cn2c(=O)[nH]nc2c(NC(C)C)n1
Temperature: 75 °C
Reaction time: 14 h

Procedure:
A solution of 521 mg of the product of Step E, 313 mg of 1,3-bis-(diphenylphosphino)propane, 212 mg of palladium(II) acetate and 13.8 g of TEA in a 10:1 mixture of MeOH/DMSO (209 mL) was agitated under a carbon monoxide atmosphere (45 psi) at 75° C. After 14 h, the reaction was cooled to ambient temperature and portioned between EtOAc/water. The resulting mixture was filtered through a pad of diatomaceous earth and the solids washed with EtOAc. The layers were separated and the aqueous was extracted with EtOAc. The combined organic extracts were washed with sat. sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to provide 8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-6-carboxylic acid methyl ester as an oil. MS (M+H+)=252.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[NH:24][CH:25]=[C:26]([C:28]#[N:29])[CH:27]=3)=[O:22])=[C:16]([C:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37].CO>C(Cl)Cl.CO>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[C:30]1([C:16]2[CH:15]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=[CH:18][C:17]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[CH:27]=2)=[O:22])[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3cc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution of 36.0 mg (0.0759 mmol) 4-{4-[(4-cyano-1H-pyrrole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step) in 5 mL CH2Cl2 was treated with 4 drops MeOH and 1 mL TFA and stirred at RT for 2 h. MeOH (5 mL) was added, and solvents were evaporated in vacuo. Purification of the residue by RP-HPLC (C18) with 10-80% CH3CN in 0.1% TFA/H2O over 30 min afforded 22.0 mg (59%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C23H26N4O, 375.2 (M+H), found 375.2.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.OO.[OH2:14].S([O-])(O)=[O:16].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:16])=[O:14]
Reactant: O
Reactant: O=S([O-])O
Reactant: ClCCCSc1ccccn1
Agent: OO
Agent: [Na+]
Solvent: O=CO
Product: O=S(=O)(CCCCl)c1ccccn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(3-Chloropropyl)thiopyridine (3.7 g) prepared in Reference Example 3 is dissolved in formic acid (30 ml). 30% Aqueous hydrogen peroxide (6.9 g) is added to the solution and the mixture is stirred at room temperature for 4 hours. After dilution with water, sodium hydrogen sulfite is added to the mixture with ice-cooling to destroy excess formic acid. The mixture is extracted with chloroform and the extract is washed with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by column chromatography (Kieselgel 60). The column is eluted with chloroform-methanol (50:1) to obtain 2-pyridyl 3-chloropropyl sulfone (4 g) as colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:25]=[CH:24][C:14]2[C:15]([C:18](N(OC)C)=[O:19])=[N:16][S:17][C:13]=2[CH:12]=1.Cl>C1COCC1>[Br:10][C:11]1[CH:25]=[CH:24][C:14]2[C:15]([C:18]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:19])=[N:16][S:17][C:13]=2[CH:12]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1nsc2cc(Br)ccc12
Agent: Cl
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1nsc2cc(Br)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
4-Chlorophenyl magnesium bromide (1.0N in THF, 16 mL, 16 mmol) was added to a stirred solution of 6-bromo-N-methoxy-N-methylbenzo[d]isothiazole-3-carboxamide (3.5 g, 12 mmol) in THF (100 mL). The reaction mixture was stirred at 0° C. for 1 hour. The reaction was poured into 1N HCl and extracted into ether. The combined organic layers were washed with brine, dried and concentrated. The crude product was suspended in ether and stirred for 15 minutes. The solid was collected by filtration to give (6-bromobenzo[d]isothiazol-3-yl)(4-chlorophenyl)methanone (3.3 g, 81%). 1H NMR (CDCl3, 400 MHz) δ □8.60 (d, J=8.8 Hz, 1H), 8.23 (d, J=8.4 Hz, 2H), 8.19 (s, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5][C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:3]1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].C1CCN2C(=NCCC2)CC1>CCO>[C:28]([O:27][C:23](=[O:26])[CH2:24][CH2:25][C:6]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5][C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[N:3][C:2]1=[O:1])([CH3:31])([CH3:30])[CH3:29]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCOC(=O)C1SC(Nc2ccccc2C(F)(F)F)=NC1=O
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1(CCC(=O)OC(C)(C)C)SC(Nc2ccccc2C(F)(F)F)=NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above compounds were prepared according to the procedure reported in the literature: see S. Muthusamy Synth. Commun. 2002, 32, 3247. To a stirred solution of ethyl 4-oxo-2-(2-(trifluoromethyl)phenylamino)-4,5-dihydrothiazole-5-carboxylate (1.1 g, 3.3 mol), tert-butyl acrylate (Aldrich, 2.5 mL, 16.5 mmol) in EtOH (10 mL) was added DBU (Aldrich, 0.25 mL, 1.6 mmol). The mixture was stirred at r.t. overnight and concentrated in vacuo. The crude product was purified by silica gel chromatography. MS: 461 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15](=[O:17])[CH3:16])=[N:3][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cn1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc(Br)cn1
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 2-amino-5-bromopyridine (0.50 g, 2.9 mmol) in THF (10 mL) was added pyridine (343 mg, 4.3 mmol) and acetic anhydride (295 mg, 2.9 mmol) at room temperature and stirred overnight. To the mixture water (30 mL) was added, extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, concentrated to give the title compound (0.58 g, 92%) as a white solid LCMS: 215 [M+2]+; 1HNMR (400 MHz, DMSO-d6) δ 2.09 (s, 3H), 7.97 (dd, J=8.8, 2.4 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H), 8.41 (d, J=1.2 Hz, 1H), 10.64 (s, 1H).
Reaction SMILES: Br[C:2]1[C:6]([CH:7]=[O:8])=[CH:5][S:4][CH:3]=1.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)[CH3:10].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:6]([CH:7]=[O:8])=[CH:5][S:4][CH:3]=2)=[CH:13][CH:12]=1)[CH3:10]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: O=Cc1cscc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1ccc(-c2cscc2C=O)cc1
Temperature: 128 °C
Reaction time: 5 h

Procedure:
A mixture of 3-bromo-4-formylthiophene (0.62 g, 3.18 mmol) and 4-ethylphenylboronic acid (0.95 g, 6.36 mmol) in toluene (12 mL), EtOH (12 mL) and aqueous Na2CO3 solution (2 M, 3.18 mL, 6.36 mmol) in a seal tube was deoxygenated under reduced pressure and flushed with argon for 3 times, followed by addition of Pd(PPh3)4 (184 mg, 0.16 mmol) and deoxygenated again. The resulting solution was stirred at 128° C. in an oil bath for 5 hour. The reaction progress was monitored by TLC/LCMS (ethyl acetate/petroleum ether=1:6). The reaction was partitioned between ethyl acetate and water. Collected the organic phases and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 440 mg (64%) of 4-(4-ethylphenyl)thiophene-3-carbaldehyde as light yellow oil.
Reaction SMILES: N1C[CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12]C(N3CC(C4C=NC=CC=4)C3)=O)=CC=2)C1.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=1.C[C@@H](CC)C(O)=O>>[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:12][CH2:9][CH:10]2[CH2:11][CH2:6][O:5][CH2:3]2)=[O:32])=[CH:33][CH:34]=1
Reactant: O=C(Nc1ccc(OC2CNC2)cc1)N1CC(c2cccnc2)C1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CC[C@H](C)C(=O)O
Product: Nc1ccc(C(=O)NCC2CCOC2)cc1

Procedure:
The title compound was prepared as described in Example 1E, substituting (tetrahydrofuran-3-yl)methanamine for N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide and 4-aminobenzoic acid for (S)-2-methylbutanoic acid.