Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[C:11]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)([OH:13])=[O:12].CC1C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:23][S:20]([C:17]2[CH:16]=[CH:15][C:14]([C:11]([OH:13])=[O:12])=[CH:19][CH:18]=2)(=[O:21])=[O:22])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: N#Cc1ccc(C=NS(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
In a similar manner to Example 2, 1.25 g (9 mmol) of 4-cyanobenzaldehyde, 1.91 g (9 mmol) of 4-carboxybenzenesulfonamide and 20 mg of TsOH in 150 mL of chlorobenzene under nitrogen were heated for 18 hours to give 2.58 g (86%) of SULF-7 as a white powder: IR (Nujol) 3400-2400 (br), 2224, 1682, 1605, 1155 cm-1 ; 1H NMR (DMSO-d6, TMS ext std)δ 9.35 (s, 1), 8.3-7.8 (m, 8).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=3)[C:9]=2[N:28]([CH3:30])[CH3:29])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:26])(=[O:27])[NH2:25])=[CH:20][CH:19]=3)[C:9]=2[N:28]([CH3:30])[CH3:29])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(N(C)C)c1-c1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)c1c(-c2ccc(Cl)cc2)sc(C(=O)O)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
Ethyl 5-(4-chlorophenyl)-4-(dimethylamino)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 34e, 2.00 g, 4.30 mmol) was suspended in ethanol (30 ml) and solution of NaOH (0.86 g, 21.5 mmol) in water (4 ml) was added to it at 25° C. The reaction mixture was then heated at 75° C. under stirring for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was diluted with water (10 ml) and cooled using ice bath. To the cooled mixture was added aqueous 10% HCl to bring the pH of the solution to about 6. The mixture so obtained was extracted with ethyl acetate (3×30 ml). The combined organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain the title compound (1.60 g, 85.1%)
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:11])[C:8]([CH3:10])=[CH2:9].[Cl:12][CH2:13][C:14](Cl)=[O:15].C(N(CC)CC)C>CO.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>[Cl:12][CH2:13][C:14]([NH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:11])[C:8]([CH3:10])=[CH2:9])=[O:15]
Reactant: C=C(C)C(=O)NCCCN
Reactant: O=C(Cl)CCl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCCCNC(=O)CCl
Temperature: 0 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
In a 3-liter 4-neck flask fitted with condenser, stirrer, and 2-dropping funnels were placed N-(3-aminopropyl)methacrylamide hydrochloride 157 g 0.88 moles) in methanol (1.2 L) and 2,6-ditert-butyl-p-cresol (1.0 g). In one funnel was placed chloroacetyl chloride (100 g, 0.89 mole), and in funnel two was placed triethylamine (178 g, 1.76 mole). The solution was cooled to 0°-5° C. (ice-methanol), and triethylamine was added in a slow stream over 30 minutes, and the chloroacetyl chloride was added over 1 hour. After the addition, the temperature was maintained at 0° C. for 2 hours, the ice bath was removed, and stirring was continued at room temperature overnight. The solvent was removed, and to the residue was added hot ethyl acetate (500 mL). The mixture was filtered to remove triethylamine hydrochloride, then the solid was washed with hot ethyl acetate (500 mL), filtered again, the filtrate combined, and the solvent was removed on a rotory evaporator. The residue was crystallized from ethyl acetate (400 mL) by heating to dissolve, filtering to remove any solid present, and cooling to 0° C. to crystallize. The crude monomer was purified by chromatography on a silica gel packed column. The product was eluted from the column using a 1:1 mixture of ethyl acetate and dichloromethane (4 L). The collected solvent was evaporated, and the residue crystallized from ethyl acetate (300 mL) with 2,6-di-tert-butyl-p-cresol (500 mg) to give a white crystalline compound, mp 85°-90° C., 83 g (43% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:8][CH:7]=[CH:6][N:5]2[CH:17]=1.[H-].[Na+].Cl[C:21]1[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[N:22]=1.O>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:21]4[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[C:24]5[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=5[N:22]=4)=[CH:12][CH:11]=3)=[CH:8][CH:7]=[CH:6][N:5]2[CH:17]=1
Reactant: Cc1cn2cccc(-c3ccc(O)cc3)c2n1
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn2cccc(-c3ccc(Oc4nc5ccccc5n4COCC[Si](C)(C)C)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.5 %

Procedure:
To a solution of 4-(2-methylimidazo[1,2-a]pyridin-8-yl)phenol (0.40 g) in DMF (5 ml) was added sodium hydride (60% in oil, 0.086 g), and the mixture was stirred at room temperature for 5 min. To the reaction mixture was added 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (0.50 g), and the mixture was stirred under microwave irradiation at 150° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.57 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.CO.Cl.[CH2:12](N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[O:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH3:12])=[O:7])[CH2:3]1
Reactant: O=C1CC(C(=O)O)C1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CC(=O)C1

Procedure:
3-Oxocyclobutanecarboxylic acid 1 (350 g, 3.06 mol), methanol (190 mL, 4.69 mol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (885 g, 4.69 mol), 4-dimethylaminopyridine (37 g, 0.30 mol) and dichloromethane (6 L) were stirred at ambient temperature for 24 hours. After the completion of the reaction, it was taken in a separating funnel and washed with 1.5 N HCl solution (1 L), water (2 L×2) and brine (1 L×2). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was taken to the next step without further purification. 1H NMR (300 MHz, CDCl3): δ 3.23-3.25 (m, 2H), 3.27-3.32 (m, 2H), 3.33-3.42 (m, 1H), 3.76 (s, 3H). GC-MS: [M]+ m/z=128.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]2[C:13](=[O:16])[CH2:14][O:15][C:11]=2[C:10]=1[CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH:42]=O)=[CH:34]1.N1CCCCC1>CO>[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](/[CH:42]=[C:14]2\[O:15][C:11]3[C:10]([CH2:19][N:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:18]=[CH:17][C:12]=3[C:13]\2=[O:16])=[CH:34]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OCc3ccccc3)ccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(OCc3ccccc3)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
A solution of tert-butyl 4-{[6-(benzyloxy)-3-oxo-2,3-dihydrobenzofuran-7-yl]methyl}piperazine-1-carboxylate (0.198 g, 0.452 mmol) in methanol (1.8 mL) was added with indole-3-carboxaldehyde (0.0656 g, 0.452 mmol) and piperidine (0.0308 g, 0.362 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the precipitated yellow solid was collected by filtration to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-(benzyloxy)-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.141 g, 55%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:9](Cl)(=[O:11])[CH3:10]>C(Cl)Cl>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:9](=[O:11])[CH3:10])=[CH:3][N:4]=1
Reactant: CC(=O)Cl
Reactant: Nc1cnc(Cl)nc1
Solvent: ClCCl
Product: CC(=O)Nc1cnc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
5-amino-2-chloro pyrimidine (260 mg, 2 mmol) was dissolved in DCM (5 ml), TEA (0.557 ml, 4 mmol) was added and the reaction mixture was stirred at 0° C. for 15 min. Acetyl chloride (0.213 ml, 3 mmol) was added dropwise at 0° C. and the reaction mixture was stirred for 45 min. The reaction was quenched with an aqueous saturated solution of NaHCO3. The phases were separated and the aqueous phase was basified by adding solid K2CO3 while the pH was allowed to reach ˜9-10 and extracted with dichloromethane. Combined organic phases were dried over Na2SO4 and evaporated in vacuo to afford N-(2-chloropyrimidin-5-yl)acetamide (340 mg) as a crude product.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3].[CH2:10]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Ba+2].[OH-]>CCO>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[CH:1][C:2]([CH:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:3])=[CH:24][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)C1CCCCC1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc(OCc2ccccc2)cc1)C1CCCCC1

Procedure:
The title compound was prepared as described in General Method 2 using 17.40 g (138 mmol) of cyclohexyl methyl ketone, 29.26 g (138 mmol) of 4-benzyloxybenzaldehyde, 3.17 g of barium hydroxide (anhydrous), and 300 mL of 95% EtOH. The reaction was heated at reflux for eight hours. The crude product was recrystallized from EtOAc. The 25.85 g of product, contaminated with some 4-benzyloxybenzaldehyde, was taken on without further purification.
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][N:14]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C@H:13]([C:22]([OH:24])=O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][O:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[C:32]([O:31][C:30]([NH:29][CH2:28][CH2:27][O:26][NH:25][C:22]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]([NH:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15][N:14]1[C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])=[O:24])=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCON
Reactant: O=C(O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Reaction time: 3 h
Yield: 83.5 %

Procedure:
(2S,5R)-5-(Benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylic acid (0.879 g, 2.54 mmol) described in Example 98 and tert-butyl 2-(aminooxy)ethylcarbamate (0.559 g) of Reference Example 9 were dissolved in N,N-dimethylformamide (11 mL), and to which was added 1-hydroxybenzotriazole.monohydrate (0.489 g), followed by ice-cooling. To this was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.613 g), and the temperature was elevated to room temperature, followed by reacting for 3 h. Water was added to the reacted mixture, and extracted with ethyl acetate. After the organic layer was washed with 10% citric acid aqueous solution, water, 6.5% sodium bicarbonate aqueous solution and saturated brine sequentially, and then the solvent was distilled off under reduced pressure. The resulting oil residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/2) to afford 1.07 g of the title compound (yield 84%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][Si](C=[N+]=[N-])(C)C>C1COCC1.CO>[CH3:13][O:11][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc[nH]c2c1
Reaction time: 3 h

Procedure:
To a solution of 6-indole carboxylic acid (0.91 g, 5.67 mmol) in 33 mL of 2:1 THF/MeOH is added (trimethylsilyl)diazomethane (5.0 mL of a 2.0M solution in hexanes, 10.0 mmol). The mixture is stirred for 3 h and concentrated in vacuo to give the title compound (0.87 g, 4.97 mmol). The crude product is used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ8.70 (bs, 1H), 8.20 (s, 1H), 7.82 (dd, 1H), 7.67 (d, 1H), 7.45 (m, 1H), 6.60 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:2])=[CH:10][CH:9]=1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: O=S(=O)(O)O
Solvent: COc1ccc(C)cc1
Solvent: O
Product: COc1ccc(C=O)cc1
Temperature: 80 °C

Procedure:
Into the same flask as in Example 1 are placed 400 ml of water, 87 g of sulfuric acid, 5 g of manganic sulfate and 100 g of p-methoxytoluene, and the mixture is stirred. Into a 1-liter beaker are placed 540 ml of water, 86 g of chromic anhydride and 246 g of sulfuric acid to prepare an oxidizing solution. The oxidation process of Example 2 is repeated in the same manner except that the reaction temperature is maintained at 80° C for 21/3 hours. The reaction mixture is treated in the same manner as in Example 1, affording 70 g of anisaldehyde, 27 g of unreacted p-methoxytoluene and 5 g of the residue. Conversion 73%. Yield 86%. Aldehyde selectivity 80%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[C:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH:28]3[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(N2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a stirred (30 min) solution of 1-[3-(methyloxy)-4-nitrophenyl]piperazine (3.52 g, 14.9 mmol), 1-Boc-4-piperidone (5.96 g, 29.9 mmol), HOAc (24.0 mL, 1M in DCM, 24.0 mmol) and TEA (2.00 mL, 14.3 mmol) in 1,2-DCE was added in one portion sodium triacetoxyborohydride (4.82 g, 22.7 mmol). The reaction was stirred for 30 min at which time sodium triacetoxyborohydride (2.00 g, 9.40 mmol) and HOAc (10.0 mL, 1M in DCM, 10.0 mmol) was added. The reaction was stirred at rt overnight. The reaction was quenched with saturated NaHCO3 (150 mL) and extracted with DCM. The organic layer was washed with H2O, dried (MgSO4) and concentrated. Purification by flash chromatography provided the title compound of step C (6.09 g, 14.5 mmol, 97%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.32 (m, 2H), 1.37 (s, 9H), 1.74 (d, J=10.6 Hz, 2H), 2.41 (tt, J=11.0, 3.2 Hz, 1H), 2.55-2.62 (m, 4H), 2.70 (br. s., 2H), 3.36-3.44 (m, 4H), 3.88 (s, 3H), 3.94 (d, J=13.2 Hz, 2H), 6.50 (d, J=2.6 Hz, 1H), 6.57 (dd, J=9.5, 2.6 Hz, 1H), 7.86 (d, J=9.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[C:30]([CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:25]([C:24]3[CH:27]=[CH:28][CH:29]=[C:30]([CH2:31][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[C:23]=3[O:22][CH3:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: COc1c(C=O)cccc1CN1CCOCC1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: COc1c(CN2CCOCC2)cccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 70 %

Procedure:
In a similar fashion as for the synthesis of III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-methoxy-3-morpholin-4-ylmethylbenzaldehyde were reacted to produce the title compound (70%). Mp. 133-7° C. 1H NMR (d-chloroform): 12.03 (br s, 1H), 8.18 (d, J=7 Hz, 1H), 8.13 (s, 1H), 7.56 (d, J=7 Hz, 1H), 7.29 (t, J=8 Hz, 1H), 6.37 (m, 2H), 6.29 (s, 1H), 5.82 (d, J=7 Hz, 1H), 5.41 (s, 1H), 5.25 (t, J=7 Hz, 1H), 3.83 (s, 3H), 3.75 (m, 4H), 3.67 (s, 2H), 3.17 (s, 1H), 2.94 (s, 1H), 2.83 (d, J=7 Hz, 1H), 2.58 (m, 4H), 2.36 (d, J=7 Hz, 1H). MS: 509.2 (M+H). HPLC retention time: 1.71 minutes (G Method).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:38]([O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)[CH3:39].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:38]([O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45]([O:1][CH:2]2[CH2:3][CH2:4][CH:5]([N:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[CH2:6][CH2:7]2)=[CH:44][CH:43]=1)[CH3:39]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC2CCC(N3C(=O)c4ccccc4C3=O)CC2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a stirred solution of 2-(4-hydroxycyclohexyl)isoindole-1,3-dione (8.0 g, 32.6 mmol) in dry THF (100 mL) was added triphenyl phosphine (12.8 g, 48.8 mmol) and 4-hydroxy benzoic acid ethyl ester (5.44 g, 32.7 mmol). The reaction mixture was cooled to 0° C. and DIAD (9.6 g, 47.4 mmol) was added dropwise from an addition funnel over a period of 3 h. The reaction was gradually brought to room temperature and stirring continued for 3 h. The solvent was removed under vacuum and ether (100 mL) was added and cooled to 0° C. The solid formed was filtered and the clear filtrate concentrated and purified by column chromatography over neutral alumina (8% AcOEt in hexane) to give 5.13 g (42%) of 4-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-cyclohexyloxy]-benzoic acid ethyl ester.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][C:20]([OH:22])=O)[CH:13]=2)=[N:3]1.ClC(OCC(C)C)=O.C([N:33](CC)CC)C.[NH4+]>C1COCC1>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][C:20]([NH2:33])=[O:22])[CH:13]=2)=[N:3]1
Reactant: CCN(CC)CC
Reactant: O=C(O)CCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Solvent: C1CCOC1
Product: NC(=O)CCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Reaction time: 1 h
Yield: 48.2 %

Procedure:
3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propionic acid (0.31 g, 1.00 mmol), isobutyl chloroformate (0.22 ml, 1.50 mmol) and triethylamine (0.22 ml, 1.50 mmol) were dissolved in THF (10 ml), and the mixture was stirred under ice cooling condition for 1 hr. 25% aqueous ammonium solution was added to the mixture, and the mixture was stirred under ice cooling condition for 0.5 hr. The obtained precipitates were recrystallized from ethanol to give the titled compound (0.15 g, 49%) as white crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][C:6]1=[O:14].[I-:15].[Na+]>CC(C)=O>[I:15][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][C:6]1=[O:14]
Reactant: O=c1sc2ccccc2n1CCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=c1sc2ccccc2n1CCCI
Yield: 96 %

Procedure:
To a solution of 3-(3-chloropropyl)benzo[d]thiazol-2(3H)-one (2.86 g, 12.56 mmol) in acetone (50 mL), was added sodium iodide (3.77 g, 25.12 mmol). After refluxing for 60 hours, the reaction mixture was filtered. The filtrate was washed with water and dried to obtain the title compound (3.85 g, 83%); 1H NMR (DMSO-d6): δ 2.13-2.16 (m, 2H), 3.28 (t, 2H, J=6.8 Hz), 4.05 (t, 2H, J=6.8 Hz), 7.18-7.22 (m, 1H), 7.38-7.39 (m, 2H), 7.66 (dt, 1H, J=7.6 and 0.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[CH2:8][Br:17]
Reactant: Cc1cc(Cl)ccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Cl)cc1CBr

Procedure:
A mixture of 5-chloro-2-fluorotoluene (2.9 g; prepared by a modified Schiemann reaction on 4-chloro-2-methylaniline), NBS (3.6 g) benzoyl peroxide (100 mg) and carbon tetrachloride (25 ml) was refluxed 2h. The mixture was cooled, filtered and the solvent removed. Distillation gave 5-chloro-2-fluorobenzyl bromide (3 g), b.p. 104°/15 mm.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[N:19][CH:18]=[C:17](Cl)[N:16]=1>>[Cl:14][C:15]1[N:16]=[C:17]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][CH:9]=2)[CH:18]=[N:19][CH:20]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Clc1cncc(Cl)n1
Product: Clc1cncc(Nc2ccc(N3CCOCC3)cc2)n1
Yield: 36.9 %

Procedure:
In a procedure analogous to Example 1, reaction of 4-morpholinoaniline (2.15 g, 12.1 mmol) and 2,6-dichloropyrazine (0.756 g, 5.03 mmol) furnished the product (0.54 g, 37%).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH:12]([OH:17])=[CH:13][CH:14]([CH3:16])[CH3:15].CCCCCC>CN(C1C=CN=CC=1)C.ClCCl>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O:17][CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])(=[O:3])=[O:2]
Reactant: CC(C)C=CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Product: C=C(C)CCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 3 h
Yield: 85.3 %

Procedure:
2.32 mmol (442 mg) of tosyl chloride and 2.55 mmol (312 mg) of 4-(N,N-dimethylamino)pyridine are introduced while stirring with a magnetic stirrer into 5 ml of anhydrous dichloromethane in a glass reaction vessel which is equipped for handling under an inert atmosphere and has been carefully dried. 2.32 mmol (200 mg) of isopentenol dissolved in approx. 1 ml of dichloromethane are slowly added to this mixture through a septum using a syringe. The reaction is monitored by thin-layer chromatography on silica (silica gel 60 F-254; eluent: pentane/ethyl acetate 85/15 vol./vol.; Rf (product)=0.4 and Rf (TsCl)=0.5). After approx. 3 hours' stirring under a nitrogen atmosphere, the reaction mixture is diluted in a large volume of hexane (approx. 100 ml), resulting in the immediate formation of a white precipitate. The mixture is then filtered and the filtrate concentrated by evaporation under reduced pressure. The solution is then diluted with diethyl ether and refiltered. Once the solvent has evaporated, a yellowish oil is obtained. The product is purified by preparative chromatography through a silica column (silica gel 60; eluent: pentane/ethyl acetate 85/15). In this manner, 1.98 mmol (475 mg) of 3-methyl-3-butene-1-yl tosylate (85% isolated yield) are obtained. The compound (colorless oil) is stored at +4° C. in an anhydrous medium.