Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[CH:7]2[CH:2]1[C:3]([CH2:21][F:22])([CH2:19][F:20])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][C:6]=12.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[O:29].CC(C)([O-])C.[K+]>O1CCCC1>[F:18][C:12]([F:17])([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([CH2:21][F:22])([CH2:19][F:20])[CH:2]=[C:7]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]3=[O:29])[C:6]=2[CH:8]=1)[C:13]([F:14])([F:15])[F:16]
Reactant: O=C1CCCCN1
Reactant: FCC1(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc2C2OC21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CCCCN1C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21
Temperature: 0 °C
Yield: 3 %

Procedure:
To a mixture of 0.54 g of 3,4-epoxy-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-2H-1-benzopyran, 0.24 g of 2-piperidinone and 10 ml of tetrahydrofuran was added 0.27 g of potassium tert-butoxide with stirring under ice-cooling. The mixture was stirred for 6 hours under ice-cooling and then stirred at room temperature for 16 hours. Ice water was added to the mixture, which was then extracted with methylene chloride. After the organic layer was washed with water and dried, the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain from the first eluted fraction 0.02 g of 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(2-oxo-1-piperidinyl)-2H-1-benzopyran represented by the following formula having a melting point of 149°-150° C.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][CH2:27][S:28][CH3:29])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH2:30].[O-]Cl.[Na+]>C(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:29])=[O:30])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Nc1ccccc1Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OCCCS(C)=O)cccc2c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 32 %

Procedure:
3-butyryl-4-(2-chlorophenylamino)-8-(3-methylthiopropoxy)quinoline (0.31 g, 0.72 mmol) was dissolved in methylene chloride (10 ml), 5 ml water was added and then a solution of 1.5 ml (1.09 mmol) of 5% NaOCl in 10 ml methylene chloride was added. The mixture was stirred for 4 h at room temperature. The organic phase was separated and evaporated. Chromatography with methylene chloride: methanol 95:5 as the eluent gave 0.104 g (32%) of the title compound.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[C:15]([O:23][C@H:24]1[C@@H:28]([O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:27]([CH2:38][O:39][C:40](=[O:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:26][C@H:25]1[N:48]1[CH:55]=[CH:54][C:52](=O)[NH:51][C:49]1=[O:50])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([O:23][C@H:24]1[C@@H:28]([O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:27]([CH2:38][O:39][C:40](=[O:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:26][C@H:25]1[N:48]1[CH:55]=[CH:54][C:52](=[S:2])[NH:51][C:49]1=[O:50])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(OC[C@@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: O=C(OC[C@@H]1O[C@@H](n2ccc(=S)[nH]c2=O)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Yield: 95.5 %

Procedure:
Phosphorus pentasulfide (5.99 g, 26.95 mmol) was added to a solution of compound 18 (3.75 g, 6.73 mmol) inpyridine (70 ml) and was refluxed for four hours. After cooling, the solvent was evaporated and the residue dissolved in CHCl3, washed with water and brine. After drying over anhydrous Na2SO 4, evaporation of the solvent gave the crude product which was purified on a silica gel column using 30% EtOAc/petroleum ether as solvent to give compound 19 (3.68 g, 95%) as golden yellow foam.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.[CH3:19][C:20]1[CH:24]=[CH:23][S:22][C:21]=1[CH:25]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[N:18]=[CH:25]/[C:21]2[S:22][CH:23]=[CH:24][C:20]=2[CH3:19])=[N:2]1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: Cc1ccsc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccsc1/C=N/c1ccccc1C=Cc1n[nH]c2ccccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Compound 2 (0.060 g, 0.25 mmol) was dissolved in toluene (3.0 mL) and the solution was added with 3-methylthiophene-2-carbaldehyde (55 μL, 0.51 mmol), p-toluenesulfonic acid (small amount), followed by stirring at 60° C. for 2 hours. Then, the reaction mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethanol to obtain Compound 160 (76 mg, 88%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[C:9]=1[C:29]#[N:30]>N1C=CC=CC=1>[C:29]([C:9]1[C:10]([C:25]([F:28])([F:26])[F:27])=[N:11][N:12]([C:13]2[C:14]([Cl:24])=[CH:15][C:16]([C:20]([F:22])([F:21])[F:23])=[CH:17][C:18]=2[Cl:19])[C:8]=1[NH:7][C:2]([O:4][CH2:5][CH3:6])=[O:3])#[N:30]
Reactant: N#Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1c(C#N)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 8 h

Procedure:
Ethyl chloroformate (1.6 g) was added to a stirred solution of 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (3.9 g) in pyridine (15 ml). After stirring overnight another addition of ethyl chloroformate (1.0 ml) was made, and the mixture was left for a further 12 hours. The solvent was evaporated in vacuo and the residue was acidified with dilute hydrochloric acid, and extracted with dichloromethane. This extract was washed with water (3×), dried over anhydrous magnesium sulphate, filtered, and evaporated in vacuo. Purification by chromatography on silica (Merck, 40-230 mesh, 0.7 kg cm-2) eluting with ethyl acetate--petroleum ether (1:1) gave a white solid, which was recrystallized from a mixture of dichloromethane and hexane to furnish white crystals of 4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxycarbonylamino-3-trifluoromethylpyrazole, m.p. 177-179° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:36]=[CH:35][C:16]4[N:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=5)[CH:18]=[N:19][C:15]=4[CH:14]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[CH:37]1([CH2:40][C:41](O)=[O:42])[CH2:39][CH2:38]1>>[CH:37]1([CH2:40][C:41]([N:2]2[CH2:3][CH2:4][CH:5]([N:8]3[CH:12]=[C:11]([C:13]4[CH:36]=[CH:35][C:16]5[N:17]([C:20]6[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:33])([F:32])[F:34])=[O:28])[CH:23]=[CH:24][CH:25]=6)[CH:18]=[N:19][C:15]=5[CH:14]=4)[CH:10]=[N:9]3)[CH2:6][CH2:7]2)=[O:42])[CH2:39][CH2:38]1
Reactant: O=C(O)CC1CC1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCNCC5)c4)ccc32)c1
Agent: Cl
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCN(C(=O)CC6CC6)CC5)c4)ccc32)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1 (Step 6) starting from N-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea HCl salt and cyclopropylacetic acid, (Alfa aesar, Cat. No. L09416), LCMS (M+H)+: m/z=566.2.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:11]([OH:13])=[O:12])[CH:3]=1.[F:14][C:15]([F:20])([F:19])[C@@H:16]([OH:18])[CH3:17].CC(C)([O-])C.[K+]>CN(C=O)C>[CH:8]1([C:7]2[C:2]([O:18][C@@H:16]([CH3:17])[C:15]([F:20])([F:19])[F:14])=[CH:3][C:4]([C:11]([OH:13])=[O:12])=[N:5][CH:6]=2)[CH2:10][CH2:9]1
Reactant: O=C(O)c1cc(Cl)c(C2CC2)cn1
Reactant: C[C@H](O)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
To a solution of 4-Chloro-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48b, 0.87 g, 4.4 mmol) in dry DMF (12.0 ml) under an argon atmosphere were added (S)-1,1,1-trifluoropropan-2-ol (CAN 3539-97-7, 1.00 g, 8.8 mmol) and potassium tert-butoxide (1.48 g, 13.2 mmol). The reaction mixture was stirred at room temperature for 30 minutes and stirred at 120° C. for one hour under microwave radiation. DMF was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was extracted with 20 mL of an 2.0M aqueous solution of hydrochloric acid. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/(3% solution formic acid in methanol) gradient to yield the title compound (505 mg, 33%) as a light brown solid. MS (ESI, m/z): 276.4 (M+H+).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][C:13]2[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[CH:18][C:12]=2[S:11][CH2:10]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[CH3:20][O:19][C:15]1[C:13]2[CH2:14][CH:9]([NH2:8])[CH2:10][S:11][C:12]=2[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc2c1CC(NC(=O)OC(C)(C)C)CS2
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1CC(N)CS2

Procedure:
A solution of 10 g of N-t-butoxycarbonyl-3,4-di-hydro-5-methoxy-2H-[1]-benzothiopyran-3-amine in 30 mL of trifluoroacetic acid is kept at room temperature for 1 hr. The solvent is removed in vacuo, the residue is treated with 1N NaOH and the product is extracted with ether. After drying over magnesium sulfate, the solvent is removed in vacuo to afford 3,4-dihydro-5-methoxy-2H-[1]-benzothiopyran-3-amine as an oil.
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:6]([NH:8][C@H:9]([C:14](OC)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH2:3][CH2:4][CH3:5].[NH3:25]>CO>[NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH2:25])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)OC
Reactant: N
Solvent: CO
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O
Reaction time: 8 h
Yield: 91 %

Procedure:
5.0 g (14.5 mmoles) of BOC-Nva-Leu-OMe are dissolved in 50 ml of methanol, and gaseous ammonia is introduced into the solution for 0.5 hours under ice cooling. The solution is allowed to stand at room temperature overnight, then cooled again, saturated with gaseous ammonia, and evaporated after 4 hours of standing. The crystalline residue is recrystallized from a mixture of ethyl acetate and ether. 4.37 g (91%) of BOC-Nva-Leu-NH2 are obtained; m.p.: 158°-159° C., Rf2 =0.60, [α]D25 =-48.7° (c=1%, in methanol).
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[N:5][CH:6]=[CH:7][CH:8]=1.[NH4+].[OH-:22]>C(O)C>[NH2:9][C:4]1[C:3]([CH:2]=[O:22])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: [OH-]
Reactant: O=C1c2ccccc2C(=O)N1c1ncccc1C(Br)Br
Agent: [NH4+]
Solvent: CCO
Product: Nc1ncccc1C=O
Temperature: 4 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
The compound was prepared according to the procedure as described by A. E. Moormann et al, Synthetic Communications, 17(14), 1695-1699 (1987) To a solution of 2-[3-(dibromomethyl)-2-pyridinyl]-1H-isoindole-1,3(2H)-dione (20 g, 50 mmol) in ethanol (250 ml) was added conc. NH4OH (25 ml) at 4° C. The reaction mixture was stirred 10 minutes at 4° C. then stirred at room temperature for one hour. Reaction mixture was concentrated under reduced pressure. To the concentrated residue was added con. HCl (150 ml) and mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature and concentrated. To the concentrated residue was added water (25 ml) then added saturated K2CO3 to neutralize the solution. The solution was extracted with methylenechloride (3×150 ml). Combined organic solution was washed with water (3×150 ml), brine (1×200 ml), dried over Na2SO4, concentrated. The concentrated residue was suspended in ether, filtered and washed with ether to give 4.3 g (70%) yellow solid. NMR (DMSO) δ 6.69-6.73 (m, 1H), 7.51 (bs, 2H), 7.95-7.98(m, 1H), 8.20-8.22 (m, 1H), 9.82 (s, 1H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH:10]([C:12]1[CH:13]=[N:14][NH:15][CH:16]=1)=[O:11].[H-].[Na+].O>CN(C=O)C>[CH:10]([C:12]1[CH:13]=[N:14][N:15]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:16]=1)=[O:11]
Reactant: O=Cc1cn[nH]c1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-n2cc(C=O)cn2)cc1
Temperature: 60 °C

Procedure:
To a mixture of 4-fluorobenzonitrile (2.49 g, 20.6 mmol) and 4-formylpyrazole (1.98 g, 20.6 mmo) in 50 mL of DMF at 0° C. was added 95% sodium hydride (0.54 g, 22.7 mmol) under nitrogen. The mixture was heated to 60° C. for 6 hours and cooled to room temperature. Water was added carefully and the mixture was then extracted with ethyl acetate. The combined extracts were washed with water and brine, and then dried over sodium sulfate, filtered, and concentrated in vacuo to provide crude 4-(4-formyl-1H-pyrazol-1-yl)benzonitrile.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[CH2:23]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:18][C:17]1[C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:33]3[CH2:34][CH2:35][N:30]([CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:31][CH2:32]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Product: O=C(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)N1CCN(Cc2ccccc2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-benzyl-piperazine, yield 94%. White crystals; m.p. 111-113° C. (resolidifies) and 114-115° C.; HPLC-MS m/z=492 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH:23](C(OC)=O)[C:24]([O:26]C)=[O:25])([O-:3])=[O:2]>Cl>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])[CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH2:23][C:24]([OH:26])=[O:25])([O-:3])=[O:2]
Reactant: COC(=O)C(C(=O)OC)c1ccc(-c2cccc(NC(=O)C(F)(F)F)c2)cc1[N+](=O)[O-]
Agent: Cl
Product: O=C(O)Cc1ccc(-c2cccc(NC(=O)C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 73.4 %

Procedure:
Dimethyl 2-[2-nitro-4-(3-trifluoroacetamidophenyl)phenyl]-malonate (4.4 g) was refluxed overnight in 50 mL 6N hydrochloric acid. The reaction mixture was cooled to room temperature and the solids were collected by vacuum filtration, washed with water, and dried under vacuum to give 2.7 g (73% yield) of 2-[2-nitro-4-(3-trifluoroacetamidophenyl)phenyl] acetic acid.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:10][C:11]([C:13]1[S:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[O:12])([CH2:7][O:8][CH3:9])[CH2:4][O:5][CH3:6].C(=O)([O-])[OH:20].[Na+].Cl[O-].[Na+]>O>[Cl:18][C:15]1[S:14][C:13]([C:11]([NH:10][C:3]([CH2:4][O:5][CH3:6])([CH2:7][O:8][CH3:9])[C:2]([OH:20])=[O:1])=[O:12])=[CH:17][CH:16]=1
Reactant: COCC(CO)(COC)NC(=O)c1ccc(Cl)s1
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: COCC(COC)(NC(=O)c1ccc(Cl)s1)C(=O)O
Reaction time: 2 h

Procedure:
0.20 g (0.49 mmol) 5-chloro-thiophene-2-carboxylic acid(1-hydroxymethyl-2-methoxy-1-methoxymethyl-ethyl)-amide are dissolved at room temperature in 3 ml of water/3 ml acetonitrile and combined with 0.08 g (0.51 mmol) 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) and 0.13 g (1.55 mmol) sodium hydrogen carbonate. Then 1.5 ml (3.14 mmol) of 13% sodium hypochlorite is added dropwise and the mixture is stirred for 2 h. The reaction mixture is concentrated by evaporation i.vac. And purified by chromatography through RP material (Microsorb C18 Varian; eluant: water/acetonitrile/trifluoroacetic acid=90:10:0.1=>0:100:0.1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:19](OC)(OC)OC>CN(C=O)C>[CH3:16][O:15][CH:14]([O:17][CH3:18])[CH2:13][N:12]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=[CH:19]1
Reactant: COC(=O)c1cccc(N)c1NCC(OC)OC
Reactant: COC(OC)OC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2ncn(CC(OC)OC)c12
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (0.4 g, 1.6 mmol) from Step C above in DMF (15 mL) was added trimethyl orthoformate (0.5 mL, 4.7 mmol) and the reaction was heated to reflux and stirred overnight. The reaction mixture was washed with water, extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to give the crude material which was purified by column chromatography (silica gel, 0% to 100% ethyl acetate in hexanes) to afford methyl 1-(2,2-dimethoxyethyl)-1H-benzo[d]imidazole-7-carboxylate: 1H NMR (500 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.90 (dd, J=8.0, 1.0 Hz, 1H), 7.69 (dd, J=8.0, 1.0 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 4.64 (d, J=5.0 Hz, 2H), 4.48 (t, J=5.0 Hz, 1H), 3.91 (s, 3H), 3.22 (s, 6H); MS (ESI+) m/z 264 (M+H).
Reaction SMILES: [Na+].[OH:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1)S([O-])(=O)=O.[OH-].[Na+]>O>[CH:22]([N:19]1[CH2:20][CH2:21][N:16]([C:14]([C:11]2[CH:10]=[CH:9][C:8]([CH:3]=[O:2])=[CH:13][CH:12]=2)=[O:15])[CH2:17][CH2:18]1)([CH3:24])[CH3:23]
Reactant: CC(C)N1CCN(C(=O)c2ccc(C(O)S(=O)(=O)[O-])cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxy-[4-(4-isopropyl-piperazine-1-carbonyl) -phenyl]-methanesulfonic acid sodium salt (49.0 g, 135 mmol) in de-ionized H2O (490 mL) at 0° C. was added 1 N NaOH (100 mL) in 10 mL portions with vigorous stirring. A clear solution resulted (pH 12), which was stirred at 0° C. for 1 h, then at room temperature for 30 min. The aqueous solution was extracted with EtOAc (3×200 mL), followed by CH2Cl2 (3×200 mL). The organic layers were combined, washed with brine (1×300 mL), dried (Na2SO4) and concentrated to yield the title compound as a pale yellow oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[CH2:24]([O:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)(O)[O-].[K+]>ClCCl>[CH2:24]([O:31][C:32]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)[CH2:10][CH2:9]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(CN2CCC(N3CCc4ccccc4C3)CC2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(N2CCc3ccccc3C2)CC1

Procedure:
2-(1-Benzyl-piperidin-4-yl)-1,2,3,4-tetrahydroisoquinoline (280 mg, 0.90 mmol), benzyloxycarbonyl chloride (310 mg, 1.8 mmol) and potassium bicarbonate (230 mg, 2.3 mmol) were stirred at room temperature for 23 hours in dichloromethane (5 ml). The reaction solution was mixed with dichloromethane, washed with water and saturated brine and the dried with anhydrous sodium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 300 mg (0.86 mmol, 96% in yield) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1.[NH3:18]>CO>[NH2:18][CH2:2][C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1
Reactant: BrCc1ccc2nc(-c3ccccc3)sc2c1
Reactant: N
Solvent: CO
Product: NCc1ccc2nc(-c3ccccc3)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
Add 6-bromomethyl-2-phenyl-benzothiazole (2 g, 6.57 mmol) as a suspension in methanol (100 mL) to 7M ammonia in methanol (400 mL) at 0° C. over 10 min and then stir for 3 h at room temperature. Concentrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with dichloromethane/methanol (1:0 to 3:1) to obtain the title compound (1.2 g, 76%). MS (ES+) m/z: 241 (M+H+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[N:4][CH:3]=1.[H][H]>CO.[Pd].CCOC(C)=O>[N:9]1[C:10]2[CH2:11][CH2:2][CH2:3][NH:4][C:5]=2[C:6]([O:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)=[CH:7][CH:8]=1
Reactant: Nc1ccc(Oc2ccnc3cc(Br)cnc23)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccnc3c2NCCC3)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-(7-bromo-1,5-naphthyridin-4-yloxy)benzenamine (0.150 g, 0.474 mmol) in MeOH (7 mL) at RT was added a suspension of 10% palladium on carbon (0.0505 g, 0.474 mmol) in EtOAc (2 mL). The mixture was subjected to an atmosphere of hydrogen (balloon) and stirred overnight. After 18 hrs, the mixture was filtered over celite and concentrated in vacuo. The resulting tan foam, crude 4-(5,6,7,8-tetrahydro-1,5-naphthyridin-4-yloxy)benzenamine, was advanced without further purification. MH+=242.2@0.49 min
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:16]=2)[N:11]=1.C(#N)C>O>[O:20]([C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Reactant: O=C(O)c1ccsc1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(Oc3ccccc3)nc2n1)c1ccsc1
Temperature: 4 °C
Yield: 67.5 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-thiophenecarboxylic acid (5 g), N,N'-carbonyldiimidazole (6.3 g) and 2-amino-7-phenoxy-1,8-naphthyridine (8.3 g). The product produced by precipitation in water (11.6 g; m.p. 110° C.) is dissolved in boiling acetonitrile (50 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with diisopropyl ether (3×10 cc) and dried at 35° C. under reduced pressure (0.067 kPa). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-3-thiophenecarboxamide (8.2 g) is produced, m.p. 95° C.