Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]1[F:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C@H:13]1[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1CCNC[C@H]1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
(cis)-tert-Butyl 4-(benzyloxycarbonylamino)-3-fluoropiperidine-1-carboxylate (7.5 g, 21.3 mmol) was weighed into a 500 mL 1 neck round bottom and dissolved in 200 mL of DCM, followed by addition of TFA (16.4 mL, 213 mmol) and stirring at ambient temperature for 1 hour, at which time all bubbling had ceased and the reaction appeared complete by TLC. The crude reaction was concentrated in vacuo, followed by aqueous work-up with 2 N NaOH and DCM. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford benzyl (cis)-3-fluoropiperidin-4-ylcarbamate (4.25 g, 16.8 mmol, 79.2% yield) as a white solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]1.I[CH2:16][CH2:17][CH2:18][CH3:19].Cl>CN(C=O)C>[CH2:16]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]1)[CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: CCCCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1cc(C(=O)O)c2ccccc21
Temperature: 0 °C
Yield: 86.1 %

Procedure:
A suspension of sodium hydride (34.1 g, 1.42 mol) in 300 mL of DMF was stirred in an ice/methanol bath and a solution of 3-indolecarboxylic acid (55.0 g, 0,374 mol) in 250 mL DMF was added dropwise over 45 minutes. The mixture was stirred for 30 minutes and then 100 mL of additional DMF was added. The mixture was cooled to 0° C. and 1-iodobutane (8.79 g, 40.8 mL, 0.359 mol) was added. The mixture was stirred for approximately 12 hours. The mixture was then poured in 2.0 L of ice water, acidified with 1N hydrochloric acid, extracted 3 times with ethyl acetate, washed twice with water and then dried over magnesium sulfate. The mixture was concentrated and the residue mixed with diethylether. Filtration gave 1-butylindole-3-carboxylic acid (62.74 g, 0.309 mol) as a white powder.
Reaction SMILES: O.NN.[N:4]1[C:13]2[CH:12]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[C:23]([N+:24]([O-])=O)=[CH:22][C:21]([CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:20][N:19]=3)[CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1>CO.[Ni]>[NH2:24][C:23]1[C:18]([NH:17][CH2:16][CH2:15][CH2:14][CH:12]2[C:13]3[N:4]=[CH:5][CH:6]=[CH:7][C:8]=3[CH2:9][CH2:10][CH2:11]2)=[N:19][CH:20]=[C:21]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1
Reactant: O=[N+]([O-])c1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Reaction time: 0.42 h

Procedure:
Hydrazine hydrate (7 ml) in methanol (25 ml) was added with stirring over 25 minutes to a cooled (5°-10° C.) solution of 2-[3-(5,6,7,8-tetrahydroquinol-8-yl)propylamino-3-nitro-5-(pyrid-3-ylmethyl)pyridine (6.1 g) in methanol (300 ml) containing Raney Nickel (ca. 12 g). The solution was stirred for a further hour at 5° C., the catalyst was removed by filtration and the filtrate was concentrated to dryness in vacuo giving the title compound as an orange oil (theoretical yield assumed) which was used unpurified in the next reaction.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=1[OH:18]>C(Cl)Cl>[C:1]([O:18][C:9]1[C:10]([N+:15]([O-:17])=[O:16])=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=1[Cl:7])(=[O:5])/[CH:2]=[CH:3]/[CH3:4]
Reactant: C/C=C/C(=O)Cl
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1O
Solvent: ClCCl
Product: C/C=C/C(=O)Oc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
Crotonyl chloride (7 ml) was added to a solution of 2,4-dichloro-6-nitrophenol (10.3 g) in methylene chloride (20 ml) and the mixture was heated under reflux for 12 hours. The solution was diluted with further methylene chloride (200 ml) and extracted several times with a 10% sodium hydroxide solution. The organic layer was washed with water dried (Na2SO4) and the solvent removed under reduced pressure to give a pale brown oil which crystallised on standing for 24 hours 2,4-dichloro-6-nitrophenyl crotonate melted at <60°.
Reaction SMILES: C([O:5][C:6](=[O:44])[C@@H:7]([NH:29][C:30]([O:32][CH2:33][C:34]12[CH2:43][CH:38]3[CH2:39][CH:40]([CH2:42][CH:36]([CH2:37]3)[CH2:35]1)[CH2:41]2)=[O:31])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH:17]2[CH2:19][CH:18]2[C:20](=[O:28])[NH:21][C:22]2[NH:23][CH2:24][CH2:25][CH2:26][N:27]=2)=[CH:15][CH:16]=1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:34]12([CH2:33][O:32][C:30]([NH:29][C@@H:7]([CH2:8][NH:9][C:10]([C:12]3[S:13][C:14]([CH:17]4[CH2:19][CH:18]4[C:20](=[O:28])[NH:21][C:22]4[NH:23][CH2:24][CH2:25][CH2:26][N:27]=4)=[CH:15][CH:16]=3)=[O:11])[C:6]([OH:44])=[O:5])=[O:31])[CH2:43][CH:38]3[CH2:39][CH:40]([CH2:42][CH:36]([CH2:37]3)[CH2:35]1)[CH2:41]2
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(C2CC2C(=O)NC2=NCCCN2)s1)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H](CNC(=O)c1ccc(C2CC2C(=O)NC2=NCCCN2)s1)C(=O)O)OCC12CC3CC(CC(C3)C1)C2

Procedure:
48 mg of the product obtained in step c) were dissolved in 2 ml of dichloromethane and stirred for 3 hours with 1 ml of trifluoroacetic acid under an inert gas atmosphere at room temperature. The solvents were removed in vacuo, the residue was dissolved in acetic acid and the solution was again evaporated to dryness. This procedure was repeated once. The resinous residue was triturated with diethyl ether. After filtration 30 mg of the title compound were obtained as a colourless amorphous powder.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=13)=[O:10])[NH:2]2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[O:19][CH:18]=[CH:17][C:16]=34)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:34])=[CH:25][CH:26]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2occc12
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4occc34)C[C@@H]3C[C@@H]32)c(-c2ccc(F)cc2)s1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.38 min; [M+H]+=476.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:18][CH2:19][C:20]([F:23])([F:22])[F:21].C1C(=O)N([Br:31])C(=O)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[CH:4][C:5]([CH:8]([CH2:14][CH:15]2[CH2:16][CH2:17]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:7]=1[Br:31]
Reactant: CCOC(=O)C(CC1CC1)c1ccc(N)c(OCC(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CC1CC1)c1cc(Br)c(N)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.1 %

Procedure:
To a stirred solution of ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (0.9 g, 2.7 mmol) in dry CHCl3 (50 mL), NBS (0.412 g, 2.3 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to give ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (1.02 g) as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH:8]=[C:9]([C:11](=[O:17])[N:12]([CH3:16])[CH2:13][CH2:14][CH3:15])[CH:10]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:7]1[CH:8]=[C:9]([C:11](=[O:17])[N:12]([CH3:16])[CH2:13][CH2:14][CH3:15])[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(-c2ccccc2F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(-c2ccccc2F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Chill a solution of 2′-fluoro-5-(methyl-propylcarbamoyl)-biphenyl-3-carboxylic acid methyl ester (0.297 g, 0.903 mmol) in MeOH (2 mL) and THF (2 mL) in an ice bath. Add 2 N NaOH (1.35 mL, 2.70 mmol) to the mixture and stir at room temperature for 3 h. Acidify the solution to about pH=2 and concentrate to one half of the solvent. Partition the residue between ethyl acetate and H2O and extract the aqueous layer with ethyl acetate (2×15 mL). Wash the combined organic extract with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:10]=[C:9]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:20])[C:14]=3[CH:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].[O:21]=[S:22]1(=[O:39])[CH2:26][CH2:25][CH:24]([CH2:27]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[O:21]=[S:22]1(=[O:39])[CH2:26][CH2:25][CH:24]([CH2:27][O:20][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[CH:13]=[CH:12][N:11]3[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH2:1][CH2:2][CH3:3])[N:10]=2)[CH2:23]1
Reactant: CCCSc1nccc(-n2ccc3c(O)cccc32)n1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCS(=O)(=O)C2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCCSc1nccc(-n2ccc3c(OCC4CCS(=O)(=O)C4)cccc32)n1
Temperature: 70 °C
Reaction time: 60 h
Yield: 129.7 %

Procedure:
1-(2-Propylsulfanyl-pyrimidin-4-yl)-1H-indol-4-ol (1.56 g) and toluene-4-sulfonic acid 1,1-dioxo-tetrahydro-1lambda*6*-thiophen-3-ylmethyl ester (2.37 g) were added to NMP (20 mL), followed by cesium carbonate (5.08 g). The mixture was stirred at 70° C. for 60 hours, after which solvent was removed by distillation. The residue was diluted with 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to give 2.96 g of 4-(1,1-dioxo-tetrahydro-1lambda*6*-thiophen-3-ylmethoxy)-1-(2-propylsulfanyl-pyrimidin-4-yl)-1H-indole.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[F:28][C:13]1([F:12])[CH2:14][CH2:15][C:16]([CH2:26][NH:27][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[F:1])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18]1
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Reactant: Cc1cccc(C(=O)O)c1F
Product: Cc1cccc(C(=O)NCC2(c3ccc(F)nc3)CCC(F)(F)CC2)c1F

Procedure:
From 2-fluoro-3-methylbenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=381.1, tR (minutes, Method D)=0.74
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:13][CH:12]=3)=[CH:10][C:3]=12.[N+:33]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:46](B3OC(C)(C)C(C)(C)O3)=[CH:45][N:44]([CH2:56][CH2:57][OH:58])[N:43]=2)=[CH:38][CH:37]=1)([O-:35])=[O:34]>>[N+:33]([C:36]1[CH:37]=[CH:38][C:39]([C:42]2[C:46]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[N:8]([S:24]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)(=[O:26])=[O:25])[C:9]([C:11]5[CH:12]=[CH:13][C:14]([CH2:17][N:18]6[CH2:19][CH2:20][O:21][CH2:22][CH2:23]6)=[CH:15][CH:16]=5)=[CH:10][C:3]=34)=[CH:45][N:44]([CH2:56][CH2:57][OH:58])[N:43]=2)=[CH:40][CH:41]=1)([O-:35])=[O:34]
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccc(CN3CCOCC3)cc2)cc2c(Br)ccnc21
Reactant: CC1(C)OB(c2cn(CCO)nc2-c2ccc([N+](=O)[O-])cc2)OC1(C)C
Product: O=[N+]([O-])c1ccc(-c2nn(CCO)cc2-c2ccnc3c2cc(-c2ccc(CN4CCOCC4)cc2)n3S(=O)(=O)c2ccccc2)cc1

Procedure:
Following the procedure for Intermediate 100 using 4-bromo-2-[4-(N-morpholinylmethyl)phenyl]-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine and 3-(4-nitrophenyl)-1-(2-hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole provided the title compound. ESMS [M+H]+: 665.2
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:18])[CH2:4][N:5]([CH2:13][C:14]([NH:16][CH3:17])=[O:15])CC1C=CC=CC=1>CO.[Pd]>[CH3:17][NH:16][C:14](=[O:15])[CH2:13][NH:5][CH2:4][C:3]([NH:2][CH3:1])=[O:18]
Reactant: CNC(=O)CN(CC(=O)NC)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)CNCC(=O)NC
Temperature: 40 °C

Procedure:
The mixture of N-(2-methylamino-2-oxoethyl)-N-(phenylmethyl)-glycine methylamide (3.09 g, 11.2 mmol) in MeOH (30 mL) was added 10% Pd/C (0.15 g). The mixture was stirred and heated to 40° C. under 40 psi H2 for 10 h, filtered and concentrated in vacuo to yield N-(2-methylamino-2-oxoethyl)-glycine methylamide in quantitative yield (1.76 g). 1H NMR (CDCl3): δ 6.95 (br s, 2H), 3.23 (s, 4H), 2.79 (d, J=6.0, 4.8 Hz), 2.25 (br s 1H); MS (ESI) m/e 160 (M+H+)
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCn1c2ccccc2c2cc(NS(C)(=O)=O)ccc21
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a solution of 9-Ethyl-9H-carbazol-3-ylamine (210 mg, 1 mmol) and pyridine (105 μl, 1.3 mmol) in CH2Cl2 (8 ml) at room temperature was added methanesulfonyl chloride (85 μl, 1.1 mmol). After stirring overnight the reaction mixture was diluted with CH2Cl2 and washed with saturated aq. NaHCO3 and brine, then the organic layer dried (Na2SO4) and concentrated to afford the crude product. Chromatographic purification (silica, CH2Cl2) afforded the desired product as a pale yellow solid (203 mg, 70% yield).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11]([OH:20])(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:14].C([O-])([O-])=O.[K+].[K+].C(OCCO)C.Cl>O>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:14][C:13]1[C:12](=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:20])=[O:19])([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1Cl
Reactant: Nc1ccccc1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCCO
Product: O=C(O)c1ccccc1Nc1ccccc1C(=O)O
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of 2-chlorobenzoic acid (100 g), anthranilic acid (90 g), anhydrous powered K2CO3 (135 g), Cu/CuO (2 g) and 2-ethoxyethanol (200 ml) was heated with swirling on the steam bath until gas evolution ceased and then stirred at 145° for a further 21/2 hours. The thick reaction mixture was diluted with water, acidified (HCl) and then the crude product was collected and washed well with hot water. This was dissolved in hot dilute aqueous Na2CO3 treated liberally with charcoal-celite and filtered through a celite pad. The hot filtrate was diluted with half the volume of EtOH and then slowly acidified (HCl). The pale yellow product which separated was collected when still warm, washed well with hot water, benzene and dried, providing material (84% yield) of sufficient purity for use in the next step (lit, m.p. 295° dec.).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[C:11]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][C:15]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[S:16])[C:11]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCNCC1
Reactant: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Product: CN1CCN(C(=S)Nc2cc3sc(C(C)(C)C)nc3cc2N2CCN(C)CC2)CC1

Procedure:
Using the procedure described in Example 1 by reaction of 2-tert-butyl-6-isothiocyanato-5-(4-methyl-piperazin-1-yl)benzothiazole with 4-methylpiperazine is obtained 2-tert-butyl-6[(4-methylpiperazin-1-yl)thiocarbonylamino]-5-(4-methyl-piperazin-1-yl)benzothiazole, melting at 190°-193°.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[O:15][CH2:16][C:17](Cl)=[O:18].Cl>[OH-].[Na+]>[CH3:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[O:15][CH2:16][C:17]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])=[O:18]
Reactant: Cc1cccc(OCC(=O)Cl)c1
Reactant: Nc1ccccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(OCC(=O)Nc2ccccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.6 %

Procedure:
Anthranilic acid 7.95 g (58 mmol) was dissolved in 10% aqueous sodium hydroxide solution 48 ml and to this solution, 3-methylphenoxyacetyl chloride 11.8 g (64 mmol) was added dropwise at 0° C. The resulting solution was stirred at room temperature for 5 minutes and acidified with 10% hydrochloric acid solution. Deposited crystals were collected by filtration and washed with hot water to obtain N-(3-methylphenoxyacetyl)anthranilic acid 14.0 g (yield: 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[CH2:11](Br)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].O>C(O)C>[C:12]([C:11]1[O:10][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=2[CH:7]=1)(=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=Cc1cc(Cl)ccc1O
Solvent: CCO
Solvent: O
Product: O=C(c1ccccc1)c1cc2cc(Cl)ccc2o1
Temperature: 80 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of 5-chloro-2-hydroxybenzaldehyde (2 g) and phenacyl bromide (1.85 g) in ethanol (10 ml) potassium carbonate (3.53 g) was added. The mixture was stirred at 80° C. for 1 h. Then the reaction mixture was poured into water (50 ml) and extracted with dichloromethane (3×20 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4), and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel (hexane/ethyl acetate 12:1) to give 2-benzoyl-5-chlorobenzofuran (1.85 g) as colourless solid.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][OH:13])=[C:8]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(OCC)(=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][O:13][S:38]([C:35]2[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=2)(=[O:40])=[O:39])=[C:8]([S:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:20][CH:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2CO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCc2c(SCc3ccc(C(C)(C)C)cc3)cnn(C(C)(C)C)c2=O)cc1
Reaction time: 4 h

Procedure:
To a 15 ml round bottom flask charged with 2-tert-butyl-4-hydroxymethyl-5-(4-tert-butylbenzyl)thio-3(2H)-pyridazinone (1.0 g, 2.77 mmol) is added pyridine. p-Toluenesulfonyl chloride (0.79 g, 4.15 mmol) is then added to it and the mixture stirred for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with 5% copper sulfate solution and then with water and dried. After removing the solvent on the rotary evaporator the crude is purified by flash chromatography using (silica gel; ethyl acetate/hexanes) as the eluting mixture to give the product.
Reaction SMILES: [N+:1]([CH:4]([N+:6]([O-:8])=[O:7])[CH3:5])([O-:3])=[O:2].[OH-].[K+].[C:11]([O:15][CH:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:17][CH3:18])(=[O:14])[CH:12]=[CH2:13].CO>O>[N+:1]([C:4]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:13][CH2:12][C:11]([O:15][CH:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:17][CH3:18])=[O:14])([O-:3])=[O:2]
Reactant: CC([N+](=O)[O-])[N+](=O)[O-]
Reactant: C=CC(=O)OC(CC)CCCCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCC(CC)OC(=O)CCC(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
Dinitroethane (2.4 g, 0.02 mol) and potassium hydroxide (1.2 g, 0.22 mol) were dissolved in 50 mL of water to form a first solution. 50 mL of water was added to the first solution to dissolve a salt remaining in the first solution to form a second solution. Octane-3-yl acrylate (8.3 mL, 0.05 mol) was mixed with 50 mL of methanol, and then the mixture was slowly added to the second solution to form a third solution. The third solution was stirred at room temperature for 5 hours. The reaction product was extracted by diethyl ether, and was then distilled under reduced pressure to obtain yellow liquid octane-3-yl 4,4-dinitropentanoate (4.9 g, yield: 80%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30]CC)=[CH2:29])CCC.Cl.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([C:28](=[O:30])[CH3:29])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A flask was charged with tetrakis-(triphenylphosphine)-palladium (1.7 g, 1.48 mmol) under nitrogen. A solution of 6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (5.8 g, 18.55 mmol) in DMF (150 mL) was added. The flask was purged with nitrogen gas three times and tributyl-(1-ethoxy-vinyl)-stannane (6.59 ml, 19.47 mmol) was added. The temperature was increased to 100° C. and stirred overnight. The reaction mixture was cooled to room temperature, 20 ml of 3N HCl was added and the mixture was stirred for additional 2 hrs. Water was added and the product was then extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to afford 4.8 g (yield: 79%) title compound as a dark yellow solid. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.82 (dd, 1H), 8.31 (d, 1H), 8.10 (d, 1H), 7.98 (d, 1H), 7.85 (s, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.50 (q, 1H), 4.72 (s, 2H), 2.68 (S, 3H). LCMS (method A): [MH]+=321, tR=5.07 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[OH:24][CH:25]1[CH2:30][CH2:29][N:28]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:27][CH2:26]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: OC1CCNCC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCC(O)CC2)cn1
Yield: 73 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (155 mg, 0.50 mmol) was converted, using 4-hydroxypiperidine instead of methylamine, to the title compound (145 mg, 73%) which was obtained as a white solid. MS: m/e=394.2 [M+H]+.