Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@H:8]([CH2:12][NH2:13])[CH2:7]1.[C:18]1([C:24]2[O:25][C:26]([CH3:33])=[C:27]([CH2:29][C:30](O)=[O:31])[N:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@H:8]([CH2:12][NH:13][C:30](=[O:31])[CH2:29][C:27]2[N:28]=[C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:25][C:26]=2[CH3:33])[CH2:7]1
Reactant: Cc1oc(-c2ccccc2)nc1CC(=O)O
Reactant: NC[C@@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: Cc1oc(-c2ccccc2)nc1CC(=O)NC[C@@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 44.3 %

Procedure:
Example 55 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 10 (0.055 g) and 2-phenyl-5-methyl-4-oxazolylacetic acid (0.050 g) to give the title compound (0.042 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]([CH:12]=[O:13])=[N:7]2.[OH-:19].[Na+].OO.Cl>CO.OO.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]([C:12]([OH:19])=[O:13])=[N:7]2
Reactant: [OH-]
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2nc1C=O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)Nc1nc2c(Br)cccc2nc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a slurry of 5-bromo-3-(tert-butylamino)quinoxaline-2-carbaldehyde (306a) (250 mg, 0.81 mmol) in MeOH (0.4 mL) and NaOH 1.0 N (1.62 mL, 1.62 mmol) was added two drops H2O2 30% in water (0.10 mL, 1.01 mmol) from a pasteur pipette. The reaction was stirred rapidly at RT and became a yellow/orange solution. Additional 0.05 mL 30% aq H2O2 was added. After 30 min, additional 0.05 mL 30% aq H2O2 was added. After 30 min, the reaction mixture was treated with ice, acidified to pH <2 with 1.0 N HCl, and diluted with 10 mL water. The orange suspension was filtered, rinsing with 10 mL of water to give 5-bromo-3-(tert-butylamino)quinoxaline-2-carboxylic acid (0.26 g, 0.80 mmol, 99% yield) as an orange solid. m/z (ESI, +ve ion) 324.0/326.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=O)[CH2:8][O:9][CH2:10][C:4]=2[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:23]2)=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[S:23])[CH2:8][O:9][CH2:10][C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1COCc2cc(Cl)ccc2N1
Solvent: C1CCOC1
Product: S=C1COCc2cc(Cl)ccc2N1
Yield: 107.5 %

Procedure:
To a suspension of 7-chloro-3,5-dihydrobenzo[e][1,4]oxazepin-2(1H)-one (3.01 g, 15.2 mmol) in tetrahydrofurane (102 ml) was added 2,4-bis-(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (3.45 g, 8.53 mmol) at room temperature. The reaction mixture was heated at reflux for 4 h. The solvent was evaporated and the residue was crystallized from hot ethanol to give the title compound (1.96 g, 60%) as light yellow solid. MS m/e: 211.6 ([M−H]−).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][NH:7][C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C=O.[CH:54](O)=O.O>CC(C)=O>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][N:7]([CH3:54])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: O=CO
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)CN[C@H](C)[C@@H](O)[C@]1(C)O
Agent: C=O
Solvent: CC(C)=O
Solvent: O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)CN(C)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 58 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
In a 0.25 L three-necked round bottom flask equipped with a mechanical stirrer, a condenser and thermometer, 25 g of desmethyl-azithromycin was dissolved in 102 mL of acetone. Formaldehyde (5.3 mL) and formic acid (2.6 mL) were added and the clear solution was heated to reflux (˜58° C.). The mixture was maintained under reflux for 3 hours then cooled to less than 40° C. and 102 mL of water was added. The acetone was separated from the reaction mixture by distillation under low vacuum (˜300 mbar). The distillation was stopped when the temperature of the liquid phase reaches ˜40° C./300 mbar. Activated carbon SXI (1.25 g) was added and the suspension was mixed for 1 hour. Then the activated carbon was separated from the solution by filtration on a Büchner filter containing Hyflow. The filter cake was washed with 102 mL of water. The pH was adjusted with an NaOH solution of 47% to 10-10.5 (˜3.14 g). A massive precipitation of Azithromycin was observed. After stirring the suspension for 1 hour, the crude azithromycin was separated by filtration, washed twice with 25 mL of water and dried at 40° C. in a vacuum oven for>24 hours. After drying, 19.7 g of crude azithromycin was obtained (yield 77% based on weight). No impurities that were derivatives of azithromycin were detected.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23](O)=[O:24])=[O:19])=[CH:4][CH:3]=1.[NH2:29][CH2:30][C:31]1[C:36]([CH2:37][CH3:38])=[N:35][C:34]2[N:39]([CH2:42][CH3:43])[N:40]=[CH:41][C:33]=2[C:32]=1[NH:44][CH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:42]([N:39]1[C:34]2=[N:35][C:36]([CH2:37][CH3:38])=[C:31]([CH2:30][NH:29][C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([C:18]([NH:17][CH2:16][C:5]4[CH:6]=[C:7]([C:8]5[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=5)[C:2]([F:1])=[CH:3][CH:4]=4)=[O:19])[CH:21]=3)=[O:24])[C:32]([NH:44][CH:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)=[C:33]2[CH:41]=[N:40]1)[CH3:43]
Reactant: O=C(O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CO)c3)c2)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CO)c3)c2)c1
Reaction time: 8 h

Procedure:
3-[({[6-Fluoro-3′-(hydroxymethyl)-3-biphenylyl]methyl}amino)carbonyl]benzoic acid (0.06 g, 0.158 mmol), 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.048 g, 0.158 mmol), HBTU (0.06 g, 0.158 mmol), TEA (44 μL, 0.316 mmol) were combined in CH2Cl2 (10 mL) and stirred under argon overnight. Aqueous workup followed by CombiFlash purification on a 12 g column eluted with 0-8% MeOH/CH2Cl2 afforded the title compound. LC-MS m/z 664.8 (M+H)+, 1.80 min (ret time).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)=[C:8]([CH3:21])[CH:7]=1.[H-].[Na+].I[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([O:20][CH3:25])=[O:19])=[CH:16][CH:17]=2)=[C:8]([CH3:21])[CH:7]=1
Reactant: CI
Reactant: Cc1cc(C2=NCCO2)ccc1-c1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(C3=NCCO3)cc2C)cc1
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
4'-(4,5-Dihydrooxazol-2-yl)-2'-methylbiphenyl-4-carboxylic acid (D113) (0.92 g, 3.3 mmol) was stirred under Ar in dry DMF (20 ml), and sodium hydride (80% in mineral oil, 0.15 g, 5.0 mmol) was added. This mixture was stirred for 30 min, and then treated with iodomethane (0.22 ml, 3.5 mmol). After a further 15 min, the mixture was diluted with ethyl acetate (200 ml), washed with water and brine, dried (Na2SO4) and evaporated. The crude product was purified by chromatography on silica gel, eluting with 0-2% methanol/dichloromethane. This gave the title compound (0.15 g, 15%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[C:51]([Cl:52])=[C:50]([Cl:53])[CH:49]=[CH:48][N:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:51]([Cl:52])=[C:50]([Cl:53])[CH:49]=[CH:48][N:47]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Clc1ccnc(CBr)c1Cl
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3nccc(Cl)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3,4-dichloropyridine hydrobromide and isolated as white solid. MS (m/e): 442.2 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]=[O:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:31]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:28])[C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:31]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(-c2ccccc2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=O)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cccc(-c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 34, Step 3, using 1-[4′-(4-formyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-phenyl-pyridine.
Reaction SMILES: C([NH:8][C@H:9]([C:24]([NH:26][C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][OH:29])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(OC(C)(C)C)=O.[ClH:36].CCOC(C)=O>CO>[ClH:36].[C:14]([NH:13][CH2:12][CH2:11][CH2:10][C@@H:9]([C:24]([NH:26][C@H:27]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:28][OH:29])=[O:25])[NH2:8])([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1

Procedure:
Prepared according to the method described in Example 1(b) above from (R)-N2 -(Boc)-N5 -(Cbz)-(S)-N-(2-hydroxy-1-phenylethyl)ornithine amide (3.2 g; 6.6 mmol; from step (a) above), 25 mL of MeOH and 100 mL of HCl/EtOAc, yielding 2.0 g of the sub-title compound as white crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([O:23]C)=[O:22])[CH2:12][CH2:11]2)=[CH:2]1.[H-].[Na+].[CH2:31](Br)[CH:32]=[CH2:33]>>[CH2:33]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([OH:23])=[O:22])[CH2:14][CH2:15]2)=[CH:2]1)[CH:32]=[CH2:31]
Reactant: C=CCBr
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Product: C=CCn1cc(C2CCN(CCOc3ccccc3C(=O)O)CC2)c2ccccc21

Procedure:
This compound was prepared following the procedure described in Example 138 (part B) starting with 2.8 g (7.4 mmol) of methyl 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoate, 0.38 g (9.6 mmol) of NaH in 60% of mineral oil and 0.77 mL (8.9 mmol) of allyl bromide. The crude mixture was hydrolised following the procedure described in Example 138 (part C) and purified by chromatography over silica gel affording 0.62 g (23% of yield) of the desired product.
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[N:14]1([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)CC(C)C.C(#N)C>[N:22]1([C:20]([N:14]2[CH2:15][CH2:16][N:17]([C:3]3[NH:12][C:11](=[O:13])[C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[N:4]=3)[CH2:18][CH2:19]2)=[O:21])[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: O=C(N1CCNCC1)N1CCOCC1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Solvent: CC(C)CCO
Solvent: CC#N
Product: O=C(N1CCOCC1)N1CCN(c2nc3c(c(=O)[nH]2)CCCC3)CC1

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol) and piperazinocarboxylic acid morpholide (152.3 mg; 0.76 mmol) are reacted in isoamyl alcohol (1.5 ml) in accordance with the procedure for Example 1 (reaction time 8 h) and worked up. The crystals obtained are dissolved in acetonitrile and water and freeze-dried; yield: 38 mg (21%), crystals;
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[O:4][CH2:3]1.[F:15][C:16]([F:29])([C:25]([F:28])([F:27])[F:26])[CH2:17][NH:18][C:19](=[O:24])[CH2:20][C:21](O)=[O:22].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.Cl>O1CCCC1>[CH3:10][N:7]1[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[O:4][CH2:3][C@H:2]([NH:1][C:21](=[O:22])[CH2:20][C:19]([NH:18][CH2:17][C:16]([F:29])([F:15])[C:25]([F:26])([F:28])[F:27])=[O:24])[C:8]1=[O:9]
Reactant: O=C(O)CC(=O)NCC(F)(F)C(F)(F)F
Reactant: CN1C(=O)[C@@H](N)COc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)[C@@H](NC(=O)CC(=O)NCC(F)(F)C(F)(F)F)COc2ccccc21
Temperature: 25 °C
Yield: 39.4 %

Procedure:
To a solution of 0.06 g (0.31 mmol) (S)-7-amino-9-methyl-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one in 5 ml tetrahydrofurane were added 0.07 g (0.31 mmol) N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid, 0.04 g (0.31 mmol) 1-hydroxybenzotriazole hydrate, 0.06 g (0.31 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochloride and 0.1 ml (0.62 mmol) diisopropylethylamine. After stirring at room temperature over night the mixture was added to 1N aqueous hydrochloric acid. Extraction with dichloromethane, followed by washing with saturated aqueous sodium bicarbonate solution and drying with sodium sulfate, and chromatography on silicagel with ethylacetate/heptane yielded 0.05 g (39%) N-((S)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid, MS m/e (%): 410.3 (M+H+, 100).
Reaction SMILES: [C:1]([O:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[NH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1.N1C2C(=CC=CC=2)C=CC=1.C1(C)C=CC=CC=1>C([O-])([O-])OC>[C:1]([O:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[NH:11][C:12](=[O:17])/[CH:13]=[C:14](\[O:16][CH3:21])/[CH3:15])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Oc1cccc(NC(=O)CC(C)=O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC([O-])[O-]
Solvent: c1ccc2ncccc2c1
Solvent: Cc1ccccc1
Product: CCCCC(=O)Oc1cccc(NC(=O)/C=C(/C)OC)c1
Temperature: 140 °C
Yield: 2955.3 %

Procedure:
A solution of 47 g of m-valeryloxy-acetylacetanilide in 50 ml of methyl orthoformate and 0.5 g of p-toluene sulfonic acid stood at room temperature for 16 hours and then 1 g of quinoline and 200 ml of toluene were added thereto. The mixture was heated at 140°C. for 4 hours while removing the methanol formed and the solvent was then evaporated. The residue was chromatographed over silica gel and was eluted with an 8-2 methylene chloride-acetone mixture to obtain 25 g of m-valeryloxy-3-methoxy-crotonanilide (isomer E) melting at 84°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[S:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1)[NH2:5].Cl.N1C=CC=CC=1.Cl[C:24]1[C:29]([C:30]#[N:31])=[CH:28][N:27]=[C:26]2[S:32][CH:33]=[CH:34][C:25]=12>C(OCCO)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:24]2[C:29]([C:30]#[N:31])=[CH:28][N:27]=[C:26]3[S:32][CH:33]=[CH:34][C:25]=23)[CH:6]=[CH:7][C:8]=1[S:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1
Reactant: N#Cc1cnc2sccc2c1Cl
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3sccc23)cc1Cl
Yield: 26.6 %

Procedure:
A mixture of (3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]aniline (135 mg, 0.57 mmol), pyridine hydrochloride (66 mg, 0.57 mmol) and 4-chlorothieno[2,3-b]pyridine-5-carbonitrile (0.1 g, 0.52 mmol) in 4 mL of 2-ethoxyethanol is heated at reflux for 24 hours. The solution is cooled and the solvent is evaporated. The resultant residue is treated with a minimum amount of methanol and the product is purified by flash column chromatography eluting with 3% methanol in dichloromethane. The fractions containing product are combined and concentrated. Ethyl acetate is added and the insoluble material collected by filtration to provide 55 mg of 4-[(3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl)amino]thieno[2,3-b]pyridine-5-carbonitrile as a tan solid, mp>240° C.; 1H NMR (DMSO-d6) δ 3.61 (s, 3H), 6.53 (d, J=9 Hz, 1H), 7.15 (m, 1H), 7.17 (s, 1H), 7.44 (m, 1H), 7.52 (s, 1H), 7.54 (s, 1H), 7.81 (d, J=6 Hz, 1H), 8.53 (s, 1H), 9.76 (s, 1H); MS 396.2 (M−H)−.
Reaction SMILES: C(=O)(O)[O-].[Na+].[H+].[H+].Cl[Pt-2:9](Cl)(Cl)(Cl)(Cl)Cl.[CH2:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[Pt:9].[CH2:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [H+]
Agent: [Na+]
Solvent: CCO
Solvent: C=Cc1ccccc1
Product: [Pt]
Temperature: 55 °C

Procedure:
The platinum-styrene complex used in the examples is prepared by adding about 6 parts of sodium bicarbonate to a mixture containing 3 parts of chloroplatinic acid (H2PtCl6.6H2O), 6 parts of styrene and 50 parts of ethanol. The mixture is heated to reflux temperature, (about 55° C.) and refluxed for about 35 minutes with agitation, and then cooled to room temperature. The resultant mixture which contains orange crystals is filtered and the crystals washed with about 30 parts of acetone. After adding about 30 parts of xylene to the filtrate, crystals are again formed. The crystalline mixture is filtered and the orange crystals are recovered and dried. These crystals are then dissolved in isopropanol.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH3:43])=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.O>CN1CCCC1=O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([C:32]([CH3:43])=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(C)c1nc2ccc(Cl)nn2c1C
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(C)(C)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1C
Temperature: 160 °C
Reaction time: 8.5 h
Yield: 69.6 %

Procedure:
In 25 mL of N-methyl-2-pyrrolidinone were dissolved 17.0 g of 4-(diphenylmethoxy)-1-piperidinepropaneamine and 7.39 g of ethyl 2-(6-chloro-3-methylimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate, and stirred at 160° C. for 8.5 hours. After cooling, a water was added and extracted with ethyl acetate. The extract was washed with a saturated brine solution and dried over magnesium sulfate. Following to concentration under reduced pressure. The residue was subjected to silica gel column chromatography to be eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated to yield 10.4 g of ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-methylimidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate as an oily material. In 100 mL of ethanol was dissolved this oily material, and 18.3 mL of a 5N aqueous sodium hydroxide solution was added thereto and heated under reflux for 2 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with water and washed with diisopropyl ether. The aqueous layer was adjusted to pH 5 by the addition of 5N hydrochloric acid. The crystals formed were collected by filtration, recrystallized from methanol-water (10:1), and dried to yield 4.09 g (of the title compound.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[CH3:11][O:12][C:13]1[CH:14]=[C:15](/[C:16](=[CH:9]/[C:7]2[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)/[C:17]#[N:18])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Product: COc1ccc(/C(C#N)=C/c2ccc([N+](=O)[O-])o2)cc1OC
Yield: 2.9 %

Procedure:
5-Nitro-2-furaldehyde (1.41 g) was condensed with 3,4-dimethoxybenzyl cyanide (1.77 g) through Method A (production step 2), to thereby yield the target product (yield: 88 mg, 2.9%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.BrC1C=C(C(F)(F)F)C=CC=1.[Mg].[CH:25]([N:38]1[CH2:41][CH2:40][CH:39]1[C:42]#[N:43])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCOCC>[CH:25]([N:38]1[CH2:41][CH2:40][CH:39]1[C:42](=[NH:43])[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1cccc([Mg]Br)c1
Reactant: N#CC1CCN1C(c1ccccc1)c1ccccc1
Agent: FC(F)(F)c1cccc(Br)c1
Agent: [Mg]
Solvent: CCOCC
Product: N=C(c1cccc(C(F)(F)F)c1)C1CCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Suspend m-trifluoromethylphenylmagnesium bromide in ether by adding a solution of 18 g of m-bromobenzotrifluoride in 30 ml of ether to a stirred suspension of 1.94 g of magnesium turnings in 20 ml of dry ether. Upon completion of addition, allow the reaction mixture to cool to room temperature and add 7.95 g of 1-benzhydryl-2-cyanoazetidine. Stir the mixture for 18 hours at room temperature, cool to 0° C. or lower, and quench by the dropwise addition of 50 ml of water. Add 15 ml of ether and 25 ml of methylene chloride and filter the mixture through a pad of diatomaceous earth, such as commercially available Celite. Remove the aqueous layer of the filtrate. Wash the organic phase with water and dry over anhydrous sodium sulfate. Remove the solvent in vacuo to obtain the title compound as an oil. By suitable substitution, analogous halo compounds can be prepared.