Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>C1COCC1.C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]([F:20])([F:33])[F:32])=[N:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(Br)cnc21
Reactant: OB(O)c1ccccc1OC(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1nc(-c2ccccc2OC(F)(F)F)c2cc(Br)cnc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 58.5 %

Procedure:
A mixture of 5-bromo-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (3.5 g, 7.7 mmol), 2-trifluoromethoxyphenylboronic acid (2.2 g, 7.7 mmol), dichloro[1,1′bis(diphenyl-phosphino)ferrocene]palladium(II) dichloromethane adduct (284 mg, 0.4 mmol) in THF/Acetonitrile/saturated NaHCO3 (25 ml/25 ml/30 ml) was stirred at 60° C. for 4 hours. The mixture was allowed to cool down to room temperature and then extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated to dryness. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 5-bromo-3-(2-trifluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (2.2 g, 59% yield). 1H NMR (500 MHz, DMSO-d6) δ 0.02 (s, 9H), 0.94 (m, 2H), 3.77 (m, 2H), 6.00 (s, 2H), 7.75 (m, 2H), 7.80 (d, 1H), 8.01 (d, 1H), 8.66 (s, 1H), 8.91 (s, 1H). MS: m/z 489.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[S:9][N:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[N:17]1([C:2]2[C:12]3[C:11]4[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=4[S:9][N:8]=[CH:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: Clc1cccc2c1-c1ccccc1SN=C2
Product: C1=NSc2ccccc2-c2c1cccc2N1CCNCC1

Procedure:
EP 0282236-A1 reports that a dibenzothiazepine derivative can be processed to give 11-[4-(2-(2-hydroxyethoxy)-ethyl]-1-piperadinyldibenzothiazepine derivative, which is of value as, for example, an antipsychotic pharmaceutical. In more detail, dibenzo-[b,f][1,4]thiazepin-11-one, which is a representative compound of the dibenzothiazepine derivatives reported therein, is reacted with phosphorus oxychloride to yield a 11-chloro-dibenzothiazepine derivative. To the 11-chloro-dibenzothiazepine derivative is added piperazine to yield a 11-piperazinyl-dibenzothiazepine derivative, which is subsequently reacted with 2-chloroethoxyethanol under basic conditions to give the desired 11-[4-(2-(2-hydroxyethoxy)-ethyl]-1-piperadinyldibenzothiazepin.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[SH:11].[CH3:12][O:13][C:14]([CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24](Cl)=O)[CH:20]=[CH:21][CH:22]=1)=[O:15]>CN1CCCC1=O.O>[F:8][C:7]1[C:2]2[N:1]=[C:24]([CH2:23][C:19]3[CH:18]=[C:17]([CH2:16][C:14]([O:13][CH3:12])=[O:15])[CH:22]=[CH:21][CH:20]=3)[S:11][C:3]=2[C:4]([F:10])=[CH:5][C:6]=1[F:9]
Reactant: COC(=O)Cc1cccc(CC(=O)Cl)c1
Reactant: Nc1c(F)c(F)cc(F)c1S
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)Cc1cccc(Cc2nc3c(F)c(F)cc(F)c3s2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a solution of monomethyl 1,3-phenylene diacetate (531 mg, 2.6 mmol) in benzene (5 ml) was gradually added thionyl chloride (607 mg, 5.2 mmol). The mixture was heated to reflux for 2 hours. An excess of thionyl chloride was then distilled off in vacuo leaving 3-methoxycarbonylmethylphenylacetyl chloride. 2-Amino-3,4,6-trifluorothiophenol (507 mg, 2.8 mmol) was dissolved in N-methylpyrrolidone (NMP, 5 ml) under a nitrogen stream. To the resultant solution was gradually added the product 3-methoxycarbonylmethylphenylacetyl chloride thus obtained and the mixture was stirred at 100° C. for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and then evaporated to yield a residue, which was purified on a silica gel column to give methyl 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]phenylacetate (267 mg, 27%) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:4]([F:19])[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[C:27]([O:29]C)=[O:28]>>[F:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[S:10][C:11]4[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=4[N:13]=3)=[C:4]([F:19])[CH:3]=2)[CH:24]=[CH:25][C:26]=1[C:27]([OH:29])=[O:28]
Reactant: Fc1ccc2nc(Nc3ccc(Br)cc3F)sc2c1
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Product: O=C(O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)cc1F

Procedure:
As shown in Reaction Scheme 8, Intermediate VI-8 (3,3′-difluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-carboxylic acid) was prepared using a method similar to that employed in the preparation of Intermediate VI-1 using N-(4-bromo-2-fluorophenyl)-6-fluoro-1,3-benzothiazol-2-amine and commercially available [3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid as starting materials.
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([O-:12])=O)=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Na+].[CH3:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[F:30])[NH:22]1>>[F:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([N:22]2[C:23]3[C:28](=[C:27]([F:30])[CH:26]=[CH:25][CH:24]=3)[CH2:29][CH:21]2[CH3:20])=[O:12])=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CC1Cc2c(F)cccc2N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Agent: [Na+]
Product: CC1Cc2c(F)cccc2N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Yield: 60.1 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 125 mg of sodium (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate obtained in step 2a of example 6a and 74 mg of (+)-2-methyl-4-fluoro-2,3-dihydro-1H-indole (reference example 5a). After silica column purification: eluent 98/02 dichloromethane/methanol, 105 mg of 5-fluoro-2-[2-((−)-2-methyl-4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:45][OH:46])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]#[N:29])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:38])=[CH:33][CH:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C1C[O:50]CC1>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:45][OH:46])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]([NH2:29])=[O:50])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:40][CH2:41][O:42][CH2:43][CH2:44]5)=[O:38])=[CH:33][CH:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3CO)ncc2c1
Reactant: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3CO)ncc2c1
Reaction time: 1 h
Yield: 76.1 %

Procedure:
1-(3-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-3-(4-(morpholine-4-carbonyl)phenylamino)-1H-pyrazole-4-carbonitrile (46 mg, 0.074 mmol) was dissolved in 4 mL of THF and 0.5 mL of water. Then dihydrogen tris(dimethylphosphinito)hydroplatinate (3 mg, 0.0069 mmol) was added and the mixture was stirred under fluxing. After 1 hr, TLC indicated complete consumption of the starting material. LC/MS indicated clean desired product formed. The mixture was evaporated and the residue was dissolved in dichloromethane and dried over sodium sulfate, filtered through micron filter and evaporated. The residue was purified through flash column chromatography using methanol in methylene chloride (1.5% to 5% methanol in 10 minutes, 12 g silica gel) to give 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-[4-(morpholine-4-carbonyl)-phenylamino]-1H-pyrazole-4-carboxylic acid amide as a white solid (36 mg, 76.1% yield). LC/MS clacd for C34H34FN7O5 (m/e) 639.26, obsd 640.1 (M+H, ES+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (s, 9H), 3.50 (br., 4H), 3.59 (br., 4H), 4.38 (br. s., 2H), 4.78 (t, J=5.2 Hz, 1H), 7.36 (d, J=8.6 Hz, 3H), 7.52-7.69 (m, 5H), 7.76 (d, J=13.1 Hz, 2H), 7.88 (s, 1H), 8.54 (m, 2H), 9.44 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11]C)=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:13]([O:15]C)=[O:14].B(Br)(Br)Br.CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1[nH]c2cc(OC)ccc2c1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)c1[nH]c2cc(O)ccc2c1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 7.5 %

Procedure:
Methyl 3-Bromo-6-(methyloxy)-1H-indole-2-carboxylate (0.075 g, 0.26 mmol) was dissolved in CH2Cl2 (5 mL), cooled to 0° C. under nitrogen and BBr3 (1.0 M in CH2Cl2, 1.6 mL, 1.6 mmol) added dropwise. The reaction mixture was allowed to warm to RT and stirred overnight. Ice cold water (1 mL) and EtOAc (5 mL) were added. The layers were separated and the aqueous layer extracted with EtOAc (3×5 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.005 g, 7%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 13.06 (br. s., 1H), 11.63 (br. s., 1H), 9.55 (s, 1H), 7.30 (d, 1H), 6.78 (d, 1H), 6.70 (dd, 1H). MS: m/z 256.13 (M+1).
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[NH:11][C@:10]([CH3:16])([C:12]([F:15])([F:14])[F:13])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.P(Cl)(Cl)([Cl:19])=O>ClCCCl>[Cl:19][C:2]1[N:3]=[C:4]2[NH:11][C@:10]([CH3:16])([C:12]([F:15])([F:14])[F:13])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(O)cc2=O)N1
Solvent: ClCCCl
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(Cl)cc2=O)N1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of 5.6 g of (2S)-7-hydroxy-2-methyl-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one in 100 mL of 1,2-dichloroethane, are added at room temperature and under an argon atmosphere, 11 mL of phosphorus oxychloride. The resulting mixture is then heated to 70° C. After two hours of stirring and after monitoring with LC/MS, the reaction is completed. After cooling, the reaction mixture is dry evaporated under reduced pressure. The obtained residue is taken up with 5 mL of cold water and 200 mL of ethyl acetate. On the obtained mixture, 32% soda is added up to a pH=6. The organic phase is then separated and then dried on magnesium sulphate, filtered and concentrated under reduced pressure in order to obtain 6 g of (2S)-7-chloro-2-methyl-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one including the following characteristics:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CCN(CC)CC>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:16]1[CH2:15][NH2:14])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NCC1C=CC=CN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
A solution of 2-nitrobenzenesulfonylchloride (16.62 g, 0.075 mol) in dry CH2Cl2 (120 mL) was added dropwise via cannula to a stirred solution of 2-(aminomethyl)pyridine (5.41 g, 0.05 mol) and Et3N (13.9 mL, 0.10 mol) in dry CH2Cl2 (150 mL) under nitrogen. The reaction mixture was stirred for three hours at room temperature, and then quenched with water (20 mL). The aqueous layer was separated and extracted with EtOAc (5×80 mL). The combined organic extracts were dried (MgSO4) and evaporated to small volume to give a white precipitate which was collected by filtration and washed with cold CH2Cl2 to give the desired product (11.37 g, 78%) as a white solid: 1H NMR (Acetone-d6) δ 4.46 (s, 2H), 7.19 (dd, 1H, J=7.4, 4.5 Hz), 7.25-7.35 (br s, 1H), 7.39 (d, 1H, J=7.7 Hz), 7.68 (ddd, 1H, J=7.7, 7.5, 1.8 Hz), 7.76-7.88 (m, 2H), 7.94 (dd, 1H, J=7.7, 1.5 Hz), 8.04 (dd, 1H, J=7.5, 1.8 Hz), 8.38 (d, 1H, J=4.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:50])[N:4]([CH2:47][CH2:48][CH3:49])[C:5](=[O:46])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]=1Cl.[CH:51]([SH:55])([CH2:53][CH3:54])[CH3:52].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:50])[N:4]([CH2:47][CH2:48][CH3:49])[C:5](=[O:46])[N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]=1[S:55][CH:51]([CH3:52])[CH2:53][CH3:54]
Reactant: CCCn1c(=O)c(Cl)c(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Reactant: CCC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1c(=O)c(Cl)c(SC(C)CC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A mixture of 5,6-dichloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.22 g), sec-butylmercaptan (0.04 g) and potassium carbonate (0.09 g) in acetonitrile (5 ml) was heated under reflux for 4 hours. The reaction mixture was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and 1N hydrochloric acid (1.5 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give yellow amorphous powders (90 mg, 56%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.[CH2:12]([O:14][C:15](=[O:27])[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=[O:17])[CH3:13].C([O-])([O-])=O.[K+].[K+]>>[CH2:12]([O:14][C:15](=[O:27])[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]2)[CH:19]=1)=[O:17])[CH3:13]
Reactant: CN1CCN(CCCCl)CC1
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(=O)c1cn(CCCN2CCN(C)CC2)c2ccccc12
Yield: 53 %

Procedure:
The general procedure 1 was then followed using 1-(3-chloropropyl)-4-methylpiperazine (12.5 mmol, 2.2 g), ethyl-2-(1H-indol-3-yl)-2-oxoacetate (10 mmol, 2.17 g) and K2CO3 (10.8 mmol, 1.5 g). The purification was achieved by column chromatography (petro-lether:ethylacetate:diethylamine 5:5:1) to yield ethyl-2-{1-[3-(4-methylpiperazin-1-yl)propyl]-1H-indol-3-yl}-2-oxoacetate (5.3 mmol, 42%). IR [cm−1]=2936; 2790; 1727; 1638. FD-MS m/z (rel. int.)=359.9 (2.05%; M+•.). 1H NMR (300 MHz, CDCl3) 8.40 (m; 2H; indole-H); 7.36 (m; 3H; indole-H); 4.38 (q; 3J=7.1 Hz; 2H; OCH2CH3); 4.25 (t; 3J=6.5 Hz; 2H; indole-CH2CH2CH2N); 2.44 (m; 8H; 4× piperazin-CH2); 2.30 (s; 3H; CH3); 2.26 (t; 3J=6.5 Hz; 2H; indole-CH2CH2CH2N); 2.00 (m; 2H;
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[C:26]1[C:33]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])=[C:32]([I:39])[CH:31]=[CH:30][C:27]=1[CH:28]=O>C1(C)C=CC=CC=1>[CH2:35]([O:34][C:33]1[CH:26]=[C:27](/[CH:28]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[CH:30]=[CH:31][C:32]=1[I:39])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCOc1c(I)ccc(C=O)c1C
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCOc1cc(/C=C/C(=O)OC)ccc1I
Yield: 87.2 %

Procedure:
65.08 g (0.195 mol, 2 eq) of methyl triphenylphosphoranylideneacetate are added to a solution of 29.60 g (0.097 mol, 1 eq) of methyl-3-butoxy-4-iodobenzaldehyde in 360 ml of toluene. The reaction mixture is refluxed for 2 hours. The solvent is evaporated off and the oil obtained is chromatographed on silica gel (50/50 heptane/dichloromethane). 30.47 g of methyl (E)-3-(3-butoxy-4-iodophenyl)acrylate are obtained in the form of pale yellow crystals. Yield=87%
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1.O>CS(C)=O>[CH3:22][CH:23]1[NH:24][CH2:25][CH2:26][N:27]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[N:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=[C:6]([C:19]([OH:21])=[O:20])[C:7](=[O:18])[C:8]3=[CH:9][C:10]=2[F:17])[CH2:28]1
Reactant: CC1CNCCN1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CS(C)=O
Solvent: O
Product: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 55 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
Forty grams of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid and 28.4 g (2.1 eq) of 2-methyl piperazine were suspended in DMSO (800 mL) under nitrogen atmosphere. The mixture was heated to 55° C. during 24 hours. Then water (70 mL) was added, the reaction mixture was cooled to 2° C. and left at this temperature overnight. The solution was filtered, washed with acetonitrile and dried under vacuum to obtain 38.5 g after assay (75.8% yield) of gatifloxacin.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[N:11]=[N:10]2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[NH2:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:23][C:15]([C:12]2[N:11]=[N:10][N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:13]=2[CH3:14])=[O:17])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(N)cc1OC
Reactant: Cc1c(C(=O)O)nnn1Cc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2nnn(Cc3ccc(F)cc3)c2C)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[(4-fluorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (0.2 g, 0.85 mmol), 3,4-bis(methyloxy)aniline (0.156 g, 1.2 eq), HATU (0.485 g, 1.5 eq) and DIPEA (240 μL, 1.5 eq) in DMF was stirred at room temperature overnight. The solvent was evaporated and the residue was washed with water and extracted with DCM. The organic phase was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with DCM to give after precipitation from ether, the title compound as a white solid (180 mg, 57%). HRMS calculated for C19H19FN4O3 (M+H)+371.1519, found: 371.1500, Rt: 2.78 min. MP: 119.7° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=O)=O.[CH3:21][N:22](C=O)C>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[C:21]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)#[N:22]
Reactant: O=C1CCC(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)N1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C2CCC(=O)N2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of 5-(4-trifluoromethanesulfonyloxyphenyl)-2-pyrrolidinone (2.45 g, 8.22 mmol), tetrakis(triphenylphosphine)palladium (475 mg, 0.41 mmol), and zinc cyanide (1.45 g, 12.3 mmol) in 10 mL of DMF was flushed with nitrogen three times and then stirred at 80° C. After 3 hr, the mixture was cooled down to rt, diluted with EtOAc (10 mL), and filtered through a cake of Celite. The solid was washed with EtOAc, and the filtrates were combined and concentrated. Chromatography on a Biotage 40+M cartridge using 9:1 v/v EtOAc/CH3OH as the eluant gave 2.68 g (100%) of the title compound containing trace amount of DMF: 1H NMR (CD3OD) δ 1.90-1.97 (m, 1H), 2.43-2.51 (m, 2H), 2.60-2.67 (m, 1H), 4.85 (t, J=7.2, 1H), 7.41 (d, J=8.8, 2H), 7.65 (d, J=8.5, 2H).
Reaction SMILES: O=[C:2]([CH3:13])[CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl.C(N=C=NCCCN(C)C)C.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([N:20]2[C:2]([CH3:13])=[CH:3][C:4]3[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:6]2=[O:8])=[CH:18][CH:17]=1
Reactant: CC(=O)Cc1ccccc1C(=O)O
Reactant: COc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-n2c(C)cc3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
2-(2-oxopropyl)benzoic acid (100 mg, 0.56 mmol), 4-methoxyaniline (76 mg, 0.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.84 mmol) and pyridine (0.5 mL) were dissolved in chloroform (5 mL) and stirred at room temperature overnight. Chloroform was added, the organic phase was washed by aqueous citric acid solution, sodium hydrogen carbonate aqueous solution and saturated brine in that order, and dried with anhydrous sodium sulfate. The product was purified by silica gel column chromatography (hexane/ethyl acetate=10/0-3/7) to obtain the target compound (66 mg, 44%) as a light brown solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>CN(C=O)C.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:15]([C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(F)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: C=CCc1cc(F)ccc1C(=O)OC
Temperature: 90 °C
Yield: 39.6 %

Procedure:
A mixture of methyl 2-bromo-4-fluorobenzoate (1 g, 4.29 mmol), allyltributylstannane (1.464 mL, 4.72 mmol), lithium chloride (0.364 g, 8.58 mmol) in DMF (1 mL), acetonitrile (10 mL) was added bis(triphenylphosphine)palladium(ii) dichloride (0.151 g, 0.215 mmol). It was then degassed for 2 min, then filled with N2. After heating at 90° C. for 16 h, it was quenched with NH4Cl, extracted with EtOAc. The organic layer was washed with KF solution, dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 10% EtOAc/hexane to isolate methyl 2-allyl-4-fluorobenzoate (330 mg, 1.699 mmol, 39.6% yield) as an white solid. 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J=8.6, 6.1 Hz, 1H), 7.09-6.87 (m, 2H), 6.01 (ddt, J=16.9, 10.3, 6.6 Hz, 1H), 5.19-4.96 (m, 2H), 3.90 (s, 3H), 3.80 (d, J=6.6 Hz, 2H).