Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([CH2:11][CH2:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17]O)=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[C:5]1([CH2:11][CH2:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][Br:2])=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCc1ccc(CCc2ccccc2)cc1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: BrCc1ccc(CCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
3.14 ml (33.4 mmol) of phosphorus tribromide in 11 ml of toluene are added dropwise, while cooling and under an N2 atmosphere, to 8.36 g (85%; 33.4 mmol) of p-(2-phenylethyl)benzyl alcohol in 100 ml of toluene. After 2 h at RT, the mixture is poured onto ice-water and the organic phase is separated off; it is washed with sat. NaHCO3 solution, water and saline. The aqueous phases are extracted 2× with ether, and the combined organic phases are dried with Na2SO4 and evaporated: TLC Rf (A)=0.77; 1H-NMR (200 MHz, CDCl3): 2.92 (s, 4H), 4.50 (s, 2H), 7.15-7.35 (m, 9H); additional signals of approximately 20% p-(2-phenylethyl)toluene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[N:12][CH:11]=[CH:10][N:9]=2)[C:5]2[N:14]([CH2:29][C@H:30]3[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]3)[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][C@H:18]3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:16][C:4]=2[CH:3]=1.[CH3:37][N:38](C=O)C>[C-]#N.[C-]#N.[Zn+2]>[CH3:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([CH2:29][N:14]2[C:5]3[C:6]([C:8]4[CH:13]=[N:12][CH:11]=[CH:10][N:9]=4)=[N:7][C:2]([C:37]#[N:38])=[CH:3][C:4]=3[N:16]=[C:15]2[N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:31][CH2:32]1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(Cl)nc(-c4cnccn4)c32)CC1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C#N)nc(-c4cnccn4)c32)CC1
Temperature: 140 °C

Procedure:
To a sealable tube were added 6-chloro-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-4-(pyrazin-2-yl)-3H-imidazo[4,5-c]pyridine (250 mg, 0.497 mmol) and Zn(CN)2 (46 mg, 0.397 mmol). DMF (4 mL) was added, and the mixture was purged with nitrogen for 5 minutes. Pd(dppf)Cl2 dichloromethane complex (20.2 mg, 0.024 mmol) was added, and the mixture was degassed with nitrogen again for 5 minutes. The tube was sealed and heated to 140° C. for 2.5 hours. The reaction mixture was cooled to room temperature, filtered, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column using 30-45% ethyl acetate/petroleum ether as eluent to afford 3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-4-(pyrazin-2-yl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ES/APCl calc'd. for C29H31N7O [M+H]+ 494. found 494.
Reaction SMILES: [OH:1]CCCNC(=O)[C@H](C(CO)(C)C)O.[CH3:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23](Cl)=[O:24])=[CH:19][CH:18]=1.N1C=CC=CC=1>C(OC)(=O)C>[CH3:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23]([OH:1])=[O:24])=[CH:19][CH:18]=1
Reactant: CC(C)(CO)[C@H](O)C(=O)NCCCO
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Solvent: COC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)O)cc1
Yield: 86 %

Procedure:
17.4 g of D-panthenol )0.085 mol) are placed in 300 ml of methyl acetate while gassing with argon in a 750 ml 4-necked sulphonation flask provided with a thermometer, a 100 ml dropping funnel, a magnetic stirrer and a reflux condenser. A solution of 75.5 g of 4-methoxycinnamic acid chloride (0.38 mol) in 150 ml of methyl acetate is then added dropwise within about 20 minutes. A solution of 33.6 g of pyridine (0.425 mol) is added dropwise within about 40 minutes. The reaction mixture is finally heated to reflux temperature for 4 hours. After cooling the precipitate is filtered off under suction. The filtrate is washed with 2× 150 ml of 5% HCl and then with 2× 100 ml of water. After drying over Na2SO4 the organic phase is concentrated on a rotary evaporator. The yellow, viscous residue (74.2 g) is chromatographed (toluene/ethyl acetate, 7:1) on 1 kg of silica gel (0.040-0.063 mm) under 0.5 bar pressure. There are obtained 50.1 g of yellow <R>-panthenol triester of p-methoxycinnamic acid (yield 86%).
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([C:8]1(O)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)#[N:7].C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[C:6]([C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C#N)CC1
Agent: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC=C(C#N)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Methanesulfonyl chloride (0.189 mL, 2.43 mmol) was added to a mixture of tert-butyl 4-cyano-4-hydroxypiperidine-1-carboxylate (500 mg, 2.21 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.579 mL, 3.31 mmol) in chloroform (8.8 mL) at 0° C. The reaction mixture was stirred at 0° C. for 45 minutes, and was then partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate, and the dried solution was filtered. The filtrate was concentrated in vacuo, and the residue was dissolved in pyridine (5.5 mL). The reaction mixture was heated to 120° C. for 4 hours, and was then cooled to ambient temperature. The cooled reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed sequentially with water and saturated aqueous sodium chloride solution. The washed solution was dried over anhydrous sodium sulfate, and the dried solution was filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash-column chromatography (using a gradient elution of 0-100%, ethyl acetate/hexanes) to afford the title compound. 1H NMR (500 MHz, CDCl3): δ 6.55 (br s, 1H), 4.05 (m, 2H), 3.55 (t, J=5.6 Hz, 2H), 2.34 (br s, 2H), 1.46 (s, 9H).
Reaction SMILES: C(OC(C(N(C1C=CN=CC=1)[C@H](C(O)=O)C)C1CC2C(=CC=CC=2)C1)=O)C.C(OC(=O)CN)C1C=CC=CC=1.C([O:47][C:48](=[O:77])[CH2:49][NH:50][C:51](=[O:76])[C@H:52]([CH3:75])[N:53]([C:69]1[CH:74]=[CH:73][N:72]=[CH:71][CH:70]=1)[CH:54]([C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH:55]1[CH2:63][C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:56]1)C1C=CC=CC=1.[H][H]>[Pd]>[CH2:67]([O:66][C:64]([CH:54]([N:53]([C:69]1[CH:70]=[CH:71][N:72]=[CH:73][CH:74]=1)[C@H:52]([C:51]([NH:50][CH2:49][C:48]([OH:77])=[O:47])=[O:76])[CH3:75])[CH:55]1[CH2:56][C:57]2[C:62](=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:63]1)=[O:65])[CH3:68]
Reactant: [H][H]
Reactant: CCOC(=O)C(C1Cc2ccccc2C1)N(c1ccncc1)[C@@H](C)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Agent: CCOC(=O)C(C1Cc2ccccc2C1)N(c1ccncc1)[C@@H](C)C(=O)O
Agent: NCC(=O)OCc1ccccc1
Product: CCOC(=O)C(C1Cc2ccccc2C1)N(c1ccncc1)[C@@H](C)C(=O)NCC(=O)O

Procedure:
Using examples given above, N-[1-Ethoxycarbonyl-1-(2,3-dihydro-1H-inden-2-yl)-methyl]-(4-pyridyl)-alanine and glycine benzyl ester are reacted and the resulting N-[1-Ethoxycarbonyl-1-(2,3-dihydro-1H-inden-2-yl)-methyl]-(4-pyridyl)-alanyl-glycine benzyl ester treated with hydrogen in the presence of palladium on carbon to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.N1C=CN=C1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>ClCCl.O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21])=[C:4]([F:10])[CH:3]=1
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromo-2,6-difluorophenol D1c (5.0 g, 24 mmol) is dissolved in dichloromethane (50 mL) and treated with imidazole (2.28 g, 33.5 mmol). The colorless solution is treated in portions, with stirring, with tert-butylchlorodimethylsilane (4 g, 26 mmol). The mixture is stirred at room temperature overnight. The mixture is diluted with water (150 mL) and extracted with dichloromethane. The organic phase is washed with sat. NH4Cl solution, dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash chromatography (hexanes/ethyl acetate gradient) affords (4-bromo-2,6-difluorophenoxy)(tert-butyl)dimethylsilane D1d as a clear oil. 1H-NMR (400 MHz, CDCl3) δ=7.05 (d, J=7.2 Hz, 2H), 1.00 (s, 9H), 0.19 (s, 6H); no MS spectrum could be obtained.
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([C:34]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[S:35][CH2:36][CH2:37][NH2:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>ClCCl>[C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13][NH:38][CH2:37][CH2:36][S:35][C:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCl)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Dissolve N-[2-((Triphenylmethyl)thio)ethyl]-chloroacetamide (5.4 g, 13.8 mmol) and 2-[(triphenylmethyl)thio]ethylamine (4.4 g, 13.8 mmol) in 100 mL dichloromethane, then add triethylamine (3.0 mL, 20.8 mmol) into the solution, heat and reflux for 48 hours. After being cooled, wash with 100 mL sodium bicarbonate aqueous solution (NaHCO3) and take the organic layer. After being dried with anhydrous sodium sulfate and concentrated, liquid chromatography (silicon dioxide, ethyl acetate hexane=1:1) is used for separation and purification so as to get light yellow oil product
Reaction SMILES: N[C:2]1[CH:7]=CC=C[CH:3]=1.C=CC.[NH2:11][C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1>>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH:2]([CH3:7])[CH3:3])[C:12]=1[NH2:11]
Reactant: Nc1ccccc1
Reactant: Cc1ccccc1N
Solvent: C=CC
Product: Cc1cccc(C(C)C)c1N

Procedure:
2-Methyl-6-isopropyl aniline was prepared by the method of Example 2 using an H-Y zeolite catalyst for the condensation of aniline and propylene. The ortho-toluidine and propylene were fed to the reactor in a 1:5 molar ratio and at an LHSV of 0.25 based on o-toluidine. The reaction was conducted at 250° C. and 861 psig. The effluent product stream was analyzed by gas chromatography. Conversion of o-toluidine was 81.5%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([CH:11]=[O:12])[N:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:6]=2[N:7]=1.[OH:18]OS([O-])=O.[K+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([OH:18])=[O:12])[N:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:6]=2[N:7]=1
Reactant: O=S([O-])OO
Reactant: CCC(CC)n1c(C=O)cc2cnc(Cl)nc21
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)n1c(C(=O)O)cc2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 43.7 %

Procedure:
To a mixture of 2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (283 mg, 1.11 mmol) in DMF (3 mL) is added oxone (820 mg, 1.33 mmol) at room temperature. The mixture is stirred at room temperature for 5 h and is quenched with 20% Na2S2O3 aqueous solution. After stirring for 10 min, the reaction mixture is acidified with 1N HCl aqueous solution (pH=5). The mixture is extracted with dichloromethane, dried over Na2SO4 and concentrated in vacuo. The solid is filtered, washed with acetonitrile, and dried under vacuum to give 130 mg of 2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid as a pale brown solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.O.[Pd]>[C:28]([O:27][C:25]([NH:24][CH:21]1[CH2:20][CH2:19][N:18]([CH2:17][CH:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[CH2:23][CH2:22]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2CCN(C(=O)OCc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(CC2CCNCC2)CC1
Yield: 101.6 %

Procedure:
To a solution of 1-(1-benzyloxycarbonyl-4-piperidinylmethyl)-4-(t-butoxycarbonylamino)piperidine (10.0 g) in ethanol (100 ml) and water (10 ml) is added a 10% palladium-on-carbon (1.2 g), and the mixture is reduced at a room temperature under at a moderate pressure (3.0 kg/cm2). After the consumption and disappearance of the starting compound is confirmed (about 2 hours thereafter), the catalyst is removed by filtration. The filtrate is evaporated under reduced pressure to give crude 4-(t-butoxycarbonylamino)-1-(4-piperidinyl-methyl)piperidine (about 7 g) as a white solid.
Reaction SMILES: [Mg].[CH3:2]I.[CH2:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=O.O>C(OCC)C>[CH3:2][C:5]1[CH2:6][C:7]2[C:12]([CH:4]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CI
Reactant: O=C1Cc2ccccc2C1
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: CC1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.7 %

Procedure:
50 ml of diethyl ether was added to 2.5 g of magnesium. A solution of 14.3 g of methyliodide in 50 ml of diethyl ether was added in 1 hour, with cooling with the aid of a water bath. Then the reaction mixture was stirred for 30 minutes at room temperature. A solution of 13.2 g of 2-indanone in 40 ml of diethyl ether was then added to this reaction mixture, followed by 30 minutes' stirring. 100 ml of water was then added. The organic layer was separated from the water layer. This water layer was washed twice, using 50 ml of dichloromethane, after which the combined organic layers were dried over magnesium sulphate. The filtrate obtained after removal of the drying agent through filtration was concentrated through evaporation to yield 14.0 g of residue. This residue was dissolved in 100 ml of toluene, after which 4 drops of concentrated sulphuric acid were added and the resulting reaction mixture was refluxed for 30 minutes. After cooling to room temperature, the mixture was washed once using 50 ml of water. The toluene was removed through evaporation, after which the residue was distilled under a vacuum. Yield: 4.0 g of 2-methylindene (30%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][NH2:33]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28][O:27][CH3:26])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: COCCNCCN
Product: COCCNCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12

Procedure:
The title compound was prepared in analogy to Example 3-1 1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N-(2-methoxyethyl)ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 455, 1H NMR (400 MHz, CD3OD) δ ppm 8.06-8.04 (d, J=7.6 Hz, 1 H), 7.88-7.86 (m, 2 H), 7.73-7.70 (m, 2 H), 7.59-7.56 (m, 2 H), 6.01 (s, 1 H), 5.33 (s, 2 H), 4.55 (s, 2 H), 3.88-3.78 (m, 2 H), 3.72 (s, 2 H), 3.67-3.65 (t, J=4.8 Hz, 2 H), 3.45-3.42 (t, J=6 Hz, 2 H), 3.38 (s, 3 H), 3.30-3.28 (m, 2 H), 2.45 (s, 3 H).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:12][CH2:11][C@H:10]([O:13][S:33]([C:30]3[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[CH2:9]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O[C@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H]2CCN(C(c3ccccc3)c3ccccc3)C2)cc1
Reaction time: 4.5 h
Yield: 68.4 %

Procedure:
(3S)-1-Diphenylmethyl-3-hydroxypyrrolidine (4.00 g) was dissolved in methylene chloride (11 mL), and the solution was stirred under cooling with ice. Triethylamine (3.3 mL) was added dropwise to the reaction mixture, and p-toluenesulfonyl chloride (3.61 g) was added to the resultant mixture, followed by stirring at room temperature for 12 hours and then at 40° C. for 4.5 hours. Since the starting materials partially remained unconsumed, triethylamine (1.1 mL) and p-toluenesulfonyl chloride (1.5 g) were added to the reaction mixture and then stirred for 24 hours. The reaction mixture was extracted with water and chloroform, and the organic layer was dried over sodium sulfate. The drying agent was removed through filtration, and the filtrate was concentrated under reduced pressure, to thereby yield crystalline residue. The residue was subjected to silica gel chromatography, to thereby give the target compound (4.40 g, yield 68.5%). The thus-obtained compound was purified through recrystallization from isopropyl alcohol.
Reaction SMILES: Cl[C:2]1[C:3]([F:23])=[CH:4][C:5]2[C:6]([CH:22]=1)=[N:7][C:8]1[N:9]([CH:19]3[CH2:21][CH2:20]3)[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][NH:35][CH2:34][CH2:33][NH:32]2)=[CH:27][CH:26]=1>C(N(CC)CC)C>[CH:19]1([N:9]2[C:8]3[N:7]=[C:6]4[CH:22]=[C:2]([N:35]5[CH2:34][CH2:33][NH:32][CH:31]([C:28]6[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=6)[CH2:36]5)[C:3]([F:23])=[CH:4][C:5]4=[CH:14][C:13]=3[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)[CH2:21][CH2:20]1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(Cl)c(F)cc3cc2c1=O
Reactant: Fc1ccc(C2CNCCN2)cc1
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2nc3cc(N4CCNC(c5ccc(F)cc5)C4)c(F)cc3cc2c1=O
Yield: 37.4 %

Procedure:
(RS)-1-Cyclopropyl-7-fluoro-8-[3-(4-fluorophenyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo [b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 11 below, but starting with 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (2 g), (RS)-2-(4-fluorophenyl)piperazine (6.534 g) and triethylamine (9 cc). The reaction mixture is concentrated under reduced pressure (20 kPa) at a temperature in the region of 60° C. The dry extract is taken up with water (20 cc) and acetic acid (0.5 cc). The insoluble matter is drained and washed with water (2×5 cc). After 1 recrystallization in a mixture of dimethylformamide (37 cc) and ethanol (37 cc), (RS)-1-cyclopropyl-7-fluoro-8-[3-(4-fluorophenyl) -1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid (1.07 g) is obtained in the form of a yellow solid, m.p. 306° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:10][N:11]([CH3:26])[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[C:17]2[S:22](Cl)(=[O:24])=[O:23].Cl>C([O-])(O)=O.[Na+].CC(C)=O.C(N(CC)CC)C>[CH3:10][N:11]([CH3:26])[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[C:17]2[S:22]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:24])=[O:23]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: NCCCCCC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN(C)c1cccc2c(S(=O)(=O)NCCCCCC(=O)O)cccc12
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a stirred solution of 6-aminohexanoic acid (1.5 g, 11.4 mmol) in 1 M NaHCO3 (45 as added 5-(dimethylamino)naphthalene-1-sulfonyl chloride (0.63 g, 2.33 mmol) in acetone (10 mL) and triethylamine (2 mL). The solution was stirred for 1 h, acidified to pH 3 with 2 N HCl, extracted with ethyl acetate (3×15 mL). The organic layer was washed with water (15 mL) and brine (15 mL), dried over Na2SO4. The solvent was evaporated and purified by flash chromatography using CH2Cl2-MeOH to afford 6-(5-dimethylaminonaphthalene-1-sulfonamido)hexanoic acid as a green sticky oil (0.76 g, 92%). 1H NMR (CDCl3, 400 MHz) δ 10.66 (br, 1H), 8.46 (d, 1H, J=8.4 Hz), 8.33 (d, 1H, J=8.4 Hz), 8.19 (d, 1H, J=7.2 Hz), 7.44 (m, 2H), 7.09 (d, 1H, J=7.6 Hz), 5.66 (br, 1H), 2.85 (m, 2H), 2.79 (s, 6H), 2.08 (t, 2H, J=8.8, 7.6 Hz), 1.32 (m, 4H), 1.12 (m, 2H); 13C NMR (100 MHz) δ 179.29, 151.67, 135.03, 130.18, 129.72, 129.58, 129.25, 128.26, 123.16, 119.01, 115.20, 45.30, 42.88, 33.98, 29.07, 25.74, 24.01.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.COP([CH2:17][C:18](=[O:20])[CH3:19])(=O)OC.C([O-])([O-])=O.[K+].[K+]>O>[O:20]=[C:18]([CH3:19])/[CH:17]=[CH:1]/[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: COP(=O)(CC(C)=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)/C=C/c1ccc(C#N)cc1
Temperature: 0 °C
Yield: 71.9 %

Procedure:
A two necked flask was charged with 4-formyl-benzonitrile (20.0 g, 0.152 mol) and (2-oxo-propyl)-phosphonic acid dimethyl ester (30.4 g, 0.18 mol) and cooled down at 0° C. K2CO3 (42.16 g, 0.305 mol) in H2O (45 mL) was added dropwise. Stirring was continued over night at RT. The product was extracted with EtOAc, and the organic phase was dried over Na2SO4. Flash chromatography (SiO2, Heptane/EtOAc 1:1) afforded 18.7 g (72%) of the title compound as alight yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5](Cl)=[N:6][CH:7]=1.[C:10](#[N:12])[CH3:11].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5]([CH2:11][C:10]#[N:12])=[N:6][CH:7]=1
Reactant: CC#N
Reactant: Clc1cc(Br)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCc1ncc(Br)cc1Cl
Yield: 84.9 %

Procedure:
27.0 g of 5-bromo-2,3-dichloropyridine was dissolved in 450 ml of anhydrous tetrahydrofuran and 7.33 g of acetonitrile was added at ambient temperature under argon. 262 ml of lithium hexamethyldisilazide (1N solution in tetrahydrofuran) was added dropwise over a period of 45 min, during which the temperature rose to 35° C. Subsequently, the reaction mixture was stirred at ambient temperature for 1h, then the reaction mixture was poured into 800 ml of cold water and was extracted with two 1 L portions of diethyl ether. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. 29.4 g of crude material was obtained as a brown oil. It was purified by chromatography on silica gel, using heptane/ethyl acetate (9:1) as a eluent. Thus, 23.4 g of (5-bromo-3-chloro-pyridin-2-yl)-acetonitrile was obtained as a orange oil. 1H-NMR (CDCl3): 8.60 ppm (s, 1H), 7.92 ppm (s, 1H), 4.00 ppm (s, 2H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[CH:11]=2)[S:6][CH:7]=1)[CH3:2].[C:17](OC1C=CC(Cl)=C(Cl)C=1Cl)(=[O:22])[CH2:18][C:19]([O-])=[O:20]>C1(C)C(C)=CC=CC=1>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]3[C:19](=[O:20])[CH:18]=[C:17]([OH:22])[N:16]=[C:12]3[CH:11]=2)[S:6][CH:7]=1)[CH3:2]
Reactant: O=C([O-])CC(=O)Oc1ccc(Cl)c(Cl)c1Cl
Reactant: CCc1csc(CCc2ccnc(N)c2)n1
Solvent: Cc1ccccc1C
Product: CCc1csc(CCc2ccn3c(=O)cc(O)nc3c2)n1
Temperature: 140 °C
Reaction time: 3 h
Yield: 21.9 %

Procedure:
4-[2-(4-Ethyl-1,3-thiazol-2-yl)ethyl]-2-pyridinamine (480 mg, 2.044 mmol) dissolved in xylene (10 ml) was added with trichlorophenyl malonate (1 g, 2.160 mmol) and refluxed by heating at 140° C. The reaction solution was stirred for 3 hours and returned to room temperature. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=80:1→50:1→5:1) to obtain 135 mg (22%) of orange crystals.