Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[NH:5][C:6]([CH3:31])=[C:7]([P:24]2(=[O:30])[O:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[C:9]=1[C:10]([O:12][CH3:13])=[O:11].Cl>CC(C)=O>[CH:3]([C:4]1[NH:5][C:6]([CH3:31])=[C:7]([P:24]2(=[O:30])[O:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:21])[F:22])[C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: COC(=O)C1=C(C(OC)OC)NC(C)=C(P2(=O)OCCCO2)C1c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CC(C)=O
Product: COC(=O)C1=C(C=O)NC(C)=C(P2(=O)OCCCO2)C1c1ccccc1C(F)(F)F
Yield: 81.8 %

Procedure:
The dimethylacetal compound (1.43 g) obtained in Example 2 was dissolved in 6 ml of acetone, 1 ml of 6N hydrochloric acid was added thereto with ice cooling and stirring, the mixture was allowed to stand, stirred at ambient temperature for 1 hour, and purified by treating the same as that in Example 4 to give 1.06 g of oily product.
Reaction SMILES: S(Cl)(C)(=O)=O.[CH2:6]([N:8]([CH:11](O)[CH2:12][CH3:13])[CH2:9][CH3:10])[CH3:7].[C:15]([NH:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1)(=[O:19])[CH2:16][CH2:17][CH3:18].C([O-])([O-])=[O:29].[K+].[K+]>C(Cl)Cl.CN(C=O)C>[CH2:6]([N:8]([CH2:11][CH2:12][CH2:13][O:29][CH2:18][CH2:17][CH2:16][C:15]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[CH2:9][CH3:10])[CH3:7]
Reactant: CCC(O)N(CC)CC
Reactant: O=C([O-])[O-]
Reactant: CCCC(=O)Nc1ccc(O)cc1
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)CCCOCCCC(=O)Nc1ccccc1
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
Mesyl Chloride (6.0 mmol) was added dropwise at 0° C. to a stirred solution of N,N-diethylaminopropanol (6.0 mmol), TEA (6.0 mmol) in anhydrous DCM (6 mL), and the mixture was stirred at the same temperature for 10 min, and at room temperature for additional 1 h. After the removal of the solvent in vacuo, the solid residue was mixed with 4-butyramidophenol (5.0 mmol), and K2CO3 (10 mmol) in anhydrous DMF (10 mL), following general procedure B. The crude product is purified using silica gel column chromatography 5% MeOH/DCM as eluent to yield 4-(N,N-diethylaminopropoxy)butyranilide (1.4 g).
Reaction SMILES: Cl.C(=O)(O)O.[CH:6]1([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH2:15][NH2:16])[CH2:10][CH2:9][CH2:8][CH2:7]1.[O-:22][C:23]#[N:24].[Na+]>O.C1COCC1>[CH:6]1([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH2:15][NH:16][C:23]([NH2:24])=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: N#C[O-]
Reactant: COc1ccc(CN)cc1OC1CCCC1
Agent: Cl
Agent: O=C(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNC(N)=O)cc1OC1CCCC1
Yield: 97 %

Procedure:
25 ml of 5N HCl was added to a solution of 31.54 g of 3-cyclopentyloxy-4-methoxy-benzylamine carbonate and 8.30 g of sodium cyanate in 440 ml of water and 50 ml of THF over 15 minutes. After 3 hours another 0.83 g of sodium cyanate was added. After 20 hours the solid was collected, washed with water containing 5% of THF, suspended in 2.21 of ether and collected to give the title compound as a white solid (28.55 g) mp 134-5° C.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([C:29]([F:32])([F:31])[F:30])[CH:4]=[C:5]([O:7][CH2:8][CH:9]([OH:28])/[CH:10]=[CH:11]/[CH:12]2[CH:16]([CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:15]([OH:26])[CH2:14][CH:13]2[OH:27])[CH:6]=1.[CH3:33]O>CC(O)=O>[OH:27][C@@H:13]1[CH2:14][C@H:15]([OH:26])[C@H:16]([CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:33])=[O:24])[C@H:12]1/[CH:11]=[CH:10]/[C@@H:9]([OH:28])[CH2:8][O:7][C:5]1[CH:6]=[CH:1][CH:2]=[C:3]([C:29]([F:31])([F:30])[F:32])[CH:4]=1
Reactant: O=C(O)CCC/C=C\CC1C(O)CC(O)C1/C=C/C(O)COc1cccc(C(F)(F)F)c1
Reactant: CO
Solvent: CC(=O)O
Product: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O

Procedure:
To fluprostenol in MeOH at 0° C. was added TMS-CH2N2 until the solution persisted a yellow color. AcOH (2 drops) were added to quench excess TMS-CH2N2 and the solvents were evaporated. Column chromatography 90%-100% EtOAc/Hexanes gave pure (Z)-methyl 7-((1R,2R,3R,5 S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-1-enyl)cyclopentyl)hept-5-enoate (9).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH2:14][C:15]([O:17]CC)=[O:16])[O:9][CH2:8][CH2:7]2>C(O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH2:14][C:15]([OH:17])=[O:16])[O:9][CH2:8][CH2:7]2
Reactant: CCOC(=O)CC1OCCc2cc(Br)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1OCCc2cc(Br)ccc21

Procedure:
Sodium hydroxide (1N, 19.8 ml) is added to ethyl (6-bromoisochroman-1-yl)acetate (LXXVII, 3.96 g, 13.2 mmol) in ethanol (20 ml). The mixture is stirred for 2 hr, at which time the ethanol is removed under reduced pressure. The residue is acidified with hydrochloric acid (4N, approximately 6 ml) and extracted with ether. The organic phase is separated and is washed with dilute aqueous hydrochloric acid, dilute aqueous hydrochloric acid /saline, and saline, dried over magnesium sulfate, and concentrated under reduced pressure. The (6-bromoisochroman-1-yl)acetic acid (LXVIII) thus obtained is stirred at 0° with THF (20 ml) and borane-methyl sulfide (3.75 ml, 39.6 mmol) is added over several minutes. After stirring at 0° for 3.5 hr, the mixture is allowed to slowly warm to 20°-250 and methanol is added to quench excess borane, until no further gas evolution is observed. The mixture is then concentrated under reduced pressure and methanol is again added and removed under reduced pressure. This procedure is repeated twice and the residue is then partitioned between dichloromethane, aqueous sodium bicarbonate and saline. The organic phase is separated, dried over sodium sulfate and concentrated to give 2-(6-bromoisochroman-1-yl)ethanol (LXXIX), NMR (CDCl3) 2.04, 2.21, 2.65, 3.02, 3.70-3.87, 4.17, 4.92, 6.93 and 7.28 δ.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])=[CH:4][C:3]=1[CH:18]=O.[CH3:20][NH:21][CH2:22][CH2:23][C:24]#[N:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:24]([CH2:23][CH2:22][N:21]([CH2:18][C:3]1[CH:4]=[C:5]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:6]=[CH:7][C:2]=1[F:1])[CH3:20])#[N:25]
Reactant: CNCCC#N
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(C=O)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN(CCC#N)Cc1cc(C#Cc2cncc(C#N)c2)ccc1F
Reaction time: 5.5 h
Yield: 43 %

Procedure:
Dissolve 5-(4-fluoro-3-formylphenylethynyl)nicotinonitrile, (prepared as described in PREPARATION 38) (100 mg, 0.40 mmol) in dichloroethane (2 mL) and treat with N-methyl-β-alaninenitrile (0.041 mL, 0.44 mmol) and sodium triacetoxyborohydride (110 mg, 0.52 mmol). After stirring for 5.5 h, quench with water (2 mL), dilute with dichloromethane and extract three times with 0.5 N hydrochloric acid, but thin layer chromatography shows some product still remaining in the organic phase. Add 1 N sodium hydroxide to the aqueous layer until it is basic then extract twice with ethyl acetate. Combine the dichloromethane layer with the ethyl acetate extracts and wash with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter, and concentrate. Purify by silica gel chromatography, eluting with 90:10 to 80:20 dichloromethane:ethyl acetate, to give the title compound as a white crystalline solid (55 mg, 43%).
Reaction SMILES: [CH:1]([S:4][C:5]1[S:6][C:7]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[N:8][N:9]=1)([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1>ClCCl>[CH:1]([S:4]([C:5]1[S:6][C:7]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[N:8][N:9]=1)=[O:24])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)Sc1nnc(S(=O)(=O)C(C)C)s1
Solvent: ClCCl
Product: CC(C)S(=O)c1nnc(S(=O)(=O)C(C)C)s1

Procedure:
13.3 g 2-isopropylthio-5-isopropylsulfonyl-1,3,4-thiadiazole are dissolved in 50 ml dichloromethane and to the solution is added drop by drop at 10° to 15° C. under agitation and cooling a solution of 8.63 g m-chloroperbenzoic acid in 200 ml dichloromethane. The reaction mixture is stirred for another thirty minutes, then extracted with aqueous soda ash solution for removing the m-chlorobenzoic acid, the organic phase is separated and dried with magnesium sulfate. After distilling off the solvent a residue is obtained, which is recrystallized from acetonitrile.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[OH:30][CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][C:34]1=[O:38]>O1CCOCC1>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([O:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][C:34]4=[O:38])[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: O=C1CCCN1CCO
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OCCN4CCCC4=O)c3)nc12

Procedure:
From 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and 1-(2-hydroxyethyl)-2-pyrrolidone in dioxane. ES-MS m/e (%): 520 (M+Na+, 47), 498 (M+H+, 100). Analogously to Example 7 there were obtained:
Reaction SMILES: [CH3:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]([N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[C:5](=[O:24])[CH:4]([NH:25]C(=O)OCC2C=CC=CC=2)[N:3]=1.C([O-])=O.[NH4+]>[Pd].CO.O>[NH2:25][CH:4]1[N:3]=[C:2]([CH3:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]([N:16]([CH3:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:15])[C:5]1=[O:24]
Reactant: CC1=NC(NC(=O)OCc2ccccc2)C(=O)N(CC(=O)N(C)c2ccccc2)c2ccccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC1=NC(N)C(=O)N(CC(=O)N(C)c2ccccc2)c2ccccc21
Reaction time: 1 h
Yield: 84.5 %

Procedure:
A mixture of 5% palladium on carbon (300 mg) and phenylmethyl [2,3-dihydro-5-methyl-1-[2-(methylphenylamino)-2-oxoethyl]-2-oxo-1H-1,4-benzodiazepin-3-yl]carbamate (500 mg) in MeOH-water 4:1(40 ml) at 40° under nitrogen was treated with ammonium formate (201 mg) and the mixture stirred at 40° for 1 h. The mixture was cooled to 23° and was filtered through hyflo. The filtrate was evaporated in vacuo and the residue partitioned between 2 N sodium carbonate solution and chloroform. The organic phase was dried and the solvent evaporated in vacuo. The residue was purified by chromatography, elution with MeOH-DCM (1:9) gave the title compound(302 mg).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:34]=[C:33]([CH2:35][CH2:36][NH2:37])[O:32][N:31]=2)=[CH:26][CH:25]=1.O>CN1CCCC1=O>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:37][CH2:36][CH2:35][C:33]2[O:32][N:31]=[C:30]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH:34]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: NCCc1cc(-c2ccc(F)cc2)no1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCCc1cc(-c2ccc(F)cc2)no1
Temperature: 6 °C
Yield: 63 %

Procedure:
Under a nitrogen atmosphere, triethylamine (14.9 mL, 107 mmoL) was added to a solution of 2,4-dichloro-3-nitroquinoline (17.29 g, 71.15 mol) in anhydrous 1-methyl-2-pyrrolidinone (NMP) (100 mL). The mixture was stirred until it was homogeneous and then was cooled to 6° C. 2-[3-(4-Fluorophenyl)isoxazol-5-yl]ethylamine (14.9 mL, 107 mmol) was added dropwise over a period of 30 minutes; the temperature did not rise above 10° C. during the addition. After the reaction was stirred for 1.75 hours, deionized water (100 mL) was added. A precipitate formed, and the mixture was stirred for 30 minutes. The precipitate was isolated by filtration, and washed with deionized water until the filtrate was pH 8. The filter cake was then washed sequentially with toluene (100 mL) and a small amount of diethyl ether and dried for 18 hours to provide 27.84 g of 2-chloro-N-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-3-nitroquinolin-4-amine as a bright yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.COC1[CH:29]=[CH:28][C:27](OC)=[CH:26]O1.[OH-].[Na+]>CC(O)=O>[CH:17]([C:5]1[CH:4]=[C:3]([O:20][CH3:21])[C:2]([N:1]2[CH:29]=[CH:28][CH:27]=[CH:26]2)=[CH:16][C:6]=1[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N
Reactant: COC1=COC(OC)C=C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1-n1cccc1
Yield: 71.9 %

Procedure:
To a solution of 5-(5-amino-2-Isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.303 g, 1.0 mmol) in 15 mL AcOH was added 2,5-dimethoxypyran (0.152 g, 1.2 mmol). The solution was warmed to reflux. After 2 h the solution was cooled and poured over ice/H2O. The solution was converted to pH=8 with 50% NaOH and extracted with ethyl acetate (3×75 mL). The combined organics were washed with H2O, washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to give a brown solid. Purification via flash chromatography (CH2Cl2/MeOH 97:3) afforded 5-(2-isopropyl-4-methoxy-5-pyrrol-1-yl-phenoxy)-pyrimidine-2,4-diamine (0.244 g, 72%) as a pale yellow solid. (M+H)=340.
Reaction SMILES: [Br:1][C:2]1C=CC(C(O)=O)=C[N:3]=1.F[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=C[CH:13]=1.CC[O:21]C1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:13][CH:12]=[CH:18][C:17]=1[C:15]([NH2:16])=[O:21]
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CN(C)C=O
Product: NC(=O)c1cccnc1Br
Reaction time: 8 h

Procedure:
6-Bromonicotinic acid (5.28 g, 26 mmol) and 4-fluoroaniline (2.90 g, 26 mmol) was dissolved in anhydrous DMF (30 mL). EEDQ was added, and the reaction was allowed to progress overnight at room temperature. The solvent was removed by rotary evaporation, and the crude material was dissolved in hot EtOAc (50 mL). Upon cooling, the product crystallized from the solution. The product was filtered, washed with cold EtOAc to yield 3.29 g (43%) as a white solid. ESI-MS m/z=294.9, 296.8 [M+H]+.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][CH2:10]Br.[F:12][C:13]1[CH:14]=[C:15]([OH:29])[CH:16]=[C:17]([C:19]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)([O:22][CH3:23])[CH2:20][CH3:21])[CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([O:29][CH2:10][C:9]#[C:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:16]=[C:17]([C:19]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)([O:22][CH3:23])[CH2:20][CH3:21])[CH:18]=1
Reactant: CCC(OC)(c1cc(O)cc(F)c1)c1nccs1
Reactant: BrCC#Cc1ccccn1
Agent: Br
Product: CCC(OC)(c1cc(F)cc(OCC#Cc2ccccn2)c1)c1nccs1
Yield: 54 %

Procedure:
Using a similar procedure to that described in Example 8, 3-(2-pyridyl)prop-2-yn-1-yl bromide hydrobromide was reacted with 2-[1-(5-fluoro-3-hydroxyphenyl)-1-methoxypropyl]thiazole to give 2-[1-[5-fluoro-3-(3-(2-pyridyl)prop-2-yn-1-yloxy)phenyl]-1-methoxypropyl]thiazole in 54% yield, as an oil.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.C(O[C:14](=[O:29])[CH2:15][CH2:16][C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[N:19][CH:18]=1)C.O>O1CCCC1>[CH2:22]([N:21]1[C:17]([CH2:16][CH2:15][C:14]([C:3]2[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[CH:4]=2)([C:3]2[CH:4]=[C:5]([CH3:10])[CH:6]=[C:7]([CH3:9])[CH:8]=2)[OH:29])=[CH:18][N:19]=[CH:20]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)CCc1cncn1Cc1ccccc1
Reactant: Cc1cc(C)cc(Br)c1
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C(O)(CCc2cncn2Cc2ccccc2)c2cc(C)cc(C)c2)c1
Temperature: 25 °C

Procedure:
1,06 g of magnesium turnings are covered with 30 ml of dry tetrahydrofuran. To the mixture is then added dropwise a solution of 5-bromo-m-xylene (8,14 g) in 10 ml of dry tetrahydrofuran at such a rate that a smooth reaction is maintained. After the addition is complete, the reaction mixture is refluxed for one additional hour and cooled to room temperature. The reaction mixture is then added dropwise to a solution of 1-benzyl-5-imidazole propionic acid ethyl ester (5,0 g) in 40 ml of tetrahydrofuran at 60° C. After the addition is complete, the reaction mixture is refluxed for 2 hours, cooled and poured into cold water. Tetrahydrofuran is evaporated and to the solution is added conc. hydrochloric acid. The solution is cooled, some ether is added and the precipitate which contains the product as hydrochloride salt is removed by filtration, washed and dried. Yield 4,1 g. M.p. 120°-124° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:13]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]2)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[NH2:26][NH2:27].O.C(OCC)(=O)C>C(O)C(C)C>[F:10][C:9]([F:12])([F:11])[CH:8]([N:13]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]1)[C:5]1[CH:6]=[N:7][C:2]([NH:26][NH2:27])=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(c2ccc(Cl)nc2)C(F)(F)F)C1
Reactant: NN
Solvent: CC(C)CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(c2ccc(NN)nc2)C(F)(F)F)C1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
A solution of tert-butyl (3S)-1-(1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (5.74 g, 15.11 mmol) and anhydrous hydrazine (4.74 mL, 151.1 mmol) in i-BuOH (20 mL) in a sealed tube was stirred at 130° C. for 18 hours. After cooling to ambient temperature, water (10 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with saturated sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give tert-butyl (3S)-1-(2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (5.34 g, 94.1%) as a white foam solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:13])=[C:5]2[OH:23].ClC1C=CC(CNC(C2C=NC3C(C=2O)=CC=C(N[S:47]([CH3:50])(=[O:49])=[O:48])C=3)=O)=CC=1.NC1C=C2C(C(O)=C(C(NCC3C=CC(Cl)=CC=3)=O)C=N2)=CC=1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[OH:23])=[CH:3][C:2]([NH:1][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:11][CH:10]=3)=[O:13])=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)Nc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Reactant: Nc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: Nc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Product: CS(=O)(=O)Nc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1

Procedure:
This compound is prepared from 6-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide using a procedure similar to that used to prepare N-[(4-chlorophenyl)methyl]-4-hydroxy-7-[(methylsulfonyl)amino]3-quinoline-carboxamide from 7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinoline-carboxamide. The product is obtained as a tan powder.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:27])([CH3:26])[CH3:25]>>[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:23][C:24]([NH:27][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:26])[CH3:25]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: COCCOCC(C)(C)N
Product: COCCOCC(C)(C)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 2-(2-methoxy-ethoxy)-1,1-dimethyl-ethylamine (CAN 947723-29-7) as starting materials, MS (EI): m/e=363.2 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:41]=[CH:40][C:22]([O:23][C:24]2[C:29]([F:30])=[CH:28][C:27](/[CH:31]=[C:32](\[CH3:38])/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:26][C:25]=2[F:39])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[N+]=[N-].CP(C)C>C1COCC1.O>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:41]=[CH:40][C:22]([O:23][C:24]2[C:25]([F:39])=[CH:26][C:27](/[CH:31]=[C:32](\[CH3:38])/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:28][C:29]=2[F:30])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccc(S(=O)(=O)NCCOCCOCCOCCN=[N+]=[N-])cc2)c(F)c1
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccc(S(=O)(=O)NCCOCCOCCOCCN)cc2)c(F)c1
Reaction time: 3 h
Yield: 101 %

Procedure:
To a solution of (E)-ethyl 3-(4-(4-(N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-3,5-difluorophenyl)-2-methylacrylate (169 mg, 0.28 mmol) in THF (6 ml) and water (0.6 mL) under nitrogen was added trimethylphosphine (26 mg, 0.34 mmol). After stirring for 3 hours, the solvents were removed at reduced pressure and. The residue was dissolved in water (5 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were dried (Na2SO4) and concentrated to give the title compound (162 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH:5]1[C@@H:10]2[CH2:11][CH2:12][C@H:6]1[CH2:7][CH:8]([C@H:13]([NH:24][S@:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9]2)=[O:4].C(O)(=O)C.[CH3:35][C:36]([CH3:38])=O.C([BH3-])#N.[Na+]>CO>[NH3:1].[CH:36]([NH:1][CH2:2][C:3]([CH:5]1[C@@H:6]2[CH2:12][CH2:11][C@H:10]1[CH2:9][CH:8]([C@H:13]([NH:24][S@:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:7]2)=[O:4])([CH3:38])[CH3:35]
Reactant: CC(C)(C)[S@](=O)N[C@H](Cc1cc(F)c(F)cc1F)C1C[C@H]2CC[C@@H](C1)C2C(=O)CN
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)NCC(=O)C1[C@@H]2CC[C@H]1CC([C@@H](Cc1cc(F)c(F)cc1F)N[S@@](=O)C(C)(C)C)C2
Product: N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (S)-2-Methyl-propane-2-sulfinic acid [(R)-1-[(1S,5R)-8-(2-amino-acetyl)-bicyclo[3.2.1]oct-3-yl]-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide (150 mg, 0.33 mmol) in methanol (3 mL) is added acetic acid until to have pH 5-5.5. After addition of acetone (124 uL, 1.68 mmol), the reaction is stirred at rt during 1 h and sodium cyanoborohydride (43 mg, 0.67 mmol) is added before stirring at rt during 16 h. The reaction is quenched with ethylacetate and an aqueous saturated NaHCO3 solution, the organic phase is dried and evaporated to afford the crude compound before purification onto a SCX-2 cartridge (5 g, DCM/MeOH 1:1, then 2N NH3 in MeOH) to yield the title compound.