Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.N(C(OCC)=O)=NC(OCC)=O.[C:43]([O:47][C:48]([NH:50][CH:51]1[CH:56](O)[CH2:55][CH2:54][N:53]([C:58]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[O:59])[CH2:52]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>O.C1COCC1>[C:43]([O:47][C:48]([NH:50][CH:51]1[CH:56]([N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])[CH2:55][CH2:54][N:53]([C:58]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[O:59])[CH2:52]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
PPh3 (412 mg), phthalimide (252 mg), and diethyl azodicarboxylate (40% in toluene solution) (0.712 ml) were added to a THF (5 ml) solution containing benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypiperidin-1-carboxylate (500 mg), followed by stirring at room temperature for 4 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 15:7). Colorless oily matter of benzyl 3-((tert-butoxycarbonyl)amino)-4-(1,3-dioxoisoindolin-2-yl)piperidin-1-carboxylate (205 mg) was thus obtained.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH:15]S(C(C)(C)C)=O)[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].Cl.O1CCOCC1>CO>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:15])[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CCCC(NS(=O)C(C)(C)C)c1ccccc1-c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CCCC(N)c1ccccc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) slightly yellow solution of methyl 5-([1,1′-biphenyl]-2-yl)-5-(1,1-dimethylethylsulfinamido)pentanoate (270 mg; 0.69 mmol) in MeOH (4 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (0.35 ml; 1.40 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The reaction mixture was then concentrated to dryness under reduced pressure and the colorless solid residue was further dried under HV to give the chlorhydrate salt of methyl 5-([1,1′-biphenyl]-2-yl)-5-aminopentanoate as a colorless solid. LC-MS (conditions A): tR=0.57 min.; [M+H]+: 284.13 g/mol.
Reaction SMILES: [ClH:1].[CH3:2][S:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:21]([OH:44])[CH2:22][NH:23][C:24]([CH3:43])([CH3:42])[CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=3)[C:28]2=[O:41])[CH:10]=[CH:11][C:12]=1[O:13]CC1C=CC=CC=1)(=[O:5])=[O:4].Cl>CO.[Pd]>[ClH:1].[CH3:2][S:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:21]([OH:44])[CH2:22][NH:23][C:24]([CH3:42])([CH3:43])[CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][N:29]([C:32]3[CH:33]=[CH:34][C:35]([NH2:38])=[CH:36][CH:37]=3)[C:28]2=[O:41])[CH:10]=[CH:11][C:12]=1[OH:13])(=[O:4])=[O:5]
Reactant: CC(C)(CCN1CCN(c2ccc([N+](=O)[O-])cc2)C1=O)NCC(O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(CCN1CCN(c2ccc(N)cc2)C1=O)NCC(O)c1ccc(O)c(NS(C)(=O)=O)c1

Procedure:
A solution of 3.7 g of 1-(3-methanesulfonamido-4-benzyloxyphenyl)-2-{1,1-dimethyl-3-[3-(4-nitrophenyl)-imidazolidin-2-on-1-yl]-propylamino}-ethanol hydrochloride in 250 ml of methanol was mixed with 0.2 g of HCl in 10 ml of methanol and, after addition of 0.7 g of 5% palladium/charcoal, the mixture was hydrogenated at 26° C. and under normal pressure. The resulting solution, freed from the catalyst, was evaporated, and the title compound was obtained with a yield of 3.3 g. After recrystallization from methanol the melting point was 225° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.N.[CH3:22][N:23](C)C=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:22]#[N:23])[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: CN(C)C=O
Agent: N
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 0 °C

Procedure:
Ten grams of 2-benzyloxy-6-bromonaphthalene was dissolved in 65 ml of dimethyl formamide, 2.83 grams of cuprous cyanide and 5 to 6 drops of pyridine were added thereto, and the mixture was heated to reflux with stirring for twelve hours. After the reaction was completed, the reaction solution was poured into a mixture of 150 ml of concentrated ammonia water and 150 grams of ice, the mixture was extracted with chloroform, the chloroform extract was washed with diluted hydrochloric acid and then with water, dried with anhydrous sodium sulfate, and the solvent was evaporated therefrom. The resulting residue was subjected to a column chromatography using 200 grams of silica gel and eluted with n-hexane and chloroform mixture (1:1) to afford 2-benzyloxy-6-naphthonitrile, colourless crystals, yield 6.8 grams.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:12][CH:11]=[C:10]([OH:22])[C:9]=3[C:8]2=[O:23])=[CH:4][CH:3]=1.C([OH:28])C>C(O)(=O)C>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([OH:22])[CH:11]=[N+:12]([O-:28])[C:13]=3[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]2=[O:23])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Reactant: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1c2c(c(O)c[n+]1[O-])C(=O)N(Cc1ccc(F)cc1)CC2
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To ethyl 6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (0.5 gm, 1.09 mmol; see Example 8, Step 4) in glacial acetic acid (25 mL) at room temperature under nitrogen was added, with stirring, aqueous peroxide (30% by wt) (1.24 mL, 10.9 mmol). The reaction was warmed to 100° C. and stirred for 1.5 hours. The reaction was allowed to cool, ethanol (1 mL) was added and volatile components were removed under reduced pressure. The resulting oil was placed under high vacuum for 16 hours, then used as is. Alternatively, after cooling, water can be added and the volatile components removed under reduced pressure. The residue can be partitioned between CHCl3 and saturated Na2SO3. The organic extract can be dried with Na2SO4, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][CH:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6](F)[N:5]1[O:12][CH:13]([F:15])[F:14]>C(OCC)C>[NH2:3][CH:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6]([NH:2][CH3:1])[N:5]1[O:12][CH:13]([F:15])[F:14]
Reactant: CN
Reactant: NC1N=C(Cl)N=C(F)N1OC(F)F
Solvent: CCOCC
Product: CNC1=NC(Cl)=NC(N)N1OC(F)F
Reaction time: 8 h

Procedure:
2.9 g (0.093 mol) of gaseous methylamine were passed into a solution of 10 g (0.047 mol) of 2-amino-4-chlorodifluoromethoxy-6-fluoro-1,3,5-triazine in 150 ml of diethyl ether at 0° C. in the course of 20 minutes, while stirring. Stirring was continued for one hour at 0° C. and overnight at 22° C. Washing with water, drying and evaporating down gave 9.4 g (89.5% of theory) of the title compound of melting point 143° C. (decomposition).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:23](#[N:27])[CH2:24][C:25]#[N:26].CC(C)([O-])C.[K+].Cl>O1CCOCC1>[C:25]([CH:24]([C:23]#[N:27])[C:11]1[C:12]([F:14])=[C:13]2[C:8]([C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][N:4]2[CH:1]2[CH2:2][CH2:3]2)=[CH:9][C:10]=1[F:16])#[N:26]
Reactant: N#CCC#N
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(C(C#N)C#N)c(F)cc2c1=O
Temperature: 25 °C

Procedure:
2.7 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylate and 1.1 g of malononitrile are initially introduced into 30 ml of dioxane. 1.91 g of potassium tert-butoxide are added in portions. The mixture is warmed to 50° for 4 hours, cooled to room temperature, and acidified using HCl, and the red solid is isolated. It is recrystallized from glycol monomethyl ether.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH:15](OCC)=[O:16]>>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][CH:15]=[O:16])[CH2:3]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: CCOC=O
Product: CC(C)(C)OC(=O)N1CCCC(NC=O)C1

Procedure:
The title compound of Example 4 (10.1 g, 50.5 mmol) was dissolved in ethyl formate (50 mL) and the solution was refluxed overnight when TLC (solvent system A) showed the reaction to be complete. The solvent was evaporated in vacuo and the residue was dried under high vacuum to give the product (11.5 g, quantitative) as a colorless oil: 1H-NMR (CDCl3) ∂8.16. (s, 1H), 6.03 (20%), 5.77 (80%) (br s, 1H), 4.06 (m, 1H), 3.22-3.58 (complex m, 4H), 1.20-1.89 (complex m, 4H), 1.46 (s, 9H). CIMS (MH+ calcd for C11H20N2O3): 229. Found (MH+): 229; HRMS (M+ calcd for C11H20N2O3): 228. 1474. Found (M+): 228. 1469.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18]CC3C=CC=CC=3)=[CH:15][CH:16]=2)[C:11]([OH:26])=[CH:10][C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.C(O)(=O)C.[C].[Pd]>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[C:11]([OH:26])=[CH:10][C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(O)c2cc(OCc3ccccc3)ccc2n1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1cc(O)c2cc(O)ccc2n1Cc1ccccc1
Yield: 66.9 %

Procedure:
A solution of the title compound of Step (1) (2.8 g) in a mixture of methanol (180 ml) and acetic acid (75 ml) was hydrogenated at atmospheric pressure in the presence of 10% palladium-carbon (2.0 g) until no further uptake of hydrogen was observed. The reaction mixture was then filtered and the filtrate was evaporated to dryness. The solid residue was crystallized to give the title compound (1.4 g). That the expected product was obtained was confirmed by the spectral data: MS: m/e 267 (M.+).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:50]1[C:55]2[CH:56]=[CH:57][C:58]([C:60]3[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=3)=[CH:59][C:54]=2[O:53][CH2:52][CH2:51]1>CN(C=O)C>[O:50]1[C:55]2[CH:56]=[CH:57][C:58]([C:60]3[CH:61]=[C:62]([NH:66][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:63]=[CH:64][CH:65]=3)=[CH:59][C:54]=2[O:53][CH2:52][CH2:51]1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2ccc3c(c2)OCCO3)c1
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: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5c(c4)OCCO5)c3)c(=O)oc12
Temperature: 25 °C
Yield: 76.5 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.067 mmol) and HATU (0.028 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-phenylamine (0.015 g, 0.067 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 79% yield: LCMS (ESI) m/z 430 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](F)[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:7]=1.[NH3:17]>C(O)C.CO>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([NH2:17])[CH:3]=1
Reactant: N
Reactant: O=[N+]([O-])c1c(F)cc(Br)cc1-n1cccn1
Solvent: CO
Solvent: CCO
Product: Nc1cc(Br)cc(-n2cccn2)c1[N+](=O)[O-]
Temperature: 80 °C
Yield: 86 %

Procedure:
To a solution of 1-(5-bromo-3-fluoro-2-nitro-phenyl)-1H-pyrazole (240 mg, 0.84 mmol) in ethanol (3 mL) was added ammonia (3 mL, 2N in methanol. The resulting mixture was heated in a sealed tube at 80° C. for 16 hours then concentrated in vacuo. The residue was purified by column chromatography over silica gel eluted with ethyl acetate:hexanes (1:3) to afford 205 mg (86%) of the title compound as a yellow solid. 1H NMR (CDCl3) δ 5.20 (br s, 2H), 6.50 (t, 1H), 6.9 (d, 1H), 7.1 (d, 1H), 7.7 (d, 1H), 7.8 (d, 1H). MS M+1 283, M+1+2 285.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][C@@:7]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:12][C:11](=[O:13])[N:10]([C@H:14]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[CH2:23])=[CH:18][CH:17]=2)[CH3:15])[CH2:9][CH2:8]1.[CH2:30]1[CH2:34][O:33][CH2:32][CH2:31]1>>[CH3:32][O:33][C:34]1[CH:30]=[CH:31][C:6]([CH2:7][O:3][CH2:4][CH2:5][CH2:6][C@@:7]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:12][C:11](=[O:13])[N:10]([C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([CH:22]=[CH2:23])=[CH:20][CH:21]=3)[CH3:15])[CH2:9][CH2:8]2)=[CH:5][CH:4]=1
Reactant: C1CCOC1
Reactant: C=Cc1ccc([C@H](C)N2CC[C@](CCCO)(c3ccccc3)OC2=O)cc1
Agent: [H-]
Agent: [Na+]
Product: C=Cc1ccc([C@H](C)N2CC[C@](CCCOCc3ccc(OC)cc3)(c3ccccc3)OC2=O)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (180 mg, 4.4 mmol) in THF (5 mL) was added a solution of (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (800 mg, 2.2 mmol) in THF (10 mL) at 0° C. The resulting mixture was stirred for 30 min. Then PMBCI (520 mg, 3.3 mmol) was added to the above mixture. The mixture was stirred for 3 h. The reaction was quenched with aqueous NH4Cl solution. The organic phase was separated, and concentrated to give the crude (R)-6-(3-(4-methoxybenzyloxy)propyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one, which was used for the next step without purification (460 mg, 46%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH3:28])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: CNCCOC
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Product: COCCN(C)CCCCOc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and N-(2-Methoxyethyl)Methylamine were converted to yield {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine, MS: 405 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:23]2[CH2:27][CH2:26][CH:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[CH2:24]2)=[C:6]([CH:22]=1)[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:23]2[CH2:27][CH2:26][CH:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:34]=3)[CH2:24]2)=[C:6]([CH:22]=1)[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2N2CCC(Oc3ccc(C(F)(F)F)cc3)C2)cc1
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NC(=O)c1cc(Cl)cnc1N1CCC(Oc2ccc(C(F)(F)F)cc2)C1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.3 %

Procedure:
To a solution of methyl 4-((1S)-1-(5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinamido)ethyl)benzoate (D191) (50 mg, 0.091 mmol) in 1,4-dioxane (3 ml) and water (1 ml) lithium hydroxide monohydrate (5.8 mg, 0.14 mmol) was added and the resulting mixture was stirred at room temperature for 2 days. Solvents were evaporated in vacuo. The residue was diluted with water (5 ml) and 1M HCl (15 ml) and extracted with ethylacetate (3×20 ml). Collected organics, after solvent evaporation, afforded the title compound (E57) (40 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[N:16]([CH3:17])[CH2:15][CH2:14][N:13]([CH2:18][CH2:19][CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N:30]4[CH:34]=[N:33][N:32]=[CH:31]4)[CH:28]=3)[NH:23][CH:22]=2)[CH2:12]1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1.CO.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH2:1]([NH:8][CH2:9][CH:11]1[N:16]([CH3:17])[CH2:15][CH2:14][N:13]([CH2:18][CH2:19][CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N:30]4[CH:31]=[N:32][N:33]=[CH:34]4)[CH:28]=3)[NH:23][CH:22]=2)[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1C(=O)NCc1ccccc1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1CNCc1ccccc1
Temperature: 25 °C
Yield: 45.1 %

Procedure:
To a solution of 3-(N-benzylaminocarbonyl)-4-methyl-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperazine (29 mg, 0.06 mmol) in THF (5 mL) at room temperature, under nitrogen, was added borane-THF (1.0 mL of a 1.0M solution in THF, 1.0 mmol). The mixture was heated at reflux for 18 h, then cooled to room temperature. MeOH (2 mL) was added and the solvents evaporated. The residue was dissolved in EtOH (10 mL), and K2CO3 (17 mg, 0.13 mmol) was added. The mixture was heated at 75° C. for 20 h, before the solvent was evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2 :MeOH:NH3 (95:5:1), to afford the amine (12 mg, 45%) as a gum. The title compound was characterised as its hydrogen oxalate salt. 1H nmr (360 MHz, d6 -DMSO) δ 1.80-1.96 (2H, m), 2.31 (3H, s), 2.37-2.62 (4H, m), 2.66-2.79 (3H, m), 2.80-3.06 (6H, m), 3.98 (1H, d, J=13.4 Hz), 4.03 (1H, d, J=13.4 Hz), 7.28-7.50 (8H, m), 7.78 (1H, s), 9.02 (2H, s), 11.12 (1H, br s). MS (ES+) 444 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:19])=[C:15]([Cl:18])[N:16]=3)[C:11](=[O:20])[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]2)[CH:7]=1.Cl[CH2:29]CCl.CO.C=O>[Pd].C(O)(=O)C>[Cl:18][C:15]1[N:16]=[C:17]2[C:12]([C:11](=[O:20])[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9][N:8]2[C:6]2[CH:7]=[C:2]([NH:1][CH3:29])[C:3]([F:27])=[CH:4][C:5]=2[F:26])=[CH:13][C:14]=1[F:19]
Reactant: CCOC(=O)c1cn(-c2cc(N)c(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Reactant: ClCCCl
Agent: [Pd]
Agent: C=O
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(-c2cc(NC)c(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Reaction time: 16 h

Procedure:
Ethyl 1-(5-amino-2,4-difluorophenyl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (500 mg) was added to a mixture of 10 ml of 1,2-dichloroethane, 5 ml of methanol and 0.5 ml of acetic acid together with 100 mg of 37% formalin. Using 0.08 g of 10% palladium on carbon, hydrogenation was carried out for 16 hours. After the catalyst was filtered off, the filtrate was concentrated in vacua. The residue was dissolved in 50 ml of chloroform, washed with an aqueous solution of 50% sodium carbonate, dried over anhydrous magnesium sulfate, and then concentrated in vacua. The residue was subject to chromatography using 20 g of silica gel (eluting solution: chloroform) to give 150 mg of the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([F:14])[C:11]([F:13])=[CH:12][C:7]=3[N:6]=[C:5]2[C:15]2[CH:16]=[C:17]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=[N:19][CH:20]=2)[CH2:3][CH2:2]1.[H-].[Na+].I[CH3:28]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([F:14])[C:11]([F:13])=[CH:12][C:7]=3[N:6]=[C:5]2[C:15]2[CH:20]=[N:19][CH:18]=[C:17]([C:21]([O:24][CH3:28])([CH3:22])[CH3:23])[CH:16]=2)[CH2:3][CH2:2]1
Reactant: CI
Reactant: CC(C)(O)c1cncc(-c2nc3cc(F)c(F)cc3n2C2CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(C)(C)c1cncc(-c2nc3cc(F)c(F)cc3n2C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 2-[5-(1-Cyclopropyl-5,6-difluoro-1H-benzimidazol-2-yl)pyridin-3-yl]propan-2-ol (from Example 38 Step E) (0.086 g, 0.26 mmol) in tetrahydrofuran (1.3 mL) was added sodium hydride (60% dispersion in mineral oil, 0.026 g, 0.65 mmol). After 1 hour, iodomethane (0.024 mL, 0.389 mmol) was added. The reaction was then warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (30-60% ethyl acetate in hexanes) provided the title compound: LCMS m/z 344.03 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.09 (d, J=1.9 H, 1 H), 8.79 (d, J=2.0 Hz, 1 H), 8.29 (t, J=2.0, 2.0 Hz, 1 H), 7.58 (dd, J=10.3, 7.3 Hz, 1 H), 7.40 (dd, J=9.7, 7.1 Hz, 1 H), 3.59-3.57 (m, 1 H), 3.16 (s, 3 H), 1.63 (s, 3 H), 1.60 (s, 3 H), 1.20-1.17 (m, 2 H), 0.79-0.76 (m, 2 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1>[Pd]>[C:6]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=[CH:2][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Product: NS(=O)(=O)c1ccccc1-c1ccccc1

Procedure:
In Scheme 1 the compounds of the invention, 1, are prepared in 4 steps. Sulfonylation of valine methyl ester with 4-bromo-benzenesulfonyl chloride was carried out in the presence of Hunig base to give sulfonamide Intermediate 1. This 4-bromo-benzenesulfonamide was furthered coupled with boronate ester using Palladium catalyst under Suzuki coupling condition to provide biphenyl sulfonamide Intermediate 2. Biphenyl sulfonamide Intermediate 2 was then alkylated with various alkylating reagents to provide biphenyl sulfonamide ester (Intermediate 3). Hydrolysis of Intermediate 3 was carried out using bases such as NaOH, or LiOH to form the final product 1.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([OH:31])[CH2:25]OS(C)(=O)=O)=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:32])[CH2:4][CH3:5])[CH3:2].[CH2:33]([CH2:35][NH2:36])[OH:34]>>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH:24]([OH:31])[CH2:25][NH:36][CH2:35][CH2:33][OH:34])=[CH:21][CH:22]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:32])[CH2:4][CH3:5])[CH3:2]
Reactant: NCCO
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)COS(C)(=O)=O)cc3)no2)cc1C
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)CNCCO)cc3)no2)cc1C
Yield: 17.3 %

Procedure:
The title compound (16 mg) is prepared starting from rac-methanesulfonic acid 3-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-2-hydroxy-propyl ester (100 mg, 208 μmol) and ethanolamine (64 mg, 1.04 mmol) in analogy to Example 168 step b); LC-MS: tR=0.63 min; [M+1]+=445.07; 1H NMR (CDCl3): δ1.10 (t, J=7.0 Hz, 6H), 2.25 (s, 3H), 2.53 (s br, 2H), 2.59-2.67 (m, 5H), 2.77-2.90 (m, 5H), 3.69 (t, J=5.0 Hz, 2H), 3.72 (s, 2H), 3.95-4.03 (m, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.66 (s, 1H), 8.08 (d, J=8.0 Hz, 2H).