Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:14][CH2:13]2)=[CH:8][C:5]=1C=O)([O-:3])=[O:2].[C:30](O)(=O)[CH2:31][C:32]([OH:34])=[O:33].N1CCCCC1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:14][CH2:13]2)=[CH:8][C:5]=1[CH:30]=[CH:31][C:32]([OH:34])=[O:33])([O-:3])=[O:2]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C(=O)N2CCN(c3ccc([N+](=O)[O-])c(C=O)c3)CC2)cc1OC
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(C(=O)N2CCN(c3ccc([N+](=O)[O-])c(C=CC(=O)O)c3)CC2)cc1OC
Temperature: 80 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
2-Nitro-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]benzaldehyde (4 g) was dissolved in 20 ml of pyridine followed by adding 2.1 g of malonic acid and 0.4 ml of piperidine, and the mixture was stirred at 80° C. for 4 hours. After evaporating pyridine and piperidine the reaction mixture was poured in a dilute aqueous hydrogen chloride solution and extracted with methylene chloride. After washing the methylene chloride layer with water the solvent was distilled off and methanol was added to the residue. After cooling, crystals which formed were collected by filtration to give 3.7 g of 2-nitro-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-cinnamic acid, m.p. 197°-202° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:19]=[C:20]([N:37]2[CH2:41][C@H:40]([CH2:42][N:43]3[CH:47]=[CH:46][N:45]=[N:44]3)[O:39][C:38]2=[O:48])[CH:21]=[CH:22][C:23]=1[C:24]1[CH:25]=[N:26][C:27]([C:30]2[CH2:34][C@@H:33]([CH2:35]O)[O:32][N:31]=2)=[CH:28][CH:29]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:35][C@H:33]1[O:32][N:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]3[CH:22]=[CH:21][C:20]([N:37]4[CH2:41][C@H:40]([CH2:42][N:43]5[CH:47]=[CH:46][N:45]=[N:44]5)[O:39][C:38]4=[O:48])=[CH:19][C:18]=3[F:17])=[CH:25][N:26]=2)[CH2:34]1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCCCC(=O)O)C(=O)OC(C)(C)C
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The crude carbamate prepared as above (2 g, 8.6 mmol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1: 1 g, 2.28 mmol), 4-dimethylaminopyridine (0.05 g, 0.4 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.28 g, 6.67 mmol) were combined in DMF (10 ml). The suspension was allowed to stir for 16 hours at room temperature, diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 0.5 to 5% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as an off-white solid (1.28 g), melting point: 121° C.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[N:12]=[C:11]([C:13]2[N:14]=[C:15]([NH:18][C:19]([NH2:21])=[S:20])[S:16][CH:17]=2)[CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH2:2][CH3:3].[CH3:22][I:23]>CO>[IH:23].[NH2:21][C:19](=[N:18][C:15]1[S:16][CH:17]=[C:13]([C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:6][NH:5][C:1](=[O:4])[CH2:2][CH3:3])[N:12]=2)[N:14]=1)[S:20][CH3:22]
Reactant: CCC(=O)NCc1cccc(-c2csc(NC(N)=S)n2)n1
Reactant: CI
Solvent: CO
Product: CCC(=O)NCc1cccc(-c2csc(N=C(N)SC)n2)n1
Product: I
Yield: 64.7 %

Procedure:
A suspension of 4-(6-propionylaminomethylpyridin-2-yl)-2-thioureidothiazole (14.67 g) and methyl iodide (7.77 g) in methanol (300 ml) was refluxed for 3 hours. The solvent was removed under reduced pressure. The residue was crystallized from ethyl acetate to afford 2-[(amino)(methylthio)methyleneamino]-4-(6-propionylaminomethylpyridin-2-yl)thiazole hydriodide (13.68 g).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:15])[CH2:11][CH2:12][CH2:13]Cl)=[CH:6][CH:5]=1.C(O)(=O)C>O>[CH:11]1([C:10]([C:7]2[CH:8]=[CH:9][C:4]([OH:3])=[CH:5][CH:6]=2)=[O:15])[CH2:13][CH2:12]1
Reactant: O=C(CCCCl)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1ccc(O)cc1)C1CC1
Temperature: 25 °C
Yield: 119.9 %

Procedure:
Sodium hydroxide in water (50% (w/w), 40.4 mL) was treated over a period of 15 minutes with para-hydroxy-4-chlorobutyrophenone (25.0 g, 137 mmol), followed by additional aqueous sodium hydroxide (25% (w/w), 177 mL). Additional para-hydroxy-4-chlorobutyrophenone (25.0 g, 137 mmol) was added portionwise to the reaction mixture, followed by solid sodium hydroxide (40.4 g). A yellow precipitate formed. After refluxing for 60 minutes, water (50 mL) was added and the resulting mixture was refluxed for another 60 minutes, cooled to room temperature, diluted with water (100 mL) and neutralized with acetic acid. The precipitate was collected by filtration, washed with water, air-dried, and triturated at 40° C. with chloroform (1.5 L). The chloroform solution was dried (MgSO4), filtered, and concentrated. The concentrate was recrystallized from chloroform/hexanes to afford 26.65 g (95%) of the desired product.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:19]=[N:18][C:6]2[NH:7][C:8]3[CH:13]=[N:12][C:11]([C:14]([NH:16][NH2:17])=[O:15])=[CH:10][C:9]=3[C:5]=2[CH:4]=1.[N:20]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>O>[Br:2][C:3]1[CH:19]=[N:18][C:6]2[NH:7][C:8]3[CH:13]=[N:12][C:11]([C:14]([N:16]=[N+:17]=[N-:20])=[O:15])=[CH:10][C:9]=3[C:5]=2[CH:4]=1
Reactant: NNC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (3.0 mL, 90 mmol) was added dropwise to a suspension of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid hydrazide (530 mg, 1.73 mmol) in water (12.4 mL). Once homogeneous, the solution was cooled to 0° C. and a solution of 3N sodium nitrite in water (0.60 mL, 2.0 mmol) was added to the mixture. After 1 h, added another 1.03 eq. of 3N sodium nitrite in water (0.60 mL, 2.0 mmol) and allowed the reaction to warm to ambient temperature over night. After 17 h at room temperature, the reaction was cooled to 0° C. and a solution of 3N sodium nitrite in water (0.60 mL, 2.0 mmol) was added and then warmed to room temperature. The reaction was made basic with a solution of saturated sodium bicarbonate, and the solid precipitate was collected by filtration, washed with water, and dried in a dessicator under vacuum to provide a solid material that was 70% pure by LCMS analysis.
Reaction SMILES: ICI.[F:4][C:5]1([F:35])[C@@H:22]([O:23]C2CCCCO2)[CH2:21][CH2:20][C@@:19]2([CH3:30])[C:6]1=[CH:7][CH2:8][C@@H:9]1[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]1[CH2:11][CH2:12][C@@H:13]2[O:31][CH:32]1[CH2:34][CH2:33]1.Cl>C(OCC)C.O1CCOCC1.[Zn]>[F:4][C:5]1([F:35])[C@@H:22]([OH:23])[CH2:21][CH2:20][C@@:19]2([CH3:30])[C:6]1=[CH:7][CH2:8][C@@H:9]1[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]1[CH2:11][CH2:12][C@@H:13]2[O:31][CH:32]1[CH2:33][CH2:34]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C(F)(F)[C@@H](OC5CCCCO5)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Agent: Cl
Agent: [Zn]
Solvent: C1COCCO1
Solvent: ICI
Solvent: CCOCC
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C(F)(F)[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1

Procedure:
To a suspension of 0.3 g of zinc dust in 3 ml of diethyl ether is added 50 mg of cuprous chloride. The resulting mixture is refluxed for 30 minutes and then 1.06 g of diiodomethane is added. The resulting solution is refluxed for 30 minutes and 0.3 g of 4,4-difluoro-3β-(2-tetrahydropyranyloxy)-17β-ethenyloxyadrost-5-ene is added. The resulting mixture is refluxed for 16 hours and then diluted with 10 ml of diethyl ether and filtered. The solid which is separated is washed with ethyl acetate (3 times, 50 ml) and the combined filtrate and washings are washed with saturated aqueous ammonium chloride and dried over magnesium sulfate. The solvent is then removed under reduced pressure to leave a residual solid which is crude 4,4-difluoro-3β-(2-tetrahydropyranyloxy)-17β-(cyclopropyloxy)androst-5-ene containing some 17β-(cyclopropyloxy)cycloprop[5,6]androstane product. This material is treated with a catalytic amount of hydrochloric acid in aqueous dioxane to remove the tetrahydropyranyl protecting group. The solvent is then removed under reduced pressure to leave a residual crude solid which is purified by reverse phase high-pressure liquid chromatography to give 4,4-difluoro-17β-(cyclopropyloxy)androst-5-en-3β-ol. The compound has the following structural formula: ##STR4##
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([OH:9])[CH2:4]1.Br[CH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:13]=1[C:14]([O:16]C)=[O:15].[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][CH:32]=[C:33]([CH2:35]I)[N:34]=2)=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[O:31][CH:32]=[C:33]([CH2:35][O:9][C@@H:5]3[CH2:6][CH2:7][CH2:8][C@H:3]([CH2:2][O:1][CH2:11][C:12]4[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:13]=4[C:14]([OH:16])=[O:15])[CH2:4]3)[N:34]=2)=[CH:28][CH:29]=1
Reactant: Fc1ccc(-c2nc(CI)co2)cc1
Reactant: COC(=O)c1c(C)cccc1CBr
Reactant: OC[C@@H]1CCC[C@H](O)C1
Product: Cc1cccc(COC[C@H]2CCC[C@@H](OCc3coc(-c4ccc(F)cc4)n3)C2)c1C(=O)O

Procedure:
Reacting cis-3-hydroxymethylcyclohexanol, bromide 4 and iodide 2 in a reverse order relative to Example XXIV gave the product 41 of molecular weight 453.52 (C26H28FNO5); MS(ESI): 454 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[CH3:17])[CH:5]=[CH:6][C:7]=1[CH:8]=O.Cl.[NH2:19][OH:20]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[CH3:17])[CH:5]=[CH:6][C:7]=1[CH:8]=[N:19][OH:20]
Reactant: Cc1cc(O)ccc1-c1ccc(C=O)c(Cl)c1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(O)ccc1-c1ccc(C=NO)c(Cl)c1

Procedure:
The title compound was prepared by reacting 3-chloro-4′-hydroxy-2′-methyl-1,1′-biphenyl-4-carbaldehyde (500 mg, 2.03 mmol) with hydroxylamine hydrochloride (425 mg, 6.10 mmol) in anhydrous tetrahydrofuran (50 mL) and methanol (20 mL) according to Method C to yield 350 mg (57% over two steps) of white solid: mp 169-171° C.; 1H NMR (DMSO-d6): δ 2.19 (3H, s), 6.65-6.70 (2H, m), 7.06 (1H, d, J=8.14 Hz), 7.31 (1H, d, J=8.05 Hz), 7.41 (1H, d, J=1.40 Hz), 7.83 (1H, d, J=8.08 Hz), 8.38 (1H, s), 9.51 (1H, s), 11.69 (1H, s); MS (ESI) m/z 260/262 (M−H)−, 262/264 (M+H)+.
Reaction SMILES: CN(C=O)C.C[O-].[K+].[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[CH3:19])([O-:11])=[O:10].[N:20](OCCCC)=[O:21]>C(O)(=O)C.O>[CH3:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N+:9]([O-:11])=[O:10])[C:13]=1[CH:19]=[N:20][OH:21]
Reactant: CCCCON=O
Reactant: Cc1cccc([N+](=O)[O-])c1C
Agent: C[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1C=NO
Temperature: -40 °C

Procedure:
1200 ml of anhydrous DMF are initially charged in a 4 l reaction flask and cooled to −40° C. At this temperature, 336.5 g (4.56 mol) of potassium methoxide (95%) are added and suspended with stirring. A mixture of 300 g (1.92 mol) of 3-nitro-o-xylene (97%) and 274 g (2.52 mol) of n-butyl nitrite (95%) is then added dropwise at −40° C. over a period of 7 hours (if the mixture is cooled accordingly, the duration of this addition can be reduced as desired; a longer period of addition has not yet been tested; temperature variations between −35 and −45° C. are tolerated). The complete conversion of the starting material is checked by HPLC. The reaction discharge is then added with stirring, at from −5 to 0° C., to a mixture of 300 ml of water and 300 ml of glacial acetic acid. The reaction mixture is then poured onto 6 kg of ice-water and the solid is separated off by filtration (without any problems, filter resistance has not yet been determined) and washed twice with in each case 500 ml of water (careful: the crude product smells strongly). The crude product (HPLC: 96 area %) is purified by suspending the moist solid in 800 ml of toluene for 1.5 h. The solid is filtered off (without any problems, the filter resistance has not yet been determined) and dried at 50° C. in a vacuum drying cabinet.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.C(N([CH2:17][CH3:18])CC)C.C[O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27]>>[CH3:27][O:26][C@@H:25]1[CH2:18][C@H:17]([OH:8])[C@H:22]2[CH2:21][O:20][C@@H:24]1[O:23]2
Reactant: CCN(CC)CC
Reactant: COCCOCCOC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CO[C@@H]1C[C@H](O)[C@H]2CO[C@@H]1O2
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of this compound (9.6 g) in bis-(2-methoxyethyl) ether (100 ml) containing anhydrous p-toluenesulphonic acid (500 mg) was heated under reflux, while passing a stream of nitrogen through the condenser, for 1 h. The cooled solution was neutralised with triethylamine and evaporated at 50° C. and 1 torr to a dark brown oil. Purification by flash chromatography on silica gel gave the title compound (4.5 g, 57%), identical by melting point, optical rotation, 1H-nmr, and 13C-nmr to the compound described in Preparative Example 1.
Reaction SMILES: Br[C:2]1[C:3]([OH:10])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[C:11]([Zn]C#N)#[N:12]>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.CN(C)C=O>[OH:10][C:3]1[C:2]([C:11]#[N:12])=[C:7]([CH3:8])[N:6]=[C:5]([CH3:9])[N:4]=1
Reactant: N#C[Zn]C#N
Reactant: Cc1nc(C)c(Br)c(O)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1nc(C)c(C#N)c(O)n1
Temperature: 140 °C
Reaction time: 12 h
Yield: 98.9 %

Procedure:
A mixture of 5-bromo-2,6-dimethylpyrimidin-4-ol (3.7 g, 18.3 mmol), dicyano zinc (10.7 g, 91.5 mmol) and tetrakis(triphenylphosphine)palladium (6.3 g, 5.1 mmol) and N,N-dimethylformamide (60 mL) was stirred at 140° C. for 12 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give 4-hydroxy-2,6-dimethylpyrimidine-5-carbonitrile as a white solid (2.7 g, 99%). LRMS (M+H) m/z: calcd 149.06. found 149.
Reaction SMILES: ClC1C=CC(N[CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)=C(C=1)C(O)=O.[ClH:23].[CH3:24][O:25][C:26](=[O:49])[C@@H:27]([NH2:48])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:31][CH:30]=1>>[CH3:24][O:25][C:26](=[O:49])[CH:27]([NH:48][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH2:28][C:29]1[C:30]([Cl:23])=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2Oc2ccccc2)cc1
Reactant: O=C(O)c1cc(Cl)ccc1NCc1cccc2ccccc12
Reactant: Cl
Product: COC(=O)C(Cc1ccc(-c2ccccc2Oc2ccccc2)cc1Cl)NCc1cccc2ccccc12
Yield: 92.8 %

Procedure:
5-Chloro-2-[(napthalen-1-yl-methyl)-amino]-benzoic acid (0.1 g, 0.32 mmol) was treated with (2S)-amino-3-(2′-phenoxy-biphenyl-4-yl)propionic acid methyl ester hydrochloride salt (0.123 g, 0.32 mmol) according to the general procedure A to give 2-{5-Chloro-2-[(naphthalene-1-yl-methyl)-amino]-3-(2′phenoxy-biphenyl-4-yl)-propionic acid methyl ester (0.155 g, 75.6%). This methyl ester (0.15 g, 0.23 mmol) was treated with LiOH (2 eq, 1N aqueous solution) according to the general procedure C to give 2-{5-chloro-2-[(naphthalene-1-yl-methyl)-amino]-3-(2′phenoxy-biphenyl-4-yl)-propionic acid (0.13 g, 90.0%) as white solid. 1HNMR (400 MHz, DMSO-d6): 3.36 (dd, 1H), 3.46 (dd, 1H), 4.79–4.88 (m, 1H), 5.10 (d, 2H), 7.01 (d, 1H), 7.18 (d, 2H), 7.26 (d, 1H), 7.33 (t, 1H), 7.50–7.90 (m, 14H), 7.96 (d, 1H), 8.10–8.20 (m, 1H), 8.22–8.30 (m, 1H), 8.32–8.48 (m, 2H), 9.07 (d, 1H), 13.10 (s, 1H). LC/MS (m/z): 627.2 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH2:33][NH2:34])=[CH:23][CH:22]=2)[C:10]1=[O:35])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.Cl[C:40]([O:42][CH3:43])=[O:41]>C(N(CC)CC)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH2:33][NH:34][C:40]([O:42][CH3:43])=[O:41])=[CH:25][CH:26]=2)[C:10]1=[O:35])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)OC(C)(C)C)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A solution of 31 mg (0.066 mmol) of the intermediate obtained in Step C in I mL of methylene chloride at room temperature was treated with 1 drop of triethylamine followed by 5 μL (6 mg, 0.067 mmol, 1 eq.) of methyl chloroformate. The mixture was stirred at room temperature for 1 hour then diluted into 10 mL of ethyl acetate and washed with 5% aqueous citric acid and saturated aqueous sodium chloride. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was purified by medium pressure liquid chromatography on silica, eluting with 5% methanol in ethyl acetate, to give 33 mg (0.062 mmol, 95%) of the product as a colorless glass. 1H NMR (400 MHz, CDCl3): δ 1.38 (s, 9H), 1.91 (m, 1H), 2.43-2.60 (m, 3H), 3.62 (s, 3H), 4.26 (m, 3H), 4.68 (br t, 1H), 4.93 (d, 15 Hz, 1H), 5.18 (d, 15 Hz, 1H), 5.45 (br d, 7 Hz, 1H), 7.13-7.35 (m, 11H), 7.41 (d, 8 Hz, 1H). FAB-MS: calculated for C31H35N3O5 529; found 530 (M+H, 25%), 430 (M-BOC, 100%).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][NH:6][C:7]([C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][N:10]=1)=[O:8])C.CO.O.O[Li].O>C1COCC1>[C:14]1([C:12]2[NH:11][N:10]=[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:20])=[O:3])=[O:8])[CH:13]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reaction time: 2 h
Yield: 38.8 %

Procedure:
To a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid (1.25 g, 0.00665 mol) in DMF (3 mL) was added DIPEA (4.296 g 0.03324 mol), HOBt (1.123 g, 0.00831 mol) and EDCI.HCl (1.593 g, 0.00831 mol) at ambient temperature. After 2 minutes glycine acid ethyl ester hydrochloride (0.928 g, 0.00665 mol) was and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.76 g (42% of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid ethyl ester. LCMS: 274.11 (M+1)+, 96.7%. To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid ethyl ester (0.615 g, 0.0025 mol) in a mixture of THF (10 mL), methanol (5 mL) and H2O (5 mL) was added LiOH.H2O (0.283 g, 0.00675 mol) at ambient temperature. The reaction mixture was stirred at the same temperature for 2 hours. Volatiles were evaporated and the residue was diluted with water, acidified with 10% HCl solution. The resulting precipitate was isolated by filtration, washed water followed by hexane and to afford 0.238 g (38%) of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid. LCMS: 246.08 (M+1)+, 95.60%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.[CH3:46][N:47]1[CH2:52][CH2:51][CH:50]([N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)[CH2:49][CH2:48]1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21]([N:56]3[CH2:55][CH2:54][N:53]([CH:50]4[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]4)[CH2:58][CH2:57]3)=[O:22])[N:20]=2)(=[O:11])=[O:12])=[C:5]([CH3:24])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)O)co2)c(C)c1
Reactant: CN1CCC(N2CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N3CCN(C4CCN(C)CC4)CC3)co2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3-oxazole-4-carboxylic acid (50 mg, 0.14 mmol) was dissolved in DMF (3 mL) and EDCI (32 mg, 0.17 mmol) and HOAt (23 mg, 0.17 mmol) were added. The resulting solution was stirred for 60 min at ambient temperature prior to the addition of a solution of 1-(1-methylpiperidin-4-yl)piperazine (31 mg, 0.17 mmol) in DMF (2 mL) and the reaction stirred at ambient temperature for 18 h. The reaction was diluted with EtOAc (20 mL) and washed with water (2×5 mL), saturated brine (5 mL), dried over Na2SO4 and concentrated in vacuo. The resulting oil was purified using FCC, eluting with 10% MeOH in DCM, to afford the title compound.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH2:16])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])=[CH:10][CH:9]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: C[Si](C)(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[Si](C)(C)CNCCc1ccc(Cl)cc1
Yield: 49.9 %

Procedure:
The compound of formula (P11), wherein n=2 and R″ is chloro, was prepared from a mixture of chloromethyltrimethylsilane (3.7 mL, 42.8 mmol), 2-(4-chlorophenyl)ethylamine (10 g, 64.25 mmol), and K2CO3 (4 g, 28.9 mmol) in acetonitrile (80 mL). The reaction mixture was refluxed for 13 h and after cooling, the precipitate was filtered off and the filtrate concentrated under vacuum. The resulting oil was chromatographed over silica gel (CH2Cl2/MeOH/Et3N: 97/2/1) to yield the above-referenced compound as a colorless oil (5.17 g). 1H NMR (CDCl3): 7.25 (2H, d, J=8.3 Hz), 7.12 (2H, d, J=8.3 Hz), 2.7-2.9 (4H, m), 2.08 (3H, s), 0.95 (1H, br s), 0.02 (9H, s).