Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:23])([CH3:22])[CH2:10]OS(C2C=CC(C)=CC=2)(=O)=O)=[C:4]([N+:24]([O-:26])=[O:25])[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:23])([CH3:22])[CH2:10][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:4]([N+:24]([O-:26])=[O:25])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)Nc2ccc(Br)cc2[N+](=O)[O-])cc1
Reactant: C1COCCN1
Product: CC(C)(CN1CCOCC1)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 105 °C

Procedure:
In a 250 mL flask, mix toluene-4-sulfonic acid 2-(4-bromo-2-nitro-phenylamino)-2-methyl-propyl ester (19.5 g, 44 mmol) and morpholine (50 mL). Heat at 100-110° C. for 2 days. Follow the progress of the reaction by HPLC. Cool the reaction and partition between water and EtOAc. Wash the organic layer with water (2×), dry (MgSO4) and concentrate to give 14 g dark oil. Recrystallize from heptane (400 mL) to give 11 g that is 80% pure by HPLC. Recrystallize a second time to give 6.6 g (42%) orange crystals; MS (es) 358, 360 (M+1), HPLC (ISO80-10M) t=3.17 (94%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([N:10]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11]1)[CH2:6]2.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[OH:1][C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([N:10]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:11]1)[CH2:6]2
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C2CC3CCC(C2)C3=O)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C2CC3CCC(C2)C3(O)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of the ketone obtained in Step B (65 mg, 0.21 mmol) in THF (2 mL) cooled in an ice bath was added a 1 M solution of phenyl magnesium bromide in THF (0.25 mL). After being stirred at −78° C. for 3 hours, the reaction was quenched with aqueous ammonium chloride. The resulting solution was extracted with EtOAc 3 times. The combined EtOAc layers were dried over MgSO4 and concentrated. Flash chromatography on silica gel eluting with 5%, 10% and 50% MeOH/CH2Cl2 provided 27 mg of the title compound as a mixture of two isomers (7:3). MS calculated (M+H)+ 387, found 387.1.
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:41])[C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][C@H:36]([N:35]([CH3:41])[CH3:34])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](N(C)C)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 446 [M+H]
Reaction SMILES: N12CCCN=C1CCCCC2.[NH:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[N:19][C:20]3[N:21]([C:23]([CH2:26][C:27]4[CH:28]=[C:29]5[C:34](=[CH:35][CH:36]=4)[N:33]=[CH:32][CH:31]=[CH:30]5)=[CH:24][N:25]=3)[N:22]=2)[CH:14]=[N:13]1.[C:37]([CH:39]=[C:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]1)#[N:38]>C(#N)C>[C:37]([CH2:39][C:40]1([N:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][C:20]4[N:21]([C:23]([CH2:26][C:27]5[CH:28]=[C:29]6[C:34](=[CH:35][CH:36]=5)[N:33]=[CH:32][CH:31]=[CH:30]6)=[CH:24][N:25]=4)[N:22]=3)[CH:14]=[N:13]2)[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45]1)#[N:38]
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Reactant: c1cnc2ccc(Cc3cnc4ncc(-c5cn[nH]c5)nn34)cc2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(-c3cnc4ncc(Cc5ccc6ncccc6c5)n4n3)cn2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (68 μL, 0.46 mmol) was added to a mixture of 6-[2-(1H-pyrazol-4-yl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylquinoline (50.0 mg, 0.153 mmol) and tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate (0.068 g, 0.30 mmol) in acetonitrile (1 mL). The reaction was stirred at 60° C. overnight. After cooling to RT, the mixture was purified by chromatography on silica gel with EtOAc in CH2Cl2 (0-70%) to give the desired product (30 mg, 35.7%). LCMS: (M+H)=550.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]#N)[C:9]2=[O:17])=[CH:4][CH:3]=1.[OH-:18].[Na+].S(=O)(=O)(O)[OH:21]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]([OH:21])=[O:18])[C:9]2=[O:17])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(C#N)c(=O)n1-c1ccc(F)cc1
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Temperature: 120 °C
Yield: 74 %

Procedure:
1-(4-Fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (3 g, 13.1 mmol) was dissolved in conc. sulfuric acid (6.0 mL) and water (6.0 mL), and the mixture was stirred with heating at 120° C. for 20 hr. 8N Aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was washed with ethyl acetate. 2N hydrochloric acid was added to the aqueous layer, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue was washed with diethyl ether and collected by filtration to give the title compound (2.41 g, 74%) as a pale-brown solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[N:11]=1.[F:20][C:21]([F:40])([F:39])[CH2:22][N:23]=[C:24]([NH2:38])[NH:25][C:26]1[S:27][CH:28]=[C:29]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]=C=S)[N:30]=1.[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]\[C:44]([OH:46])=[O:45]>CO.CC(C)=O>[F:19][C:2]([F:1])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][NH:6][C:7]([NH:11][NH:35][CH2:34][CH2:33][CH2:32][CH2:31][C:29]2[N:30]=[C:26]([NH:25][C:24]([NH2:38])=[N:23][CH2:22][C:21]([F:20])([F:39])[F:40])[S:27][CH:28]=2)=[S:8])[N:11]=1.[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]\[C:44]([OH:46])=[O:45]
Reactant: NC(=NCC(F)(F)F)Nc1nc(CCCCN=C=S)cs1
Reactant: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Solvent: CC(C)=O
Product: NC(=NCC(F)(F)F)Nc1nc(CCCCNNC(=S)NNCCCCc2csc(NC(N)=NCC(F)(F)F)n2)cs1
Reaction time: 8 h

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)-guanidino]-4-(4-aminobutyl)thiazole (0.12 g.) and 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-isothiocyanatobutyl]thiazole (0.12 g.) in methanol (3 ml.) was allowed to stand at room temperature overnight. The mixture was then evaporated to dryness and purified by preparative thin layer chromatography using methanol/chloroform/ammonia 85:15:1 v/v/v as developing solvent. The appropriate band was extracted with chloroform/ethanol 1:1 v/v (200 ml.) and the resulting solution evaporated to give a brown gum. This was treated in acetone with excess maleic acid to give 1,3-di[4-(2-[2-(2,2,2-trifluoroethyl)-guanidino]thiazol-4-yl)butylamino)thiourea containing 2.25 equivalents of maleic acid. The n.m.r. spectrum in d6 dimethylsulphoxide containing tetramethylsilane as internal standard (δ=0) included the following resonances (δ):-1.5 (multiplet, 8H); 3.3 (multiplet, 4H); 4.1 (quartet, 4H); 6.5 (singlet, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:12][O:11][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2sc(N)nc12
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COc1cccc2sc(NC(=O)c3ccccc3)nc12

Procedure:
Using 2-amino-4-methoxy-benzothiazole and benzoyl chloride in pyridine the title compound was obtained as a white solid (72% yield), MS: m/e=284.1 (M+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>>[CH2:14]([N:16]([CH2:17][CH3:18])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[C:2]([F:13])([F:12])[F:1])[CH3:15]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CCNCC
Product: CCN(CC)C(=O)c1ccccc1C(F)(F)F
Yield: 97 %

Procedure:
N,N-Diethyl-2-(trifluoromethyl)benzamide was prepared from 2-trifluoromethylbenzoyl chloride and diethylamine according to General Method E1. No purification was needed to obtain 17.2 g of this compound, a 97% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[C:8]([N+:12]#[C-:13])([CH3:11])([CH3:10])[CH3:9].[Br:14][C:15]1[S:19][C:18]([CH:20]=O)=[CH:17][CH:16]=1.Cl(O)(=O)(=O)=O>C(Cl)Cl>[Br:14][C:15]1[S:19][C:18]([C:20]2[N:1]=[C:2]3[CH:7]=[N:6][CH:5]=[CH:4][N:3]3[C:13]=2[NH:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:17][CH:16]=1
Reactant: Nc1cnccn1
Reactant: O=Cc1ccc(Br)s1
Reactant: [C-]#[N+]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: CC(C)(C)Nc1c(-c2ccc(Br)s2)nc2cnccn12
Temperature: 25 °C
Reaction time: 120 h
Yield: 52 %

Procedure:
237 mg (2.50 mmol) of 2-aminopyrazine were dissolved together with 208 mg (2.50 mmol) of tert-butylisonitrile and 0.27 ml (2.50 mmol) of 5-bromothiophene-2-carbaldehyde in DCM (5 ml). After addition of perchloric acid (0.25 ml), the mixture was stirred at RT for 5 d. Washing was then performed with a sat. aq. sodium carbonate solution and a sat. aq. common salt solution. The organic phase was dried over magnesium sulfate, filtered and evaporated under a vacuum. After carrying out column chromatography (EA/DIPE/DCM 2:2:1) with the group, 471 mg (1.3 mmol, 54% of theoretical) of [2-(5-bromothiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-tert-butyl-amine were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH:15]([OH:18])([CH3:17])[CH3:16]>CN(C)C=O>[CH:15]([O:18][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1)([CH3:17])[CH3:16]
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1nc(OC(C)C)ccc1[N+](=O)[O-]

Procedure:
A procedure similar to that described in Preparation 88 was repeated, except that 6.00 g of 6-chloro-2-methylamino-3-nitropyridine (prepared as described in Preparation 66), 1.54 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 2.7 ml of isopropanol and 150 ml of dimethylformamide were used. After working up the product as described in Preparation 88, the resulting crude product was crystallized by trituration with isopropanol, to give 6.10 g of the title compound, melting at 75-76° C.
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:4]1)[CH3:3].[Cl:6][C:7]1[CH:16]=[C:15]([SH:17])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]>>[Cl:6][C:7]1[CH:16]=[C:15]([S:17][CH2:4][C:2]([OH:5])([CH3:3])[CH3:1])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC1(C)CO1
Reactant: COC(=O)c1ccc(S)cc1Cl
Product: COC(=O)c1ccc(SCC(C)(C)O)cc1Cl

Procedure:
8 g of methyl 4-amino-2-chlorobenzoate was dissolved in 16 mL of MeOH, 8 mL of H2O and 8 mL of concentrated hydrochloric acid and was then cooled to 0 C. A solution of 3.9 g of sodium nitrite in 15 mL of H2O was added dropwise over 30 min. The reaction was stirred at 0° C. for an additional 1 h. The cold diazonating mixture was added to a solution of 13.8 g of potassium ethyl xanthate in 10 mL of H2O at 50˜60° C. The reaction was heated to 65° C. for 2 h and monitored by TLC until complete. The mixture was cooled to 25° C. and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. Purified by silica gel chromatography (0-10% ethyl acetate/hexane) to afford methyl 2-chloro-4-(ethoxycarbonothioylthio)benzoate. A solution of 2.6 g of sodium hydroxide in 20 mL of H2O was added to 5.9 g of methyl 2-chloro-4-(ethoxycarbonothioylthio)benzoate in 40 mL of EtOH The reaction mixture was heated to 70° C. for 1 h. Upon completion, the mixture was cooled to 25° C., and then acidified to pH 3 by the addition of 10 N HCl. The solid was filtered and washed with H2O to give 2-chloro-4-mercaptobenzonic acid. 3.8 g of 2-chloro-4-mercaptobenzonic acid in 40 mL of 5% sulfuric acid-methanol was refluxed under nitrogen atmosphere for 3 h. After concentration of the reaction mixture, 10 mL of H2O was added and the resulting mixture was made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to yield methyl 2-chloro-4-mercaptobenzoate. 80 mg of isobutylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford methyl 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoate. 190 mg of methyl 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoate was hydrolyzed via Procedure M to give 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoic acid. 160 mg of 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoic acid was reacted via procedure R to give 2-chloro-4-(2-hydroxy-2-methylpropylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to 2-chloro-4-(2-hydroxy-2-methylpropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-methylpropylsulfonyl)benzamide. MS (Q1) 479.1 (M)+.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]3[C:21]=2[CH:22]=[CH:23][NH:24]3)[C:11]1=[O:30])[CH2:7][CH2:8][CH3:9])C.[C:32]([O-])([O-])=O.[K+].[K+].CI>C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:29][C:27]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][N:24]2[CH3:32])=[C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:3])=[O:31])[C:11]2=[O:30])[CH:28]=1
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(Cl)cc3[nH]ccc23)c2ccccc21
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(Cl)cc3c2ccn3C)c2ccccc21
Temperature: 65 °C
Reaction time: 18 h
Yield: 9 %

Procedure:
3-[3-(6-Chloro-1H-indol-4-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (300 mg, 0.68 mmol), prepared as described in example 72 using the appropriate reagents, was dissolved in acetonitrile (5 mL) and treated with K2CO3 (700 mg, 5.1 mmol), methyl iodide (0.31 mL, 5 mmol) and tetrabutylammonium bromide (161 mg, 0.5 mmol). The resulting mixture was heated at 65° C. for 60 h, filtered, and the solution was treated directly with Amberlyst® A26 (OH— form) (1.5 g, 2 mmol). This mixture was agitated for 18 h, filtered and the resin was washed with several portions of methanol. The product was eluted from the resin with 20% formic acid in methanol (2×2 mL). The eluant was concentrated and the residue was purified by preparative HPLC to provide 26 mg (9%) of the title compound. LCMS (ESMS): m/z 426 (M+H).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]=[C:21]1[CH:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][N:22]1[CH2:33][C:34](O)=[O:35].C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:34](=[O:35])[CH2:33][N:22]2[CH2:23][CH2:24][CH2:25][CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)C1=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To 1-benzhydrylpiperazine (0.238 g, 0.943 mmol), the product from Example 91D (0.200 g, 0.857 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.358 g, 0.943 mmol) in dichloromethane (1.5 mL) was added diisopropylethylamine (0.225 mL, 1.286 mmol), and the reaction mixture was stirred at room temperature. After stirring overnight, the reaction was concentrated and loaded onto a silica gel column (SF25-25, Analogix®, Burlington, Wis.) and eluted using a gradient of 0.5% to 5% methanol/dichloromethane. The product was isolated along with a slightly lower Rf spot. The mixture was rechromatographed over silica gel using a gradient of 5% to 100% ethyl acetate/hexanes to supply the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.38-7.43 (m, 4H), 7.14-7.34 (m, 11H), 4.43 (d, J=15.6 Hz, 1H), 4.24 (s, 1H), 4.00 (d, J=15.6 Hz, 1H), 3.70 (dd, J=7.7, 6.0 Hz, 1H), 3.61-3.66 (m, 2H), 3.52-3.59 (m, 1H), 3.44-3.49 (m, 2H), 3.41 (dd, J=11.6, 5.8 Hz, 1H), 2.37-2.43 (m, 4H), 2.15-2.28 (m, 1H), 1.90-2.03 (m, 2H), 1.77-1.89 (m, 1H); MS (ESI+) m/z 468 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[CH:8]2)[CH3:2].OS(O)(=O)=O.[CH3:20]O>>[CH2:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:20])=[O:13])[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[CH:8]2)[CH3:2]
Reactant: CCc1cc(C(=O)O)cc2cn[nH]c12
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCc1cc(C(=O)OC)cc2cn[nH]c12
Yield: 47 %

Procedure:
To a solution of 7-ethyl-1H-indazole-5-carboxylic acid (500 mg, 2.63 mmol) in MeOH (15 mL) was added conc. H2SO4 (0.25 mL). The mixture was heated at reflux overnight. The solvent was removed under reduced pressure to afford a tan solid that was purified by flash chromatography (40 g column) using 15-30% EtOAc/heptane to afford methyl 7-ethyl-1H-indazole-5-carboxylate (252 mg, 47%).
Reaction SMILES: [OH:1]O.[CH2:3]([C@@H:10]([CH2:26][CH2:27][C@H:28]([CH3:44])[C:29](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:30])C(N1[C@@H](CC2C=CC=CC=2)COC1=O)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O[Li].O.[O-]S([O-])=O.[Na+].[Na+].[C:54]([O-:57])([OH:56])=O.[Na+]>C1COCC1.O>[CH2:3]([C@@H:10]([CH2:26][CH2:27][C@H:28]([CH3:44])[C:29]([OH:30])=[O:1])[C:54]([OH:57])=[O:56])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@@H](CC[C@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: OO
Reactant: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CC[C@H](Cc1ccccc1)C(=O)O)C(=O)O
Reaction time: 0.08 h
Yield: 59 %

Procedure:
An aqueous solution of 50% H2O2 (0.12 mL, 2.1 mmol) was added to a solution of (2R,5S)-2-benzyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-5-methylhexane-1,6-dione (200 mg, 0.352 mmol) in THF (3 mL) and water (1 mL) at 0° C. After 5 min of stirring, LiOH.H2O (44 mg, 1.1 mmol) was added and the reaction mixture was stirred for 1 hr at rt. Saturated aqueous Na2SO3 (0.2 mL) and saturated aqueous NaHCO3 (0.2 mL) were added and the reaction mixture was concentrated to remove the organic solvent. The aqueous solution was extracted with DCM (3 mL) to remove organic impurities. The aqueous phase was then acidified using aqueous 5 N HCl to pH<2. The cloudy mixture was extracted with DCM (2×2 mL). The organic extracts were combined, dried over Na2SO4 and concentrated to give (2R,5S)-2-benzyl-5-methylhexanedioic acid (52 mg, 0.21 mmol, 59% yield) as a white powder. Anal. Calcd. for C14H18O4 m/z 250.1. found: 249.2 (M−): 1H NMR (400 MHz, CDCl3) δ ppm 7.28 (m, 2H), 7.17 (m, 3H), 2.99 (m, 1H), 2.75 (m, 1H), 2.65 (m, 1H), 2.4 (m, 1H), 1.79 (m, 1H), 1.63 (m, 2H), 1.44 (m, 1H), 1.15 (d, J=7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[C:56]([C:57](O)=[O:58])=[CH:55][O:54][N:53]=2)=[CH:48][CH:47]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:13])[CH2:12][CH2:11][N:10]([C:57]([C:56]3[C:52]([C:49]4[CH:50]=[CH:51][C:46]([CH3:45])=[CH:47][CH:48]=4)=[N:53][O:54][CH:55]=3)=[O:58])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Reactant: OC1(c2ccc(F)cc2)CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccc(F)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of 3-(4-fluorophenyl)pyrrolidin-3-ol (9 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (10 mg). MS (ESI, pos. ion) m/z calcd for C21H19FN2O3: 366.1380, found 366.1381.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH:31][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(Nc2cccc(F)c2)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Nc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
A mixture of 4-(3-fluorophenylamino)benzoic acid (0.040 g, 0.173 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.040 g; 0.173 mmol), HATU (0.072 g; 0.190 mmol) and N,N-diisopropylethylamine (0.075 mL; 0.432 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 1 to 10% ethyl acetate in dichloromethane) to yield 0.027 g (39%) of the title compound as a colourless solid.