Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:13]2)=[O:11])[CH2:5][CH2:4]1.[Cl:34][Si](C)(C)C>CC(CC)=O>[ClH:34].[CH3:33][N:2]([CH3:1])[C:3]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:13]2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(=CC(=O)N2CCCC(c3c[nH]c4ccccc34)C2)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-dimethylamino-4-phenylcyclohexylidene)-1-[3-(1H-indol-3-yl)-piperidine-1-yl]-ethanone (316 mg, 0.716 mmole) was dissolved in ethyl methyl ketone (4 ml) and chlorotrimethylsilane (0.14 ml, 1.1 mmole) was added. After 1.5 hours the 2-(4-dimethylamino-4-phenylcyclohexylidene)-1-[3-(1H-indol-3-yl)-piperidine-1-yl]-ethanone hydrochloride was obtained as a diastereoisomer mixture in the form of a colourless compound with an m.p. of 177°-180° C. in a yield of 89% (305 mg) (Example 54).
Reaction SMILES: [CH3:1][C:2]([NH:9][C:10](=[O:35])[CH:11]([OH:34])[C@@H:12]([NH:22][C:23](=[O:33])[C@@H:24]([NH2:32])[CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].C(N(CC)CC)C.[N:43]1([C:49](Cl)=[O:50])[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>CN(C=O)C>[CH2:15]([O:14][CH2:13][C@H:12]([NH:22][C:23](=[O:33])[C@@H:24]([NH:32][C:49]([N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=[O:50])[CH2:25][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[CH:11]([OH:34])[C:10](=[O:35])[NH:9][C:2]([CH3:1])([CH3:8])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)CC(C)(C)NC(=O)C(O)[C@H](COCc1ccccc1)NC(=O)[C@@H](N)CC1CCCCC1
Reactant: O=C(Cl)N1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(C)(C)NC(=O)C(O)[C@H](COCc1ccccc1)NC(=O)[C@H](CC1CCCCC1)NC(=O)N1CCOCC1
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
N1-(1,1,3,3-tetramethylbutyl)-(3S)-3-[(2S)-2-amino-3-cyclohexylpropanoyl]amino-4-(benzyloxy)-2-hydroxybutanamide (360 mg, 0.7 mmole) was dissolved in DMF (7 mL), followed by addition of addition of triethylamine (205 ul, 1.5 mmole) and stirring under N2 for 15 min. 4-Morpholinecarbonyl chloride (93 ul, 0.8 mmole) was added. Stirring was continued overnight and DMF was removed under reduced pressure. The solution was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporation. Purification by chromatography (silica, Hexane/EtOAc with 10% MeOH, Rf=0.5) afforded N4-[(1S)-2-((1S)-1-[(benzyloxy)methyl]-2-hydroxy-3-oxo-3-[(1,1,3,3-tetramethylbutyl)amino]propylamino)-1-(cyclohexylmethyl)-2-oxoethyl]-4-Morpholinecarboxamide as a white solid (280 mg, 63%).
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][C@H:5]([OH:9])[CH2:6][O:7][CH3:8].F[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1>CC(N(C)C)=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([O:9][C@H:5]([CH2:6][O:7][CH3:8])[CH2:4][NH2:3])=[N:12][CH:13]=1
Reactant: Fc1ccc(F)nc1
Reactant: COC[C@@H](O)CN
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC[C@H](CN)Oc1ccc(F)cn1
Reaction time: 1 h
Yield: 40.7 %

Procedure:
Suspend sodium hydride (60% in mineral oil, 13.56 g, 339.1 mmol) in dimethylacetamide (245.7 mL) and add a solution of (2S)-1-amino-3-methoxy-2-propanol (31.0 g, 147.4 mmol) in dimethylacetamide (59.0 mL) over 30 minutes. Stir for one hour; then add 2,5-difluoropyridine (17.03 mL, 162.17 mmol) over a 30 min interval; and stir at ambient temperature for an additional 1.5 hours. Slowly add water (930 mL) to quench the reaction. Extract the resulting mixture with EtoAc (4×300 mL) and combine the organic extracts. Dry the combined extracts over magnesium sulfate; filter and concentrate the filtrate under reduced pressure. Purify via flash column chromatography using a gradient of 0 to 10% EtOAc in DCM to give the title compound as a brown oil (12.0 g). MS (m/z): 201 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccc(F)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(F)cc1Nc1ccccc1

Procedure:
Methyl 2-bromo-4-fluorobenzoate (1.00 g), aniline (0.47 mL), palladium(II) acetate (0.048 g), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.214 g) and Cs2CO3 (2.08 g) in toluene (12 mL) were stirred at 90° C. for 24 hours. The reaction was concentrated and chromatographed on silica gel with 5-50% ethyl acetate/hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([Cl:8])=[CH:4][C:3]=1[OH:9]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)c(O)cc1Cl
Temperature: 0 °C
Yield: 31 %

Procedure:
2,5-dichlorophenol (72 g, 440 mmol) were slurried in 100 ml dichloromethane which resulted in an endothermic reaction. To this mixture were slowly added 30 ml (480 mmol) concentrated nitric acid. The reaction was allowed to reach and maintain reflux. The mixture was stirred until it reached ambient temperature and all materials remained in solution. 50 g of ice were added and solids precipitated. The mixture was filtered cold and washed with 25 ml dichloromethane, 50 ml dichloromethane, then twice with 25 ml dichloromethane to yield 28.4 g of 2,5-dichloro-4-nitrophenol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7]Cl)=[CH:3][CH:2]=1.[N+:9]([C:12]1[O:16][C:15]([CH:17]=[CH:18][C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:23]2[CH:22]=[CH:21][N:20]=[C:19]2[CH:18]=[CH:17][C:15]2[O:16][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)=[CH:3][CH:2]=1
Reactant: ClCc1ccncc1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ncc[nH]2)o1
Product: O=[N+]([O-])c1ccc(C=Cc2nccn2Cc2ccncc2)o1

Procedure:
Using the same general procedure of Example 1, the captioned compound was prepared using 4-picolyl chloride and 2-[2-(5-nitro-2-furyl)vinyl]imidazole. Recrystallization from ethanol-water gave an orange solid product melted 130°-131°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.[F:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1Br>>[F:24][C:25]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:26]=1[C:6]1[CH:5]=[CH:4][C:3]([C:17]2[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[C:2]([F:1])[CH:7]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Product: Nc1cnc(-c2ccc(-c3ccc(C(F)(F)F)cc3F)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-fluoro-4-(trifluoromethyl)bromobenzene. MS (ESI): mass calcd. for C17H10F5N3, 351.08; m/z found, 351.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.11-7.97 (m, 2H), 7.90-7.83 (m, 2H), 7.71 (d, J=8.1, 1H), 7.61-7.54 (m, 2H), 6.78 (s, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:10][N:9]=1.[CH2:25]([OH:34])[CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33].O>CN(C=O)C>[OH:34][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:10][N:9]=1
Reactant: O=[N+]([O-])c1ccc(/C=C/c2ccc(Cl)nc2)cc1
Reactant: OCCOCCOCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(/C=C/c2ccc(OCCOCCOCCO)nc2)cc1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
The mixture of potassium carbonate (158.7 mg, 1.15 mmol), compound 3 (100 mg, 0.38 mmol) and triethylene glycol (576 mg, 3.8 mmol) in anhydrous DMF (5.0 ml) was sealed in a microwavable vial (from Biotage) and subjected to microwave irradiation (Biotage Initiator system) at 180° C. for 25 min. After cooling to room temperature, water was added and reaction mixture was extracted with ethyl acetate. Organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified with PTLC (4% MeOH in DCM as developing solvent) gave product 7 (110 mg, Yield: 77%): 1H NMR (200 MHz, CDCl3): δ.8.20 (3H, m), 7.83 (1H, d, d, J=8.6 Hz, J2=2.4 Hz), 7.61 (2H, d, J=8.8 Hz), 7.10 (2H, m) 6.84 (1H, d, J=8.6 Hz), 4.53 (2H, t, J=4.8 Hz), 3.88 (2H, t, J=4.8 Hz), 3.71 (6H, m), 3.61 (2H, m), 2.10 (1H, b), HRMS (EI) m/z calcd. for [C19H22N2O6]+ 374.1478.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].O=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl.CO>[C:1]([O:4][C@@H:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CCNc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CC[C@H](OC(C)=O)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-2,3-diphenyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-8-yl acetate (Intermediate HBS) (46 mg, 0.133 mmol) in DCE (7 ml) was added ethyl 7-oxoheptanoate (68.8 mg, 0.4 mmol) followed by sodium triacetoxyborohydride (226 mg, 1.065 mmol). The reaction mixture was left to stir at room temperature overnight under an atmosphere of nitrogen. A further portion of ethyl 7-oxoheptanoate (71.8 mg, 0.417 mmol) was added. The reaction mixture was left to stir for a further 5 hours under an atmosphere of nitrogen. Water (20 ml) was added and the resulting mixture was extracted with EtOAc (3×20 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated to give a crude oil. The resulting crude product was purified by chromatography on silica eluting with 0-40% EtOAc/iso-hexane to afford an oil. The compound was passed through a pre-conditioned Isolute SCX-2 SPE column loading with MeOH and eluting with 1M ammonia in MeOH (20 ml) to afford the title compound;
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:18]([F:19])=[C:17]2[C:9]([C:10]3[CH:11]=[CH:12][C:13](B(O)O)=[C:14]([F:20])[C:15]=3[CH2:16]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[CH2:33]([C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:34][CH2:35][CH2:36][CH3:37]>O.C1(C)C=CC=CC=1.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>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[C:15](=[C:14]([F:20])[C:13]([C:41]4[CH:40]=[CH:39][C:38]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:43][CH:42]=4)=[CH:12][CH:11]=3)[CH2:16][C:17]=2[C:18]=1[F:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2c(c1F)Cc1c-2ccc(B(O)O)c1F
Reactant: CCCCCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCc1ccc(-c2ccc3c(c2F)Cc2c-3ccc(OCCCC)c2F)cc1

Procedure:
12 mmol of 7-butoxy-1,8-difluorofluorene-2-boronic acid (Example 6, 1st stage), 20 ml of ethanol, a solution of 24 mmol of sodium carbonate in 20 ml of water and 1 mol % of tetrakis(triphenylphosphine)palladium(0) are added to a solution of 12 mmol of 4-n-pentylbromobenzene in 40 ml of toluene. The mixture is heated to boiling until the reaction is complete. After cooling, the mixture is admixed with 100 ml of water, the phases are separated and the aqueous phase is extracted with toluene. The combined organic phases are washed with saturated NaCI solution and dried over sodium sulfate, and the solvents are removed under reduced pressure. The crude product is chromatographed on silica gel (2:5 dichloromethane/heptane) and recrystallized from heptane. 2-Butoxy-1,8-difluoro-7-(4-n-pentylphenyl)fluorene is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=1)#[CH:2].[Cl:16][C:17]1[N:22]=[CH:21][C:20](I)=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:16][C:17]1[N:22]=[CH:21][C:20]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=2)=[CH:19][N:18]=1
Reactant: C#Cc1ccc(CC(C)NC(C)=O)cc1
Reactant: Clc1ncc(I)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC(C)Cc1ccc(C#Cc2cnc(Cl)nc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 1.20 g (5.96 mmol) N-(1-(4-ethynylphenyl)propan-2-yl)acetamide (I58.3) in 10 mL THF are added 1.43 g (5.96 mmol) 2-chloro-5-iodopyrimidine, 418 mg (0.60 mmol) bis(triphenylphosphine)dichloropalladium, 56.8 mg (0.30 mmol) CuI and 2.03 mL (11.9 mmol) DIPEA. The reaction mixture is stirred at r.t. for 4 h. The solvent is removed in vacuo and the residue is purified by column chromatography (silica gel, DCM/MeOH 98/2).
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][NH:6][CH2:7][CH:8]([CH3:10])[CH3:9])C.[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]=[S:24]>>[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]1[N:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[CH2:5][C:4](=[O:11])[S:24]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CCOC(=O)CNCC(C)C
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC(=O)CN1CC(C)C

Procedure:
N-Isobutylglycine ethyl ester was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C11a to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidin-5-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[CH3:22][O:23][C:24](=[O:35])[C:25]([CH3:34])([CH3:33])[NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[NH2:29].C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:22][O:23][C:24](=[O:35])[C:25]([CH3:34])([CH3:33])[NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[NH:29][C:10](=[O:12])[C:9]([CH3:14])([CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: COC(=O)C(C)(C)NC(=O)C(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(C)(C)NC(=O)C(C)(C)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
N-tert-butoxycarbonyl α,α-dimethylglycine 1 (3.20 g, 15.7 mmol) and α,α-dimethylglycyl α,α-dimethylglycine methyl ester trifluoroacetate 5 (4.98 g, 15.7 mmol) were dissolved in DMF (40 mL). N,N-Diisopropylethylamine (2.06 g, 15.9 mmol) and HOBt hydrate (2.41 g, 15.7 mmol) were added together with more DMF (10 mL). The solution was cooled to 0° C. (ice bath) and EDC hydrochloride (3.32 g, 17.3 mmol) added in portions together with additional DMF (10 mL). The reaction mixture was stirred for 15 min at 0° C., after which the ice bath was removed and stirring continued for 43 h at room temperature. The solvent was evaporated and the residue taken up in EtOAc (150 mL). The solution was washed with 1 M aqueous H2SO4 (3×50 mL), 7.5% (w/w) K2CO3 solution (3×50 mL) and saturated brine (50 mL). After dilution with EtOAc (100 mL) the solution was dried with anhydrous MgSO4 and the solvent evaporated affording an off-white solid (3.20 g, 52%), with spectral characteristics in accordance with literature data6; 1H NMR (200 MHz, DMSO-d6) δ 7.59 (s, 2H, NH(Aib2)/NH(Aib3)), 7.21 (s, 1H, NH(Aib1)), 3.53 (s, 3H, OCH3), 1.41 (s, 9H, (CH3)3), 1.33 (s, 6H, CH3), 1.28 (s, 6H, CH3), 1.25 (s, 6H, CH3); 13C NMR (75 MHz, DMSO-d6) δ 174.4, 173.8, 173.2, 155.1, 78.7, 55.8, 55.4, 54.9, 51.6, 28.1, 24.8, 24.6, 24.6; HRMS (m/z): [M+Na]+ calcd. for C18H33N3O6Na, 410.2267. found, 410.2269; Anal. Calcd. for C18H33N3O6: C, 55.80; H, 8.58; N, 10.84. Found: C, 55.9; H, 8.7; N, 11.0.
Reaction SMILES: [CH:1]([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH2:29])=[CH:13][CH:14]=2)[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:47]=[C:48]([O:50][CH3:51])[CH:49]=1)[C:44](Cl)=[O:45]>ClCCl>[CH:1]([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH:29][C:44](=[O:45])[C:43]3[CH:47]=[C:48]([O:50][CH3:51])[CH:49]=[C:41]([O:40][CH3:39])[CH:42]=3)=[CH:13][CH:14]=2)[CH:9]=1)(=[O:6])=[O:7])([CH3:3])[CH3:2]
Reactant: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(N)ccc3c2O)cc1
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(NC(=O)c4cc(OC)cc(OC)c4)ccc3c2O)cc1
Reaction time: 16 h
Yield: 39.6 %

Procedure:
7-Amino-4-hydroxy-3-(4-methoxy-phenylazo)-napthalene-2-sulfonic acid isopropyl ester (Example 6, 200 mg, 0.48 mmol ) was dissolved in dichloromethane (3 mL) and diisopropylethylamine (160 μL, 114 mg, 0.96 mmol ) was added. 3,5-Dimethoxybenzoyl chloride (111 mg, 0.6 mmol ) was added under nitrogen. The reaction mixture was allowed to stir for 16 h. The suspension was filtered to provide the title compound (110 mg, 0.19 mmol, 40% ) as a red solid: NMR (DMSO-d6): δ 10.72 (s, 1H). 8.46 (s, 1H), 8.32 (d, 9 Hz, 1H), 8.05 ( d, 9 Hz, 1H), 7.80 (d, 9 Hz, 3H), 7.12 (m, 4H), 6.79 (s, 1H), 4.86 (m, 1H), 3.86 (m, 9H), 1.22 (d, 6 Hz, 6H). Analytical HPLC: 87% pure. MS (ES-NEG): [M−H] 578; Anal. Calc. for C29H29N3O8S: C, 60.09, H, 5.04, N, 7.25. Found: C, 57.60, H, 5.17, N, 6.88.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:30]([CH3:31])=[CH:29][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C:40]([CH3:42])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.O>[C:1]([O:5][C@@H:6]([C:10]1[C:30]([CH3:31])=[CH:29][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]4[CH2:28][CH2:27][N:26]([CH:40]([CH3:42])[CH3:39])[CH2:25][CH2:24]4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: Cc1cc2nc(-c3cccc(N4CCNCC4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2nc(-c3cccc(N4CCN(C(C)C)CC4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(piperazin-1-yl)phenyl)benzo[d]thiazol-6-yl)acetic acid (30 mg, 0.055 mmol) in MeOH (1 mL) was added acetone (0.20 mL), acetic acid (0.08 mL), and sodium triacetoxyborohydride (58 mg, 0.27 mmol). Stirred at rt for 18 h then 60° C. for 3 h (reaction not to completion). H2O added (1 mL) and purified using reverse phase HPLC, eluting by 2-100% acetonitrile in H2O with 0.1% TFA to give the product. 1H NMR (400 MHz, CD3OD) δ 7.83 (s, 1H), 7.68 (m, 2H), 7.58 (m, 3H), 7.43 (t, J=8 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 5.25 (s, 1H), 4.02 (m, 2H), 3.60 (m, 4H), 3.12 (m, 3H), 2.61 (s, 3H), 1.43 (d, J=7 Hz, 6H), 0.97 (s, 9H). LCMS-ESI+: calc'd for C33H39ClN3O3S: 592.2 (M+H+); Found: 592.3 (M+H+).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([OH:28])=[O:27].C(N(CC)CC)C>O>[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](=[CH:14][C:13]1[CH:16]=[CH:17][C:10]([S:9][CH3:8])=[CH:11][CH:12]=1)[C:26]([OH:28])=[O:27]
Reactant: Cc1ccccc1CC(=O)O
Reactant: CSc1ccc(C=O)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CSc1ccc(C=C(C(=O)O)c2ccccc2C)cc1
Temperature: 100 °C

Procedure:
A mixture of acetic anhydride (160 mL), 4-(methylthio)benzaldehyde (25.32 g, 166 mmol), 2-methylphenylacetic acid (24.95 g, 166 mmol), and triethylamine (17.89 g, 176 mmol) was heated to reflux for 2.67 hours. The reaction was cooled to 100° C., and water (200 mL) was added through an addition funnel. A clear oil formed that solidified upon chilling with an ice bath. The solid was collected by filtration, and recrystallized from a mixture of ethyl acetate and isooctane to give the desired acid in two crops (18.6 g, 39%): mp 134°-137° C. 1H NMR (CDCl3) 300 MHz 9.80 (br s, 1H), 7.91 (s,1H), 7.28 (m, 3H), 7.12 (d,J=7.5 Hz, 1H), 7.00 (d, J=8.5 Hz, 2H), 6.93 (d, J=8.5 Hz, 2H), 2.42 (s, 3H), 2.16 (s, 3H). High resolution mass spectrum Calc'd. for C17H16O2S: 284.0871. Found: 284.0863.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:18][C:19]#[N:20]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2](=[O:1])[N:3]([CH2:18][C:19]#[N:20])[CH:4]=1
Reactant: Oc1ccc(Br)cn1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: N#CCn1cc(Br)ccc1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
2-Hydroxy-5-bromopyridine (5.000 g, 28.74 mmol), potassium carbonate (14.30 g, 9.283 mL, 103.5 mmol), and sodium iodide (1.077 g, 7.185 mmol) were suspended in chloroacetonitrile (10.85 g, 9.095 mL, 143.7 mmol). The reaction mixture was heated to 60° C. and stirred for 2 hours. The reaction mixture was allowed to cool to room temperature, filtered, and the filtercake was washed with dichloromethane and ethyl acetate. The filtrate was concentrated and purified on 120 g of silica gel utilizing a gradient of 0-100% ethyl acetate in hexanes over 45 minutes to yield the pure product as a beige solid (4.1 g, 67%). 1H NMR (400.0 MHz, DMSO-d6) δ 8.11 (d, J=2.7 Hz, 1H), 7.63 (dd, J=2.8, 9.8 Hz, 1H), 6.49 (d, J=9.8 Hz, 1H), 4.94 (s, 2H).