Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:20]([O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25])[CH3:21].CN1CCOCC1.O=C1C2C=CC=CC=2N=NN1OS(C)(=O)=O>C(Cl)(Cl)Cl.C(OCC)(=O)C.O>[CH2:20]([O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:25][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:21]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CS(=O)(=O)On1nnc2ccccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 66.4 %

Procedure:
N-Benzyloxycarbonyl-L-proline (1.25 g), L-leucine ethyl ester hydrochloride (1.00 g) and N-methylmorpholine (1.10 ml) are dissolved in chloroform (10 ml) and thereto is added 4-oxo-3,4-dihydro-3-methanesulfonyloxy-1,2,3-benzotriazine (1.20 g). After allowing to stand overnight, to the mixture are added water and ethyl acetate. The ethyl acetate layer is washed and dried, and then the solvent is distilled off to give N-(N-benzyloxycarbonyl-L-prolyl)-L-leucine ethyl ester (1.3 g), melting point: 65°-67° C.
Reaction SMILES: [CH:1]([C:4]1([CH3:21])[C:8](=[O:9])[N:7]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:6]([CH3:20])=[N:5]1)([CH3:3])[CH3:2].N1C(=[O:27])CN=C1>C(Cl)Cl>[C:6]([NH:5][C:4]([CH3:21])([CH:1]([CH3:3])[CH3:2])[C:8]([NH:7][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:9])(=[O:27])[CH3:20]
Reactant: O=C1CN=CN1
Reactant: CC1=NC(C)(C(C)C)C(=O)N1S(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Product: CC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C

Procedure:
The reaction mixture is checked for completeness of formation of 4-isopropyl-2,4-dimethyl-1-(p-tolylsulfonyl)-2-imidazolin-5-one by infrared spectroscopy. The product imidazolin-5-one is then hydrolyzed by diluting the solution with 100 mL of methylene cloride and washing twice with water and once with HCl 10%. The organic layer is concentrated in vacuo and the resulting yellowish oily residue is shaken with ether and allowed to stand. Upon standing the title product precipitates as a white solid, which after filtration, washing and drying has a mp of 202°-203° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([NH:33][CH3:34])=[N:31][CH:32]=1>>[CH3:34][NH:33][C:30]1[CH:29]=[CH:28][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:32][N:31]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CNc1ccc(Br)cn1
Product: CNc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and (5-bromo-pyridin-2-yl)-methyl-amine (example B.45) (168 mg, 0.9 mmol) according to general procedure II. Obtained as a red solid (25 mg, 5%). MS (ISP) 462.0 [(M+H)+]; mp 187° C.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:20])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][C:13](=[O:19])[NH:14]2)([CH3:4])([CH3:3])[CH3:2].[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.N>CN(C)P(=O)(N(C)C)N(C)C>[C:21]([O:20][CH:7]([CH2:6][NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][C:13](=[O:19])[NH:14]2)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)NCC(O)COc1cccc2c1CC(=O)N2
Agent: N
Agent: O=C(OC(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)NCC(COc1cccc2c1CC(=O)N2)OC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
1 g of 4-(3-tert-butylamino-2-hydroxypropoxy)oxindole is dissolved in 20 cc of hexamethylphosphoric acid triamide and the solution is allowed to stand at room temperature for 16 hours together with 7.9 g of benzoic acid and 0.9 g of benzoic acid anhydride. The mixture is poured into ice water, is rendered alkaline with a 10% ammonia solution and is extracted with methylene chloride. The title compound is obtained as evaporation residue of the methylene chloride phase; the hydrogen oxalate of the title compound crystallizes from ethanol. M.P. 200°-203°.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[C:25]3[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=2)[NH:28][CH:27]=[CH:26]3)O1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:12][C:11]([NH:10][S:7]([C:5]1[S:6][C:2]([C:23]2[CH:24]=[C:25]3[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=2)[NH:28][CH:27]=[CH:26]3)=[CH:3][CH:4]=1)(=[O:9])=[O:8])([CH3:14])[CH3:13]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]ccc3c2)OC1(C)C
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: [K+]
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(C(N)=O)c3[nH]ccc3c2)s1
Yield: 59.1 %

Procedure:
5-bromo-N-(1,1-dimethylethyl)-2-thiophenesulfonamide (828 mg, 2.78 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (4.17 mmol, 1.5 eq), potassium carbonate (1.524 g) and Pd(PPh3)4 (50 mg) were heated in Microwave at 150 degree for 15 mins after degassing for 5 mins with argon. The reaction solution was filtered off palladium with PL-thiol MP SPE cartridge, concentrated and purified by HPLC with CH3CN/H2O/0.1% TFA to give 620 mg title compound.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([OH:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9]>O.CC(O)C>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([O-:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9].[Na+:2]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.3 %

Procedure:
A solution of sodium hydroxide (0.63 g) in water:IPA (60:40 v/v, 19 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:IPA (60:40 v/v, 106 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 30 minutes to obtain a pH of 4.14. Then the reaction mixture was cooled to room temperature and stirred for 16 hours. Further cooling was performed using an ice-bath. The precipitate was filtered, washed with IPA (2×25 ml), and dried in a vacuum oven at 50° C. for 23 hours to give 5.2 g of ibandronate sodium crystal form F.
Reaction SMILES: O[C:2]([O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH2:19][CH2:18][CH2:17]2)([CH:4]1[O:9][CH2:8][CH2:7][N:6]([CH:10]([CH3:12])[CH3:11])[CH2:5]1)C.[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH:10]([N:6]1[CH2:7][CH2:8][O:9][CH:4]([CH2:2][O:13][C:14]2[CH:15]=[C:16]3[C:20]([C:19]([CH3:23])=[CH:18][CH2:17]3)=[CH:21][CH:22]=2)[CH2:5]1)([CH3:11])[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)N1CCOC(C(C)(O)Oc2ccc3c(c2)CCC3)C1
Solvent: Cc1ccccc1C
Product: CC1=CCc2cc(OCC3CN(C(C)C)CCO3)ccc21
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A mixture of 3.05 g. of oily 2-(1-hydroxy-1-methyl-5-indanyloxymethyl)-4-isopropylmorpholine, 100 ml. of xylene, and 20 mg. of p-toluenesulfonic acid was refluxed with stirring for 4 hours and then the solvent was distilled off. Then, the residue formed was adsorbed on a silica gel column prepared from 100 ml. of silica gel in chloroform and eluted with ethyl acetate. After removing the first 10 ml. of the ethyl acetate eluate emerging from the column, 200 ml. of the subsequent ethyl acetate eluate was collected and concentrated under reduced pressure to provide 2.1 g. (yield 73.3%) of 4-isopropyl-2-(3-methyl-6-indenyloxymethyl)morpholine. The citrate of the product had a melting point of 159°-161° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[C:17]([C:23]([OH:25])=O)[NH:18]4)=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C@H:26]1([CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]2)[C@@H:35]2[N:30]([CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:29][CH2:28][CH2:27]1>>[C@H:26]1([CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([NH:43][C:23]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[C:14]([O:13][CH2:12][C:9]3[C:8]5[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=5[O:11][CH:10]=3)[CH:22]=[CH:21][CH:20]=4)=[O:25])[CH2:39][CH2:38]2)[C@@H:35]2[N:30]([CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:29][CH2:28][CH2:27]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Reactant: COc1cccc2occ(COc3cccc4[nH]c(C(=O)O)cc34)c12
Product: COc1cccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)c12

Procedure:
This compound is synthesized analogously to example 1 from 4-(4-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (122) (preparation see below) and 1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-ylamine, 61.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15]C(C)(C)C)=[O:14])=[N:11][CH:12]=1.C(O)(C(F)(F)F)=O>ClCCl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cnccn2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2cnccn2)cn1
Reaction time: 10 h

Procedure:
To a solution of tert-butyl 5-(pyrazin-2-yl)picolinate 41-3 (1.11 g, 4.32 mmol) in dichloromethane (4.5 mL) was added TFA (4.5 mL) dropwise at room temperature. The mixture was stirred for 10 hours, and then the solvents were removed by rotary evaporation. The resulting pale yellow oil was further dried under lyophilizer to afford 5-(pyrazin-2-yl)picolinic acid 41-4 in TFA salt as a pale yellow solid. MS m/z 202.1 (M+1)
Reaction SMILES: [CH:1]1(/[CH:4]=[N:5]/[S:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[CH2:3][CH2:2]1.C[N+](C)(C)C.[F-].[Si]([C:22]([F:25])([F:24])[F:23])(C)(C)C.[NH4+].[Cl-]>C1COCC1>[CH:1]1([C@@H:4]([NH:5][S:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[C:22]([F:25])([F:24])[F:23])[CH2:2][CH2:3]1
Reactant: CC(C)(C)S(=O)/N=C/C1CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N[C@H](C1CC1)C(F)(F)F
Temperature: -55 °C

Procedure:
N-[(1E)-Cyclopropylmethylene]-2-methylpropane-2-sulfinamide ((S), 10.0 g, 57.7 mmol) and TMAF (6.45 g, 69.3 mmol) were placed in a flask and dissolved in THF (290 mL). The flask was purged with N2. The solution was cooled to −55° C. and a solution of TMSCF3 (13.53 ml, 87 mmol in 430 mL of THF) was added via syringe slowly. The mixture was stirred at −55° C. until the reaction was complete. The solution was warmed to −10° C. and treated with sat. NH4Cl (10 mL). The mixture was extracted with EtOAc, and the combined organics were dried, and concentrated. The diastereomers were separated by flash chromatography to give the title compound. 1H NMR (600 MHz, CDCl3) δ 3.32 (d, 1H); 2.93 (m, 1H); 1.24 (s, 9H); 1.08 (m, 1H); 0.82 (m, 1H); 0.72 (m, 1H); 0.67 (m, 1H); 0.52 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([OH:12])[CH:5]=1)[CH3:2].[C:15](OCC)(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].N1CCCCC1>C(O)C>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:5]=[C:6]2[C:7]([CH:8]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15](=[O:22])[O:12]2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2ccc(N(CC)CC)cc2oc1=O

Procedure:
--A solution of 4-diethylamino-2-hydroxy-benzaldehyde (29.8 g, 154 mmol) and diethyl malonate (23.8 ml, 157 mmol) in ethanol (185 ml) was treated with piperidine (1.37 ml, 13.9 mmol) and heated under reflux for 4 h. The solution was allowed to cools then concentrated under reduced pressure to approx. half-volume diluted with ether and washed with water, dilute aq. NaOH and water, dried and evaporated under reduced pressure. Trituration of the residue with EtOH (approx. 15 ml) gave yellow crystals which were recrystallised from EtOAc-light petroleum to give the ester 1 as bright yellow prisms (18 the m.p. 76-77° C. A sample recrystallised a second time had m.p. 77-78° C. (Found: C, 66.4; H, 6.7g N, 4.8. C16H9NO4 requires C, 66.4; H, 6.6; N, 4.8%). The discrepancy with the m.p. (87° C.) reported by Kendal et al. (GB 867,592), together with the sharp m.p. and satisfactory analytical result for the present sample suggests that the digits of the reported value may accidently have been transposed.
Reaction SMILES: ClC1C=CC=C([C:8](OO)=[O:9])C=1.[CH3:12][C:13]1[NH:14][C:15](=[O:25])[CH2:16][S:17][C:18]=1[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>CO>[CH3:8][O:9][CH:16]1[C:15](=[O:25])[NH:14][C:13]([CH3:12])=[C:18]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[S:17]1
Reactant: CC1=C(c2ccncc2)SCC(=O)N1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Product: COC1SC(c2ccncc2)=C(C)NC1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.4 %

Procedure:
m-Chloroperbenzoic acid (12 g) was added gradually to a stirred suspension of 5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (10 g) in methanol (400 ml) under ice/water-cooling. The reaction mixture was further stirred at ambient temperature for 3 days. The solvent was removed under reduced pressure and the residue was extracted with ethyl acetate, was washed with saturated sodium bicarbonate aqueous solution and successively with water and was dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in chloroform (about 50 ml) and was chromatographed on activated alumina (200 g, about 300 mesh, manufactured by Wako Pure Chemical Industries, Ltd.) cloumn, using chloroform as an eluant. The solvent was removed under reduced pressure and the residue was crystallized from ether to give the titled compound (6 g, yield 51.7%) as pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH:10]([OH:22])[CH2:11][N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[CH:5]=[CH:6][CH:7]=1.O.[CH3:24][N:25]1[C:29]2[CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=[CH:33][C:28]=2[N:27]=[CH:26]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][N:12]1[CH2:11][CH:10]([OH:22])[CH2:9][NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:31]2[CH:32]=[CH:33][C:28]3[N:27]=[CH:26][N:25]([CH3:24])[C:29]=3[CH:30]=2)[CH:3]=1
Reactant: Cn1cnc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: OC(CNc1cccc(Br)c1)CN1CCc2ccccc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cnc2ccc(-c3cccc(NCC(O)CN4CCc5ccccc5C4)c3)cc21
Temperature: 100 °C
Reaction time: 16 h
Yield: 33.8 %

Procedure:
To a stirred mixture of 1-((3-bromophenyl)amino)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (120 mg, 0.33 mmol) in dioxane:H2O (15 mL, 2:1) was added 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (93.6 mg, 0.33 mmol), Cs2CO3 (323 mg, 0.99 mmol) and then Pd(dppf)Cl2 (10 mg). The mixture was degassed by N2 for 4 times and then stirred at 100° C. for 16 hours. The reaction mixture was quenched with water (30 mL), extracted with EA (30 mL×3). The combined extracts were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the title compound (46 mg, 34%). 1HNMR (CDCl3, 400 MHz) δ: 7.87 (s, 1H), 7.83-7.81 (m, 1H), 7.55-7.52 (m, 2H), 7.29-7.25 (m, 1H), 7.15-7.10 (m, 3H), 7.04-6.98 (m, 2H), 6.92 (s, 1H), 6.66-6.64 (m, 1H), 4.18-4.11 (m, 1H), 3.89-3.83 (m, 4H), 3.70-3.64 (m, 1H), 3.42-3.38 (m, 1H), 3.21-3.14 (m, 1H), 3.02-2.94 (m, 3H), 2.71-2.61 (m, 3H). LCMS (m/z): 413.2 [M+H]+
Reaction SMILES: [CH2:1](C1(CC)C2C=C(C=O)C=CC=2C2C1=CC(Br)=CC=2)C.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28].CS(C)=O>O>[S:28]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[CH:1]1
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Reactant: Nc1ccccc1S
Solvent: CS(C)=O
Solvent: O
Product: c1ccc2scnc2c1
Temperature: 195 °C
Reaction time: 0.75 h
Yield: 80.3 %

Procedure:
A mixture of 9,9-diethyl-7-bromo-fluorene-2-carboxaldehyde (49.35 g., 0.15 mol.), 2-amino thiophenol (20 ml. 0.187 mol., 1,25 eq.), and DMSO (110 ml) was heated in an oil bath to a bath temperature of 195° C., held there for 45 minutes, and then poured into water. The separated solids were collected, reslurried in 1:4 acetic acid-water (1000 ml.) filtered, and washed with water and dilute sodium bicarbonate solution. These solids, 80.05 g., were then reslurried in hot ethanol, (600 ml), cooled and filtered to get the product benzothiazole, 45.69 g., m.p. 133.6-135° C. An additional 6.6 g., m.p. 134.6-135.5° C., was obtained by chromatography of the ethanol filtrate. Total recovery 52.29 g. (80.3% yield). Mass Spec: m/z 433, 435, (M+). Analysis calculated for C24H20BrNS: C, 66.37; H, 4.64; Br, 18.40; N, 3.23; S, 7.37. Found: C, 66.46; H, 4.52; Br, 18.54; N, 3.14; S, 7.19.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:59]([O:60][CH2:61][CH2:62][CH2:63][O:64][C:65]2[C:66]([O:102][CH3:103])=[CH:67][C:68]3[C:74](=[O:75])[N:73]4[CH:76]=[C:77]([C:79]5[CH:84]=[CH:83][C:82]([N:85]6[CH2:90][CH2:89][N:88]([CH3:91])[CH2:87][CH2:86]6)=[CH:81][CH:80]=5)[CH2:78][C@H:72]4[C:71](=O)[N:70](COCC[Si](C)(C)C)[C:69]=3[CH:101]=2)=[CH:58][C:6]2[N:7](COCC[Si](C)(C)C)[C:8](=O)[C@@H:9]3[CH2:15][C:14](/[CH:16]=[CH:17]/[CH2:18][NH:19][C:20](=[O:48])[C@@H:21]([NH:23][C:24](=[O:47])[C@@H:25]([NH:29][C:30](=[O:46])[O:31][CH2:32][CH:33]4[C:45]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:39]5[C:34]4=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH:26]([CH3:28])[CH3:27])[CH3:22])=[CH:13][N:10]3[C:11](=[O:12])[C:5]=2[CH:4]=1.[Li+].[B-](CC)(CC)CC>C1COCC1.O.CO>[CH3:1][O:2][C:3]1[C:59]([O:60][CH2:61][CH2:62][CH2:63][O:64][C:65]2[C:66]([O:102][CH3:103])=[CH:67][C:68]3[C:74](=[O:75])[N:73]4[CH:76]=[C:77]([C:79]5[CH:80]=[CH:81][C:82]([N:85]6[CH2:86][CH2:87][N:88]([CH3:91])[CH2:89][CH2:90]6)=[CH:83][CH:84]=5)[CH2:78][C@H:72]4[CH:71]=[N:70][C:69]=3[CH:101]=2)=[CH:58][C:6]2[N:7]=[CH:8][C@@H:9]3[CH2:15][C:14](/[CH:16]=[CH:17]/[CH2:18][NH:19][C:20](=[O:48])[C@@H:21]([NH:23][C:24](=[O:47])[C@H:25]([NH:29][C:30](=[O:46])[O:31][CH2:32][CH:33]4[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][C:39]=5[C:40]5[C:45]4=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH:26]([CH3:28])[CH3:27])[CH3:22])=[CH:13][N:10]3[C:11](=[O:12])[C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N5CCN(C)CC5)cc4)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(/C=C/CNC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C(C)C)=CN1C2=O
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N5CCN(C)CC5)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(/C=C/CNC(=O)[C@H](C)NC(=O)[C@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C(C)C)=CN1C2=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
SEM Fmoc amine 18e (0.245 g, 0.170 mmol, 1.0 eq) was solubilised in THF (10.6 mL) and cooled to −78° C. under a nitrogen atmosphere. Super hydride solution (0.347 mL, 0.347 mmol, 2.04 eq) was added drop wise over 4 minutes. After 45 minutes an aliquot was diluted with water and MeOH for LCMS After stirring for a further 10 minutes, the reaction mixture was diluted with water (35 mL) and the cold bath removed. The organic layer was extracted with EtOAc (2×35 mL) and the combined organic extracts washed with brine (35 mL), dried with MgSO4, filtered and concentrated under reduced pressure. The crude material was dissolved in MeOH (12.8 mL), DCM (6.4 mL) and water (2.15 mL) and enough silica gel was added to form a thick suspension which was left stirring for 5 days. The suspension was filtered and washed with DCM/MeOH 9:1 (˜200 mL) until complete elution of product. The organic layer was washed with brine (2×100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel; 40:1 v/v DCM/MeOH to 20:1 v/v DCM/MeOH) to afford the product (0.100 g, 51%). LC/MS (2.117 min (ES+)), m/z: 575.7 ½[M+2H]+.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:23]=[CH:22][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:11])=[CH:8][CH:7]=1)(=[O:5])[CH3:4]>CO>[OH:5][CH:3]([C:6]1[CH:23]=[CH:22][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])=[O:11])=[CH:8][CH:7]=1)[CH3:4]
Reactant: CC(=O)c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (0.28 g, 7.4 mmol) was added as solid to a solution of tert-butyl N-(4-acetylbenzoyl)-β-alaninate (2.11 g, 7.24 mmol) in MeOH (50 ml). After stirring at room temperature for 30 min, the reaction was quenched by adding ethyl acetate (150 ml) and 2N HCl (50 ml). The organic layer was washed with 1 NHCl 2×, brine 2×, and dried over Na2SO4. Evaporation of solvent and vacuum drying afforded tert-butyl N-[4-(1-hydroxyethyl)benzoyl]-β-alaninate as a colorless oil. NMR (CDCl3) δ: 1.46 (s, 9H); 1.49 (d, J=6.6 Hz, 3H); 2.55 (t, J=6.0 Hz, 2H); 3.67 (q, J=6.0 Hz, 2H); 4.94 (q, J=6.6 Hz, 1H); 6.88 (br, 1H); 7.42 (d, J=8.2 Hz, 2H); 7.72 (d, J=8.2 Hz, 2H). MS C16H23NO4 Cald: 293.16; Obsd: (M+Na) 316.12.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:2].[F:17][C:18]1[CH:23]=[C:22]([CH2:24][CH2:25][N+:26]([O-:28])=[O:27])[CH:21]=[C:20]([F:29])[CH:19]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[C:13]([O:12][C:10]([N:4]1[CH:3]([C@@H:1]([OH:2])[C@@H:25]([N+:26]([O-:28])=[O:27])[CH2:24][C:22]2[CH:23]=[C:18]([F:17])[CH:19]=[C:20]([F:29])[CH:21]=2)[CH2:7][O:6][C:5]1([CH3:9])[CH3:8])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Reactant: O=[N+]([O-])CCc1cc(F)cc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)[N+](=O)[O-])COC1(C)C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
Dissolve (R)-tert-butyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate (1.60 g, 6.98 mmol) and 1,3-difluoro-5-(2-nitroethyl)-benzene (1.40 g, 7.48 mmol) in dry tetrahydrofuran (14 mL) and add 1 M tetrabutylammonium fluoride (TBAF) in tetrahydrofuran (7.0 ml, 7.0 mmol) in one portion. Stir the resulting mixture for 30 minutes and then dilute with ethyl acetate. Quickly shake the mixture with water and then add a small amount of saturated aqueous sodium chloride. Discard the aqueous phase and wash the organic phase again with water (twice) followed by saturated aqueous sodium chloride. Dry the organic solution over magnesium sulfate (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 20:80 ethyl acetate:hexanes) to give the coupling product as an approximately ˜80:20 mixture of diastereomers (2.45 g, 84%). Isolate the major isomer by recrystallization of the diastereomeric mixture from dichloromethane (dichloromethane)/hexanes or diethyl ether/hexanes) to give 1.26 g of the desired compound as a white crystalline solid.