Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:21][O:22][CH2:23][O:24][C:25]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][C:26]=1[C:27]([NH:29][C:30]1[CH:42]=[C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:40]=[CH:39][C:31]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:28].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1C=CC=CC=1>[Br:1][CH2:53][C:50]1[CH:51]=[CH:52][C:25]([O:24][CH2:23][O:22][CH3:21])=[C:26]([CH:49]=1)[C:27]([NH:29][C:30]1[CH:42]=[C:41]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:40]=[CH:39][C:31]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1ccc(C)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COCOc1ccc(CBr)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 69 %

Procedure:
N-Bromosuccinimide (0.25 g) and azobisisobutyronitrile (0.023 g) were sequentially added to a benzene (6.3 mL) solution of the obtained tert-butyl 2-(2-(methoxymethoxy)-5-methylbenzamido)-4-phenylbenzoate (0.63 g), followed by heating to reflux for 30 minutes. The reaction mixture was cooled to room temperature, and then a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% hexane/ethyl acetate] to obtain 0.51 g of tert-butyl 2-(5-(bromomethyl)-2-(methoxymethoxy)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([OH:26])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:30]([CH3:32])[CH3:31]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[C:9]([O:26][CH:30]([CH3:32])[CH3:31])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Br
Reactant: CC(C)(C)OC(=O)c1c(O)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To the stirred solution of 6-chloro-4-(3-chloro-phenyl)-2-hydroxy-quinoline-3-carboxylic acid tert-butyl ester (prepared as described in example 91 step B, 400 mg, 1.02 mmol) in 8 ml DMF was added NaH (60%, 65 mg, 1.54 mmol) portion wise at 0° C. and the resulting reaction mixture was stirred for 30 min at 25° C. Then the reaction mixture was cooled to 0° C. and a solution of 2-bromo-propane (0.192 ml, 2.05 mmol) was added dropwise in 2 ml DMF. The reaction mixture was stirred for 16 h at 50° C. and then quenched with saturated aqueous ammonium chloride solution (10 ml). Subsequently the mixture was diluted with water (25 ml) and extracted with ethyl acetate (3×60 ml). The organic phases were combined and was washed with brine (25 ml), dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by column chromatography eluting with 2% ethyl acetate in hexane to yield 6-chloro-4-(3-chloro-phenyl)-2-isopropoxy-quinoline-3-carboxylic acid tert-butyl ester (290 mg, 65% yield) as an off white solid. LC-MS (ESI): 432 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:21]([OH:22])[C@@H:20]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:19][C@@H:11]([O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C@@H:10]1[N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>N1C=CC=CC=1>[C:43]([O:22][C@@H:21]1[C@@H:20]([CH2:23][O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:19][C@@H:11]([O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])[C@H:10]([N:32]2[C:36](=[O:37])[C:35]3=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]3[C:33]2=[O:42])[C@H:9]1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:45])[CH3:44]
Reactant: C[Si](C)(C)CCO[C@@H]1O[C@H](COCc2ccccc2)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1N1C(=O)c2ccccc2C1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](OCc2ccccc2)[C@@H](N2C(=O)c3ccccc3C2=O)[C@H](OCC[Si](C)(C)C)O[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-(trimethyl silyl)ethyl 3,6-di-O-benzyl-2-deoxy-2-phthalimido-β-D-glucopyranoside (compound 14, 8.0 g, 13.6 m mol) in pyridine (40 ml), was added acetic anhydride (10 ml) at 0° C., and the mixture was stirred for 5 hrs at room temperature, and concentrated. Column chromatography (1:2 ethyl acetate-hoxane) of the residue on silica gel (200 g) gave compound 15 (8.6 g, quantitative yield) as crystals:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:21])([C:14]2[C:15](Br)=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)[CH:52]=[O:53]>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:14]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[C:52](=[O:53])[O:21]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: OC1(c2cccnc2Br)CCN(Cc2ccccc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC2(CCN(Cc3ccccc3)CC2)c2cccnc21
Temperature: 80 °C
Reaction time: 72 h
Yield: 43 %

Procedure:
A mixture of 3.4 g (9.7 mmol) 1′-benzyl-2-bromo-2′,3′,5′,6′-tetrahydro-1′H-[3,4′]bipyridinyl-4′-ol, 3.3 ml (1.9 mmol) N,N-diisopropylethylamine, 0.22 g (1.0 mmol) Pd(II) acetate and 0.25 g (1.0 mmol) triphenylphosphine in 100 ml N,N-dimethylformamide was purged with carbon monoxide and stirred under an atmosphere of carbon monoxide at 80° C. for 72 h. The reaction mixture was diluted with tert-butyl methyl ether and washed with water (pH adjusted to 8 with saturated aqueous sodium bicarbonate solution). The aqueous layer was extracted with two portions of tert-butyl methyl ether. The combined organic layers were washed with two portions of water and brine, dried over sodium sulfate and concentrated to dryness. Flash-chromatography gave the title compound (1.2 g, 43%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:40])[N:14]([CH2:26][C:27]([NH:29][CH:30]([CH:37]([CH3:39])[CH3:38])[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[O:28])[CH:15]=[C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)[CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([CH2:47][C:48](Cl)=[O:49])C=CC=CC=1>>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:40])[N:14]([CH2:26][C:27]([NH:29][CH:30]([CH:37]([CH3:38])[CH3:39])[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[O:28])[CH:15]=[C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:48](=[O:49])[CH3:47])[CH:20]=2)[CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)C(NC(=O)Cn1cc(Cc2cccc(O)c2)cc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Product: CC(=O)Oc1cccc(Cc2cc(NC(=O)OCc3ccccc3)c(=O)n(CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c2)c1

Procedure:
2-[3-Benzyloxycarbonylamino-5-(3-hydroxybenzyl)-2-oxo-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide was acylated using conditions similar to those described in Example 14.b., substituting acetic anhydride for phenylacetyl chloride, to give the title compound; NMR: 2.25 (s,3 and m,1), 6.95-7.41 (m,10); MS: m/z=602(M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH2:18][CH2:19][CH3:20])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27](C(OC(C)(C)C)=O)[N:26](C(OC(C)(C)C)=O)[C:25]2=[O:45]>C(O)C>[O:17]=[C:16]1[NH:15][N:14]=[C:13]([CH2:18][CH2:19][CH3:20])/[C:12]/1=[C:4]1/[NH:5][C:6]2[C:11]([C:2]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][NH:26][C:25]4=[O:45])=[CH:3]/1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC(C)(C)OC(=O)n1c(=O)c2cc(N)ccc2n1C(=O)OC(C)(C)C
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Solvent: CCO
Product: CCCC1=NNC(=O)/C1=C1/C=C(Nc2ccc3[nH][nH]c(=O)c3c2)c2ccccc2N1
Temperature: 170 °C

Procedure:
(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one (0.03 g, 0.1 mmol) was dissolved in ethanol (1.5 mL) and di-tert-butyl 5-amino-3-oxo-1H-indazole-1,2(3H)-dicarboxylate (0.044 g, 0.12 mmol) was added. The reaction mixture was heated to 170° C. using a microwave reactor for 30 minutes. The mixture was concentrated and purified by LC-MS to give the title compound of Example 51. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.51 (t, J=6.95 Hz, 3H) 1.26-1.33 (m, 2H) 2.39 (dd, J=9.09, 3.28 Hz, 2H) 6.41 (s, 1H) 7.38 (dd, J=8.72, 1.64 Hz, 1H) 7.45-7.51 (m, 1H) 7.67-7.73 (m, 2H) 7.90-7.98 (m, 2H) 8.59 (d, J=7.58 Hz, 1H) 10.49 (s, 1H) 11.79 (s, 1H); ESI-MS: m/z calc'd for C22H20N6O2 400.43. found 401.3 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2].[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[O:21]=[C:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[S:16][C:1]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: COC(=O)c1cccc(C#N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: COC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)c1
Temperature: 145 °C
Reaction time: 22 h
Yield: 29.1 %

Procedure:
A mixture of methyl 3-cyanobenzoate (967 mg, 6.00 mmol), methyl thiosalicylate (1.51 g, 8.98 mmol), triethylamine (1.5 ml, 11 mmol) and xylene (6 mL) was stirred at 145° C. for 22 hours under a nitrogen flow. After the reaction mixture was allowed to cool, the crystals were taken by filtration and recrystallized from methanol to give the title compound (519 mg, 29%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[C:11](=O)([O-])[O-:12].[Na+].[Na+].Cl>O.CC(C)=O>[OH:6][CH:5]([C@H:3]1[O:4][C:11](=[O:12])[NH:1][CH2:2]1)[CH:7]([OH:8])[CH2:9][OH:10]
Reactant: NC[C@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1NC[C@@H](C(O)C(O)CO)O1
Reaction time: 8 h
Yield: 28.2 %

Procedure:
1-Amino-1-deoxy-D-ribitol (2.1 g, 0.014 mole prepared from D-ribose as described by Wolfron et. al. J. Org. Chemi. 23, 571 [1958]) was dissolved in water (30 ml), and sodium carbonate (2.9 g, 28 mole) and a solution of p-nitrophenyl-chloroformate (3.2 g, 0.016 mole) in acetone (10 ml) were added at 0° C. The solution was stirred and allowed to stand at room temperature overnight. The solution was acidified with 5N hydrochloric acid and extracted several times with ethyl acetate. The aqueous phase was evaporated and the residue extracted with ethanol. Chromatography on silica eluting with a gradient of chloroform and ethanol gave 5-(S)-(1',2',3'-trihydroxypropyl)-1,3-oxazolidin-2-one (0.7 g) an an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C@@H:5]([CH2:12][C:13]1[CH:18]=[C:17]([Br:19])[C:16]([NH2:20])=[C:15]([CH3:21])[C:14]=1[CH2:22][O:23]C(=O)C)[CH2:6][C:7]([O:9][CH2:10]C)=[O:8])C.COC(=O)[C@@H](CC1C(CO)=C2C(=CC=1)N[N:42]=C2)CC(OC)=O>>[Br:19][C:17]1[CH:18]=[C:13]([CH2:12][C@@H:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:4]([O:3][CH3:1])=[O:27])[C:14]([CH2:22][OH:23])=[C:15]2[C:16]=1[NH:20][N:42]=[CH:21]2
Reactant: COC(=O)C[C@H](Cc1ccc2[nH]ncc2c1CO)C(=O)OC
Reactant: CCOC(=O)C[C@H](Cc1cc(Br)c(N)c(C)c1COC(C)=O)C(=O)OCC
Product: COC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1CO)C(=O)OC
Yield: 96 %

Procedure:
2-(S)-(2-Acetoxymethyl-4-amino-5-bromo-3-methyl-benzyl)-succinic acid diethyl ester (2.78 g, 6.1 mmol) was converted to the title compound in a manner analogous to the preparation of 2-(S)-(4-Hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethyl ester. Material was obtained as amber solid in 96% yield. MS m/e (M−H)−=383.0, 385.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][OH:17])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.Cl[C:20]1[CH:21]=[C:22]2[N:29](C(OC(C)(C)C)=O)[C:28]([CH3:38])([CH3:37])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][O:17][C:20]3[CH:21]=[C:22]4[NH:29][C:28]([CH3:38])([CH3:37])[CH2:27][N:23]4[C:24](=[O:26])[N:25]=3)=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cc(F)c(Oc2ccnc(Cl)c2)c(F)c1
Product: CC1(C)Cn2c(cc(OCc3cc(F)c(Oc4ccnc(Cl)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((2-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)methanol and tert-butyl 7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:4][N:3]=1.[CH3:18][C:19]([CH3:31])([O:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)[C:20]#[CH:21]>C(NCC)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([O:22][C:19]([CH3:18])([CH3:31])[C:20]#[C:21][C:2]2[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])=[CH:4][N:3]=2)=[CH:24][CH:25]=1)#[N:28]
Reactant: C#CC(C)(C)Oc1ccc(C#N)cc1
Reactant: O=C(OCc1ccccc1)c1ccc(I)nc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: CC(C)(C#Cc1ccc(C(=O)OCc2ccccc2)cn1)Oc1ccc(C#N)cc1
Yield: 74.9 %

Procedure:
12.2 g of benzyl 2-iodopyridine-5-carboxylate and 5.64 g of 4-(1,1-dimethyl-2-propynyloxy)benzonitrile were stirred with 32 mg of copper(I) iodide, 162 mg of triphenylphosphine and 180 mg of palladium(II) chloride in 280 ml of diethylamine at room temperature for 7 days under a nitrogen atmosphere. The mixture was evaporated and the residue was taken up in ethyl acetate and water. The organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution. There were obtained 9.04 g of benzyl 2-[3-(4-cyanophenoxy)-3-methyl-1-butyn-1-yl]pyridine-5-carboxylate which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:34](O)[CH2:35][OH:36].C([O-])(O)=O.[Na+]>O>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([O:18][CH2:34][CH2:35][OH:36])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(OCCO)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of 4-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (Intermediate 73-2, 300 mg, 0.864 mmol), p-toluenesulfonic acid monohydrate (8.2 mg, 0.043 mmol) and ethylene glycol (1.45 mL) was stirred at rt overnight. The resulting suspension was treated with NaHCO3 (aq) and diluted with water. The precipitate was collected by filtration, washed with water and dried to provide 4-bromo-7-(2-(2-hydroxyethoxy)propan-2-yl)-9H-carbazole-1-carboxamide as a white solid (324 mg, 96%). 1H NMR (400 MHz, methanol-d4) δ 8.65 (1H, d, J=8.58 Hz), 7.77 (1H, d, J=1.10 Hz), 7.75 (1H, d, J=8.14 Hz), 7.44 (1H, dd, J=8.36, 1.54 Hz), 7.40 (1H, d), 3.69 (2H, t, J=5.17 Hz), 3.32-3.34 (2H, m), 1.68 (6H, s). Mass spectrum m/z 413, 415 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][C:8]2[CH:13]=[C:12]([NH:14]C(=O)C(F)(F)F)[CH:11]=[CH:10][C:9]=2[S:21](Cl)(=[O:23])=[O:22])[N:3]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[CH2:33][O:32][B:31]([OH:34])[C:30]=2[CH:35]=1.N1C=CC=CC=1>C(#N)C>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([S:21]([NH:25][C:26]2[CH:27]=[CH:28][C:29]3[CH2:33][O:32][B:31]([OH:34])[C:30]=3[CH:35]=2)(=[O:22])=[O:23])=[C:8]([CH2:7][C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)[CH:13]=1
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: Cc1nc(Cc2cc(NC(=O)C(F)(F)F)ccc2S(=O)(=O)Cl)no1
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1nc(Cc2cc(N)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (490 mg, 1.3 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (627 mg, 4.21 mmol) in 10 mL of ACN was added pyridine (680 uL, 8.4 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. After the mixture was concentrated, the residue was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated to give the desired compound as a yellow residue (555 mg, yield 88%). A small portion of the crude mixture was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17].CO>C1COCC1>[Cl:12][CH2:13][CH2:14][NH:15][C:16]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)=[O:17]
Reactant: O=C=NCCCl
Reactant: Nc1ccnc2ccccc12
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCCCl)Nc1ccnc2ccccc12
Reaction time: 18 h

Procedure:
To a solution of 4-aminoquinoline (3.46 g, 24 mmol) in dry THF is added chloroethylisocyanate (3.1 mL, 36 mmol). The reaction mixture is stirred for 18 h. MeOH (10 mL) is added, and stirring is continued for an additional hour. The reaction mixture is evaporated, and partitioned between DCM and aqueous 5% citric acid (150 mL). The aqueous layer is carefully adjusted to pH 9 with solid NaHCO3. The precipitate is filtered, washed with H2O (5×20 mL) and Et2O (2×20 mL), and dried in vacuo at 45° C. to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:10][C:11]([NH2:13])=O)=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCCl>[C:11]([CH2:10][N:9]([CH2:14][C:15]([F:16])([F:18])[F:17])[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:19]([F:21])([F:22])[F:20])[CH:5]=1)#[N:13]
Reactant: N#Cc1ccc(N(CC(N)=O)CC(F)(F)F)cc1C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: N#CCN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 87 °C
Yield: 54.3 %

Procedure:
A mixture of N2-[4-cyano-3-(trifluoromethyl)phenyl]-N2-(2,2,2-trifluoroethyl)glycinamide (0.060 g, 0.18 mmol), CCl4 (0.5 mL), DCE (4.5 mL) and polymer-supported triphenyl phosphine (3 mmol/g, 0.123 g, 0.36 mmol) was heated at 87° C. for 3 h. Upon cooling, the resin was filtered off, washed thoroughly with CHCl3 and the filtrate concentrated in vacuo. The residue was purified by silica gel chromatography (5-40% EtOAc-hexane gradient) and the product was crystallized from CH2Cl2-hexanes to give the title compound as a white solid (0.030 g, 55% yield): 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8.6 Hz, 1H), 7.20 (d, J=2.6 Hz, 1H), 7.09 (dd, J=8.6, 2.6 Hz, 1H), 4.38 (s, 2H), 4.06 (q, J=8.2 Hz, 2H); MS (ES) m/z 308 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24][OH:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24][O:25][S:34]([CH3:33])(=[O:36])=[O:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](COS(C)(=O)=O)N(C(=O)OCc2ccccc2)C1

Procedure:
(2S,4R)-1-Benzyloxycarbonyl-2-hydroxymethyl-4-t-butyldimethylsilyloxypyrrolidine (111 g) was dissolved in dry dichloromethane (1100 ml), and triethylamine (36.87 g) was added thereto. After addition of methanesulfonyl chloride (41.81 g) under nitrogen stream while ice-cooling, the resultant mixture was stirred at the same temperature for 30 minutes. The reaction mixture was washed with water, aqueous sodium chloride solution, water, aqueous sodium bicarbonate solution and water in order and dried over magnesium sulfate. Removal of the solvent gave (2S,4R)-1-benzyloxycarbonyl-2-methylsulfonyloxymethyl-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:24](=[O:47])[NH:25][C@H:26]([C:35](=[O:46])[NH:36][C:37]1[S:38][CH:39]=[C:40]([C:42](=[O:45])[CH2:43][CH3:44])[N:41]=1)[C@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:11][CH:10]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C@H:8]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[CH:13][CH:14]=1)[C:24]([NH:25][C@@H:26]([C@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[C:35]([NH:36][C:37]1[S:38][CH:39]=[C:40]([C:42](=[O:45])[CH2:43][CH3:44])[N:41]=1)=[O:46])=[O:47]
Reactant: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(OCCN3CCCCC3)cc2)[C@@H](C)c2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc(OCCN3CCCCC3)cc2)[C@@H](C)c2ccccc2)n1
Reaction time: 1.5 h

Procedure:
{(R)-[(1S,2S)-2-Phenyl-1-(4-propionyl-thiazol-2-ylcarbamoyl)-propylcarbamoyl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-carbamic acid tert-butyl ester (110 mg, 0.16 mmol) was dissolved in a 30% v/v solution of trifluoroacetic acid in dichloromethane (5 mL) at 0° C. After stirring for 1.5 hours the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was adjusted to pH=8 by the addition of solid sodium bicarbonate. The aqueous layer was again extracted with ethyl acetate (2×). The combined organic layers was dried over sodium sulfate, filtered and concentrated in vacuo to give crude (2S,3S)-2-{(R)-2-amino-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetylamino}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide which was used immediately and without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:17][O:18][CH2:19][CH2:20]Br>CC(C)=O>[CH3:17][O:18][CH2:19][CH2:20][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COCCOc1ccc2[nH]ccc2c1

Procedure:
5-hydroxyindole (5 g, 15 mmol) was dissolved in acetone (75 mL), cesium carbonate (5.38 g, 16.5 mmol) and 2-bromoethyl methyl ether (1.55 mL, 16.5 mmol) were added and the reaction mixture was stirred at reflux under nitrogen overnight. Acetone was concentrated. The residue was dissolved in water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 7/3) to give the desired material. TLC, Rf (c-hexane/EtOAc 1:1)=0.6; MS (LC-MS): 192.1 [M+H]+, 214.0 [M+Na]+, 405.1 [2M+Na]+; tR (HPLC conditions f): 1.56 min.