Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10](OCC)=[O:11])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[Cl-].[Na+].Cl>CO>[C:1]([C:5]1[S:9][C:8]([CH2:10][OH:11])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1nnc(C(C)(C)C)s1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Product: CC(C)(C)c1nnc(CO)s1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
1 g (4.67 mmol) of ethyl 5-tert-butyl-1,3,4-thiadiazole-2-carboxylate is dissolved in 45 mL of methanol and 0.353 g (9.33 mmol) of sodium borohydride is added portionwise, with stirring, at room temperature. The medium is stirred for 1 hour at room temperature and then concentrated under vacuum. The residue obtained is taken up in aqueous solution saturated with sodium chloride. The aqueous solution is brought to ph 7 by slowly adding, with stirring, aqueous 1N hydrochloric acid solution. After stirring for 1 hour at room temperature, the aqueous phase is extracted three times with dichloromethane and the combined organic phases are then washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. 0.802 g (100%) of the expected product is obtained in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:15])[C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:5][CH:4]=1.[N+:16]([O-])([O-:18])=[O:17].[NH4+]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:15])[C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: COc1ccc2c(=O)c(C#N)c[nH]c2c1
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc2[nH]cc(C#N)c(=O)c2cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 44.4 %

Procedure:
To a suspension of 10 g (49.6 mmol) of 1,4-dihydro-7-methoxy-4-oxo-quinoline-3-carbonitrile in 160 ml of trifluroacetic anhydride was added 6 g (74.9 mmol) of ammonium nitrate over a period of 3 hours. The mixture was stirred an additional two hours. Excess anhydride was removed at reduced pressure at 45° C. The residue was stirred with 500 ml of water. The solid was collected and washed with water. The solid was dissolved in 1000 ml of boiling acetic acid and the solution was treated with decolorizing charcoal. The mixture was filtered and concentrated to a volume of 300 ml. Cooling gave a solid which was collected giving 5.4 g of 1,4-dihydro-7-methoxy-6-nitro-4-oxo-quinoline-3-carbonitrile as a brown solid: mass spectrum (electrospray, m/e): M+H 246.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([OH:19])=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH2:24]([N:26](CC)[CH2:27][CH3:28])[CH3:25].N1CCCC1>C(Cl)Cl.C1C=NC2N(O)N=NC=2C=1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([N:26]3[CH2:27][CH2:28][CH2:25][CH2:24]3)=[O:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)O)cc2C1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)N3CCCC3)cc2C1
Reaction time: 8 h

Procedure:
A mixture of N-t-butoxycarbonyl-5-carboxyisoindoline (D13) (300 mg), EDC (440 mg), HOAT (10 mg), triethylamine (0.4 ml) and pyrrolidine (0.11 ml) in DCM (10 ml) was stirred overnight and then evaporated. The residue was redissolved in EtOAc (10 ml), washed with saturated NaHCO3 solution (10 ml), water (10 ml), brine (10 ml), dried (MgSO4) and evaporated. The residue was chromatographed on a silica gel flash column [step gradient 70-90% EtOAc in light petroleum 40-60] to give the tiUe compound (D17) (314 mg). MS electrospray (+ion) 317 (MH+). 1H NMR δ (CDCl3): 7.42 (2H, m), 7.27 (1H, m), 4.70 (2H, m), 4.67 (2H, m), 3.65 (2H, m), 3.42 (2H, m), 1.92 (4H, m), 1.52
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.Cl[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31].CO>C(Cl)Cl>[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[C:9]4[CH:26]=[CH:27][C:6]([CH:4]5[CH2:3][N:2]([CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:5]5)=[CH:7][C:8]=4[O:17][CH2:16][CH2:15][N:14]3[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(CC(=O)N(C)C)C3)cc1OCC2

Procedure:
Following the procedure for 143, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with 2-chloro-N,N-dimethylacetamide, the crude product subjected to flash chromatography (SiO2, gradient 0 to 6% MeOH in DCM) to give 198 as a white solid. 1H NMR δ (ppm)(CDCl3): 8.44 (1 H, d, J=8.28 Hz), 7.84 (1 H, d, J=0.71 Hz), 7.60 (1 H, s), 7.10 (1 H, dd, J=8.33, 1.81 Hz), 6.97 (1 H, d, J=1.72 Hz), 6.01-5.91 (1 H, m), 4.48-4.39 (4 H, m), 3.99-3.90 (2 H, m), 3.86-3.77 (1 H, m), 3.46-3.38 (4 H, m), 3.00 (3 H, s), 2.93 (3 H, s), 1.56 (6 H, d, J=6.63 Hz). LCMS: RT=5.87 min, M+H+=436.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C@@H:18]([NH:24][C:25](=[O:40])[C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])=[C:28]([CH3:39])[CH:27]=1)[CH2:19][CH2:20][C:21](O)=[O:22])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:72]1[CH2:76][CH2:75][C@H:74]([OH:77])[CH2:73]1.FC(F)(F)C(O)=O.ClCl>C(#N)C.C(OCC)(=O)C.C(O)C>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[NH:8][C:9]([C@@H:18]([NH:24][C:25](=[O:40])[C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:35][CH2:36][CH2:37][CH2:38]4)=[O:33])=[C:28]([CH3:39])[CH:27]=3)[CH2:19][CH2:20][C:21]([N:72]3[CH2:76][CH2:75][C@H:74]([OH:77])[CH2:73]3)=[O:22])=[N:10][C:11]=2[CH:16]=1
Reactant: O[C@H]1CCNC1
Reactant: Cc1cc(C(=O)N[C@@H](CCC(=O)O)c2nc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1cc(C(=O)N[C@@H](CCC(=O)N2CC[C@H](O)C2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 87 %

Procedure:
Prepared analogously to Example 1g from (S)—N-[1-(1-tert-butoxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonylpropyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, TBTU, diisopropylethylamine, (S)pyrrolidine-3-ol in acetonitrile, and subsequent reaction with trifluoroacetic acid analogously to Example 17. Yield: 87%; Rf value: 0.18 (silica gel; ethyl acetate/ethanol=85:15); C28H32ClN5O4 (538.05); mass spectrum: (M+H)+=538/540 (chlorine isotope).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:8]([CH:10]([CH2:17][S:18]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)(=[O:20])=[O:19])[CH2:11][CH2:12][C:13]([O:15]C)=[O:14])=[O:9])=[O:5])[CH3:2].C[S-].[Li+].Cl>CN(C)P(=O)(N(C)C)N(C)C>[CH2:1]([O:3][C:4]([CH2:6][N:7]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:8]([CH:10]([CH2:17][S:18]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)(=[O:20])=[O:19])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])=[O:5])[CH3:2]
Reactant: CCCCCN(CC(=O)OCC)C(=O)C(CCC(=O)OC)CS(=O)(=O)c1ccc2ccccc2c1
Agent: C[S-]
Agent: Cl
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCN(CC(=O)OCC)C(=O)C(CCC(=O)O)CS(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
To a solution of methyl 4-(N-ethoxycarbonylmethyl-N-pentylcarbamoyl)-5-(2-naphthylsulfonyl)pentanoate (50 mg) in dry hexamethylphosphoric triamide (0.3 ml) was added lithium thiomethoxide (5 mg) under argon. After stirring at room temperature for 30 minutes, a dilute hydrochloric acid was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4, and evaporated at reduced pressure. The residue was purified by medium pressure liquid column chromatography on silica eluting with chloroform/methanol (9:1), and recrystallized from isopropyl ether-hexane to give 23 mg of 4-(N-ethoxycarbonylmethyl-N-pentylcarbamoyl)-5-(2-naphthylsulfonyl)pentanoic acid. The physical properties of this compound were identical to that of compound No. 19, which was prepared in example 7.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[C:16](Cl)(=O)[C:17](Cl)=O.CN(C=O)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[N:1]1([C:6]2[CH:7]=[C:8]3[C:9](=[CH:10][CH:11]=2)[CH2:12][C:13](=[O:15])[CH2:17][CH2:16]3)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCc2cc(-n3cnnn3)ccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [4-(1H-tetrazol-1-yl)phenyl]acetic acid (0.50 g, 2.4 mmol) in DCM (10 mL) was added oxalyl chloride (0.37 g, 2.9 mmol) and a drop of DMF. The mixture was allowed to stir at RT for 2 hours. The solvent was removed under reduced pressure, and the residue was redissolved in DCM. The solution was cooled to 0° C. with an ice bath. To this solution was added aluminum chloride (0.98 g, 7.4 mmol) in small portions. Ethylene was then bubbled into the reaction via a long needle for 2 hours. LC showed formation of the desired product. The reaction was poured into ice and extracted with DCM. The extractions were combined, dried over sodium sulfate, adsorbed onto silica gel, and purified by MPLC (Hexane/EtOAc). The desired 6-(1H-tetrazol-1-yl)-3,4-dihydronaphthalen-2(1H)-one was collected as a off-white solid. LC-MS (IE, m/z): 215 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH3:9][CH:10]([OH:13])[C:11]#[CH:12].C(N(CC)CC)C>[Cu]I.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([C:12]#[C:11][CH:10]([OH:13])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)O
Reactant: Fc1cc(I)ccn1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(O)C#Cc1ccnc(F)c1
Yield: 65.2 %

Procedure:
A solution of 2-fluoro-4-iodopyridine (3.0 g, 13 mmol), 3-butyn-2-ol (2.1 mL, 26 mmol), dichlorobis(triphenylphosphine) palladium (II) (0.9 g, 1.3 mmol), copper (I) iodide (0.5 g, 2.6 mmol), triethylamine (5.4 mL 39 mmol), and anhydrous N,N-dimethylformamide (20 mL) were heated to 75° C. for 4 hours. When judged to be complete, the mixture was partitioned between ethyl acetate and water, the organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified using flash chromatography (4:1 hexanes:ethyl acetate) to provide 4-(2-fluoro-4-pyridinyl)-3-butyn-2-ol (1.4 g, 66%) as an orange oil. 1H NMR (DMSO-d6): δ 8.21 (d, 1H), 7.32 (d, 1H), 7.20 (s, 1H), 5.62 (d, 1H), 4.61 (m, 1H), 1.36 (d, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]([NH2:27])[CH2:24][CH2:23][CH2:22]2>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]([NH:27][C:8]1[CH:7]=[CH:6][C:5]3[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=1)[CH2:24][CH2:23][CH2:22]2
Reactant: COc1cccc2c1C(N)CCC2
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: COc1cccc2c1C(Nc1ccc3c(N)cccc3n1)CCC2

Procedure:
The title compound, MS: m/e=320.4 (M+H+), was prepared in accordance with the general method of example 16 from 5-nitro-2-chloroquinoline and 8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-amine (CAS 535935-61-6).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[N:12]([CH3:13])[N:11]=[C:10]([CH3:14])[C:9]=1[C:15]([NH2:17])=[O:16].CNC1CCCCC1NC.Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]([CH3:40])[CH2:36][CH:37]([CH3:39])[CH3:38].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>[Cu](I)I.C1(C)C=CC=CC=1>[CH3:40][CH:35]([C:30]1[CH:29]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:17][C:15]([C:9]1[C:10]([CH3:14])=[N:11][N:12]([CH3:13])[C:8]=1[F:7])=[O:16])[CH2:36][CH:37]([CH3:38])[CH3:39]
Reactant: Cc1nn(C)c(F)c1C(N)=O
Reactant: CC(C)CC(C)c1ccccc1Br
Agent: I[Cu]I
Agent: CNC1CCCCC1NC
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1nn(C)c(F)c1C(=O)Nc1ccccc1C(C)CC(C)C

Procedure:
A mixture of 0.221 g (1.16 mmol) of copper iodide, 3.21 g (23.22 mmol) of potash and 2.189 g of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide is admixed under argon with 330 mg (2.322 mmol) of N,N′-dimethyl-1,2-cyclohexanediamine, 2.8 g (11.6 mmol) of 1-bromo-2-(1,3-dimethylbutyl)benzene and 30 ml of toluene. After boiling under reflux for one day, the mixture is poured onto water and 10 ml of a 5% EDTA solution. Subsequently, the mixture is extracted three times with ethyl acetate and concentrated by evaporation under reduced pressure. The oily residue is dissolved in toluene and stirred into n-hexane. After the precipitated crystals have been filtered off with suction, 3.3 g (89% of the theoretical yield) of N-[2-(1,3-dimethylbutyl)phenyl]-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide are obtained with a purity (HPLC) of 99%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C(OC(O)C)C.C(=O)([O-])O.[Na+]>C(OCCO)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:14]3[S:13][CH:17]=[CH:16][CH:15]=3)[CH:3]=2)[N:8]=1
Reactant: Cc1ccc2cc(Br)ccc2n1
Reactant: OB(O)c1cccs1
Agent: [Pd]
Agent: CCOC(C)O
Agent: O=C([O-])O
Solvent: CCOCCO
Solvent: O
Product: Cc1ccc2cc(-c3cccs3)ccc2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution 6-Bromo-2-methylquinoline (17.4 g; 0.078 mol) in 2-ethoxyethanol (100 ml) was added tetrakis(triphenylphosphine) palladium (2.7 g; 0.0023 mol) and the reaction mixture was stirred at room temperature under nitrogen atmosphere for 5 minutes. 2-Thienylboronic acid (10.0 g; 0.078 mol) was added followed by ethoxyethanol (70 ml). Sodium hydrogencarbonate (20 g; 0.24 mol) in water (100 ml) was added and the reaction mixture was magnetically stirred and heated under nitrogen at 90° C. for 16 h. The cooled reaction mixture was filtered through a pad of Celite hyflo supercel and then extracted with dichloromethane (2×150 ml), after addition of de-ionised water. The organic layer was washed with brine, dried over anhydrous magnesium sulphate and solvent removed to give a light brown liquid. The liquid was distilled under reduced pressure to remove ethoxy ethanol. The residue was triturated with diethyl ether and cooled in the refrigerator to give an off white solid, 10.6 g (61%); Mp 87° C. (DSC, onset). Elemental analysis: Found C, 74.72; H 4.92; N, 6.12; S 13.43; C14H11NS requires C, 74.63; H 4.92; N, 6.21; and S, 14.24%.
Reaction SMILES: C1([C@H](O)CN)C=CC=CC=1.FC1C=CC(N2C3C(=CC(I)=CC=3)C=N2)=CC=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[C:43]3[C:38](=[CH:39][C:40]([O:44][C@H:45]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C@@H:46]([NH2:48])C)=[CH:41][CH:42]=3)[CH:37]=[N:36]2)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:30]=[CH:31][C:32]([N:35]2[C:43]3[C:38](=[CH:39][C:40]([O:44][C@@H:45]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[CH2:46][NH2:48])=[CH:41][CH:42]=3)[CH:37]=[N:36]2)=[CH:33][CH:34]=1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Agent: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Agent: NC[C@@H](O)c1ccccc1
Product: NC[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared from (1S)-1-phenyl-1-hydroxy-ethan-2-amine (294 mg, 2.15 mmol) and 1-(4-fluorophenyl)-5-iodoindazole (484 mg, 1.43 mmol) according to the protocol for 1a. Yield: 175 mg (23%).
Reaction SMILES: C[Si](C)(C)C#C[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:9]([C:20]23[CH2:29][CH:24]4[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]4)[CH2:21]2)[CH2:27]3)[CH:8]=1)[OH:6].[CH2:32]1COC[CH2:33]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[C:32]([CH:16]([O:15][CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:5][OH:6])=[CH:8][C:9]=1[C:20]12[CH2:21][CH:22]3[CH2:28][CH:26]([CH2:25][CH:24]([CH2:23]3)[CH2:29]1)[CH2:27]2)[CH2:17][O:18][CH3:19])#[CH:33]
Reactant: C1CCOC1
Reactant: COCCOCOc1ccc(C(O)C#C[Si](C)(C)C)cc1C12CC3CC(CC(C3)C1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: C#CC(COC)OCOc1ccc(CO)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.7 g (10.5 mmol) of a-trimethylsilylethynyl-3-(1-adamantyl)-4-methoxyethoxymethoxyphenylmethanol and 50 ml of THF were introduced into a round-bottomed flask and 11.4 ml (12.6 mmol) of tetrabutylammonium fluoride solution (1.1M in THF) was added dropwise. The reaction medium was stirred at room temperature for one hour and was then poured into water and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with a mixture of ethyl acetate and heptane (30/70). After evaporation of the solvents, 2.5 g (64%) of a-ethynyl-3-(1-adamantyl)-4-methoxyethoxymethoxyphenyl-methanol were recovered.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:35]([CH3:41])[C@H:36]([C:38]([OH:40])=O)[CH3:37])([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CCN(C(C)C)C(C)C.[NH2:51][CH:52]([C:78]([CH3:81])([CH3:80])[CH3:79])[C:53]([N:55]1[CH2:59][CH2:58][CH:57]2[N:60]([CH:72]3[CH2:77][CH2:76][O:75][CH2:74][CH2:73]3)[CH2:61][CH:62]([O:63][C:64]3[CH:69]=[CH:68][C:67]([F:70])=[C:66]([F:71])[CH:65]=3)[CH:56]12)=[O:54]>CN1C(=O)CCC1>[CH2:28]([O:27][C:25](=[O:26])[N:35]([CH:36]([C:38](=[O:40])[NH:51][CH:52]([C:53]([N:55]1[CH2:59][CH2:58][CH:57]2[N:60]([CH:72]3[CH2:77][CH2:76][O:75][CH2:74][CH2:73]3)[CH2:61][CH:62]([O:63][C:64]3[CH:69]=[CH:68][C:67]([F:70])=[C:66]([F:71])[CH:65]=3)[CH:56]12)=[O:54])[C:78]([CH3:80])([CH3:79])[CH3:81])[CH3:37])[CH3:41])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)C(N)C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2C1CCOCC1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2C1CCOCC1)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 81.2 %

Procedure:
HATU (126 mg, 0.33 mmol) and Cbz-N(Me)Ala-OH (79 mg, 0.33 mmol) were dissolved in NMP (0.5 mL) and DIPEA (70 μL, 0.39 mmol) was added. The reaction mixture was cooled to 0° C. and a solution of 26 (125 mg, 0.30 mmol) in NMP (2 mL) was added. The reaction mixture was warmed to ambient temperature. After 12 h, the reaction mixture was quenched with 1N NaOH (0.5 mL) and diluted with water. The product was extracted with 10:1 Et2O/EtOAc, and the combined organic extracts were washed successively with water, saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 160 mg of 27 as a beige-colored foam that was used without further purification. Mass spectrum, m/z [657.2] (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1.[CH3:14][NH2:15]>CO>[CH3:13][O:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][NH:15][CH3:14]
Reactant: COc1cccc(OCCCCl)c1
Reactant: CN
Solvent: CO
Product: CNCCCOc1cccc(OC)c1
Temperature: 100 °C

Procedure:
Crude 3-chloro-1-(3-methoxyphenoxy)propane (1.27 g, 6.33 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (25 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the solution was concentrated by rotary evaporation, and saturated NaCl solution (50 mL) was added. The mixture was acidified to pH 1 with 1 0% HCl solution, and extracted with CHCl3 (4×25 mL) to remove impurities. The pH of the aqueous phase was adjusted to 7 with 100% NaOH solution, and the mixture was extracted with ether (4×30 mL) to remove impurities. The aqueous phase was basified with 100% NaOH solution to pH 11. The mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered and concentrated by rotary evaporation to give a residue. The residue was briefly dried under high vacuum producing a light-brown oil (0.11 g). The oil was purified by column chromatography on silica gel (10 g) eluting with CHCl3—CH3OH (1:1, v/v) to remove impurities, followed by CHCl3—CH3OH—Et3N (50:50:2, v/v/v) to collect the product (Rf 0.27). Selected fractions containing the product were combined and concentrated by rotary evaporation. The resulting brown oil was dissolved in CHCl3, and the CHCl3 solution was dried (MgSO4), filtered and concentrated by rotary evaporation to a residue. The residue was dried briefly under vacuum to give 0.021 g (1.7%) of a light-brown oil. The compound exhibits a Ki of 5300 nM.
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:15]1[CH:19]=[CH:18]N=C1)(N1C=CN=C1)=[S:9].NC1C=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[C:23]([Cl:30])[CH:22]=1.Cl>O.C(Cl)Cl>[N:15]([C:19]1[CH:18]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[C:23]([Cl:30])[CH:22]=1)=[C:8]=[S:9]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1ccc(N=C=S)cc1Cl
Reaction time: 1 h
Yield: 91 %

Procedure:
A methylene chloride solution (235 mL) of triethylamine (30.6 mL, 219.5 mmol) and thiocarbonyldiimidazole (23.01 g, 129.14 mmol) was dropped to a methylene chloride solution (130 mL) of 4-amino-2-chlorobenzoic acid (18.84 g, 109.82 mmol) under cooling with ice, followed by stirring for one hour while an internal temperature of at most 10° C. was maintained. 4M hydrochloric acid (120 mL, 480 mmol) was dropped so that the internal temperature became at most 10° C., followed by stirring under cooling with ice for one hour. Water (10 mL) was added, and the formed pink solid was collected by filtration, washed with water (100 mL) five times and dried under reduced pressure to obtain 4-isothiocyanato-2-chlorobenzoic acid as a colorless solid (21.36 g, yield: 91%, HPLC purity: 98.2%).