Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[I:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O.CN(C(ON1N=NC2C=CC(Cl)=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:45][C:46]([F:56])([F:55])[O:47][C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=1>C1COCC1.CC#N>[I:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:52][C:51]1[CH:53]=[CH:54][C:48]([O:47][C:46]([F:45])([F:55])[F:56])=[CH:49][CH:50]=1)=[O:16]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cccc(I)c1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIPEA (6.34 mL, 36.3 mmol) was added to a solution of 3-iodobenzoic acid (3 g, 12.1 mmol) and 2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (HCTU, 5.50 g, 13.31 mmol) in THF (25 mL) and MeCN (5 mL) and the RM was stirred at RT for 1 h. 4-(Trifluoromethoxy)aniline (2.435 mL, 18.14 mmol) was then added and the RM was stirred at RT for 3 h. The solvent was evaporated off under reduced pressure and the residue was treated with aq. HCl (50 mL of 1 M) and extracted with TBME/EtOAc (9:1). The combined extracts were washed with aq. 1 M HCl, sat. aq. Na2CO3 (50 mL), water and brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure. The residue was suspended in water, filtered and dried to afford the title compound as a purple solid. UPLC-MS (Condition 1) tR=3.23 min, m/z=407.8-409.8 [M+H]+, m/z=405.9-406.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.33-7.41 (m, 3H) 7.88 (d, J=9.3 Hz, 2H) 7.94-8.00 (m, 2H) 8.30 (t, J=1.7 Hz, 1H) 10.50 (s, 1H).
Reaction SMILES: [C:1]([N:4]=[C:5]([N:10]1[CH2:14][CH2:13][S:12][CH:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)[O:6]C(=O)C)(=[O:3])[CH3:2].C(O)C.[OH-].[Na+].Cl>O1CCCC1.O>[C:1]([NH:4][C:5]([N:10]1[CH2:14][CH2:13][S:12][CH:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N=C(OC(C)=O)N1CCSC1c1ccccc1OCCN1CCN(c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)NC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2ccccc2)CC1
Reaction time: 1.5 h
Yield: 66.1 %

Procedure:
A mixture of 1.19 g of N,O-diacetyl-2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboximidic acid, 20 ml of ethanol, 0.287 g of sodium hydroxide, 2.7 ml of water and 20 ml of tetrahydrofuran is stirred for 1.5 hours under ice-cooling. The mixture is neutralized with 10% hydrochloric acid, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried and then concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, ethyl acetate:chloroform=5:1). The eluate is concentrated under reduced pressure to remove solvent, and the residue is recrystallized from a mixture of ethyl acetate and n-hexane. 0.72 g of N-acetyl-2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][CH2:7][C:8]([O:10]CC)=O)=[CH:4][C:3]=1[F:15].[O-:16][C:17]#[N:18].[K+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([N:6]2[CH2:7][C:8](=[O:10])[NH:18][C:17]2=[O:16])=[CH:4][C:3]=1[F:15]
Reactant: N#C[O-]
Reactant: CCOC(=O)CNc1ccc(Br)c(F)c1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CN(c2ccc(Br)c(F)c2)C(=O)N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of ethyl 2-(4-bromo-3-fluoro-anilino)acetate (86 g, 0.31 mol) in acetic acid (1.5 L) and water (100 mL) was added a solution of potassium cyanate (50 g, 0.6 mol) in water (200 mL). The reaction mixture was stirred at room temperature for 12 h and then evaporated to dryness. Then 1.5 L of 25% HCl was added to the residue and the mixture was heated to reflux for 3 h. After cooling to room temperature, the solid was filtered and dried to give the title compound. LC-MS: calculated for C9H6BrFN2O2 271.96 observed m/e: 273.35 (M+H)+ (Rt 3.44/6.5 min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[F:10].[CH2:11]([N:13](CC)CC)C.CS(Cl)(=O)=O.[Cl-].[NH4+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:13])=[CH:4][C:3]=1[F:10]
Reactant: OCc1ccc(Br)c(F)c1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: N#CCc1ccc(Br)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of (4-bromo-3-fluorophenyl)methanol from Step 2 (7.2 g) and triethylamine (5.9 mL) in dichloromethane (300 mL) was slowly added methanesulphonyl chloride (3.0 mL). The reaction mixture was stirred at 0° C. for 1 hour. Then poured into ice and saturated aqueous ammonium chloride and partitioned. The aqueous layer was extracted with dichloromethane (1×150 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was dissolved in DMF (150 mL) and sodium cyanide (5.1 g) was added. The reaction mixture was stirred at room temperature for 2 hours and poured into ice and water (100 mL). Extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on SiO2 using ethyl acetate and hexanes (1:10 to 1:5) to yield the title compound.
Reaction SMILES: C(OC(=O)NC1C=CC=[C:10]([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:40])[C@@H:22]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([Cl:39])[CH:30]=3)[CH2:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:16]2)C=1)(C)(C)C.C(Cl)(=O)C(Cl)=O.[CH:48]([O:51]CCN1C=CC(N)=N1)([CH3:50])[CH3:49].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[Cl:39][C:31]1[CH:30]=[C:29]([C@@H:22]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:21]([NH:20][C:17]2[CH:18]=[CH:19][N:15]([CH2:14][CH2:10][O:51][CH:48]([CH3:50])[CH3:49])[N:16]=2)=[O:40])[CH:34]=[CH:33][C:32]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CC(C)OCCn1ccc(N)n1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 120 mg, 0.36 mmol) was dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 210 μL, 0.42 mmol) which produced gas evolution and it was then allowed to warm to 25° C. and stirred 1 h at 25° C. After this time, the reaction was concentrated in vacuo to ⅓ of the original volume. In a separate flask, a solution of 1-(2-isopropoxy-ethyl)-1H-pyrazol-3-ylamine (67 mg, 0.40 mmol), 2,6-lutidine (63 μL, 0.54 mmol) and methylene chloride (5 mL) was cooled to 0° C. in an ice bath. To this solution was added the solution of the prepared acid chloride, diluted with another portion of methylene chloride (2 mL), dropwise. After addition was complete the reaction was then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction mixture was diluted with methylene chloride (10 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 40% ethyl acetate/hexanes to 60% ethyl acetate/hexanes) afforded (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-isopropoxy-ethyl)-1H-pyrazol-3-yl]-propionamide (168 mg, 96%) as a white foam: [α]28589=+10.0° (c=0.43, methylene chloride); ES-HRMS m/e calcd for C23H32N3O4SCl (M+H)+ 482.1875, observed 482.1874; 1H NMR (300 MHz, DMSO-d6) δ 1.01 (d, J=6.1 Hz, 6H, 2×CH3), 1.11 (m, 2H, CH2), 1.38-1.80 (m, 8H, 4×CH2), 2.09 (m, 1H, CH), 3.34 (s, 3 H, SO2CH3), 3.47 (m, 1H, OCH), 3.64 (t, J=5.5 Hz, 2H, OCH2), 3.91 (m, 1H, ArCHCO), 4.08 (t, J=5.5 Hz, 2H, NCH2), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.54 (d, J=2.2 Hz, 1H, Ar), 7.59 (dd, Jm=1.6 Hz, Jo=8.2 Hz, 1H, Ar), 7.70 (d, Jm=1.6 Hz, 1H, Ar), 8.01 (d, Jo=8.2 Hz, 1H, Ar), 10.78 (s, 1H, NH).
Reaction SMILES: Cl[C:2]1[CH2:6][C@@H:5]([C@H:7]([N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[C:8]([O:10]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:9])[O:4][N:3]=1.[BrH:35]>[N+](C)([O-])=O>[Br:35][C:2]1[CH2:6][C@@H:5]([C@H:7]([N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[C:8]([OH:10])=[O:9])[O:4][N:3]=1
Reactant: Br
Reactant: O=C(OC(c1ccccc1)c1ccccc1)[C@H]([C@@H]1CC(Cl)=NO1)N1C(=O)c2ccccc2C1=O
Solvent: C[N+](=O)[O-]
Product: O=C(O)[C@H]([C@@H]1CC(Br)=NO1)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
To 185 mg (0.4 mmole) of the (αS,5S)-chloro-4,5-dihydro-α-phthalimido-5-isoxazole acetic acid, benzhydryl ester in 3 ml of dry nitromethane in an ice bath under nitrogen is bubbled dry hydrogen bromide for five minutes. The bath is removed and the solution stirred for one hour. After concentrating the solution is vacuo the residue is chromatographed on CC-4 silica gel (30 g) with 30%) ethyl concentrating the solution in vacuo the residue is chromatographed on CC-4 silica gel (30 g) with 30%) ethyl acetate/hexane to yield 115 mg of a white foam. This foam is recrystallized from 4/1 hexane/ethanol to yield 3-bromo-4,5-dihydro-α-phthalimido-5-isoxazole acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([CH3:17])[CH:9]=2)=[CH:5][CH:4]=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([CH3:17])[CH:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccc([N+](=O)[O-])c(C)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Oc2ccc(N)c(C)c2)cc1
Yield: 100.2 %

Procedure:
A mixture of 4-(4-methoxy-phenoxy)-2-methylnitrobenzene (3.5 grams, mmol) and methanol (200 mL) was treated with 200 miligrams of 10% palladium on carbon and was shaken under 50 psi of hydrogen gas for 3 hours. Filtration through a pad of celite and concentration in vacuo afforded 3.1 grams of 4-(4-methoxy-phenoxy)-2-methyl-phenylamine as a tan solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH3:9])[C:6](Cl)=[O:7])(=[O:3])[CH3:2].[NH2:10][C:11]1[C:12]([I:25])=[C:13]([C:22]([OH:24])=[O:23])[C:14]([I:21])=[C:15]([C:19]=1[I:20])[C:16]([OH:18])=[O:17]>CC(N(C)C)=O>[C:1]([O:4][C@@H:5]([CH3:9])[C:6]([NH:10][C:11]1[C:19]([I:20])=[C:15]([C:16]([OH:18])=[O:17])[C:14]([I:21])=[C:13]([C:12]=1[I:25])[C:22]([OH:24])=[O:23])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Product: CC(=O)O[C@@H](C)C(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Temperature: 50 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
(S)-1-chloro-1-oxopropan-2-yl acetate (37.4 ml, 295.4 mmol) was added slowly to a suspension of 5-amino-2,4,6-triiodoisophthalic acid (50.0 g, 89.5 mmol) in DMA (100 ml) at a temperature of between 25° C. and 29° C. The resulting mixture was heated to about 50° C. and stirred at this temperature for about 8 hours after which heating was removed and the mixture was stirred for about 14 hours at room temperature. The reaction mixture was added slowly over water (500 ml) with strong stirring at a temperature between 22° C. and 30° C. After addition 300 ml of water were added to the suspension. The suspension was stirred for 5 further hours at about 22° C. after which the white solid was filtered and washed with water previously cooled at about 5° C. twice (30 ml each time). The product was dried in a vacuum oven at about 5.0° C. to yield (S)-5-(2-acetoxypropanamido)-2,4,6-triiodoisophthalic acid (48.8 g, 72.5 mmol).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([NH:8][CH2:9][CH:10]([OH:29])[CH2:11][O:12][C:13]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:14]=1[C:15]([CH2:17][CH2:18][C:19](OCC)=[O:20])=O)([CH3:7])([CH3:6])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O>[C:4]([NH:8][CH2:9][CH:10]([OH:29])[CH2:11][O:12][C:13]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:14]=1[C:15]1[CH2:17][CH2:18][C:19](=[O:20])[NH:2][N:3]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOC(=O)CCC(=O)c1ccc(Cl)cc1OCC(O)CNC(C)(C)C
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)NCC(O)COc1cc(Cl)ccc1C1=NNC(=O)CC1

Procedure:
Hydrazine hydrate (1.57 ml, 0.0314 mole) was added to a stirred solution of ethyl 3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-chlorobenzoyl]propionate (2.4 g, 0.0065 mole) in glacial acetic acid (36 ml) and the solution was heated under reflux for 90 minutes. Evaporation under reduced pressure gave an oil which was dissolved in water, treated with an excess of aqueous sodium carbonate solution and the mixture was extracted with dichloromethane. Evaporation of the dried or ganic extracts gave an oil which was purified on a silica column by elution with mixtures of chloroform and methanol to give 6-[2-(3-t-butylamino-2-hydroxypropoxy)-4-chlorophenyl]-4,5-dihydro-3(2H)-pyridazinone (1.1 g, 50%, m.p. (195° ). The hemisulphate, crystallised from ethanol, had m.p. 250° (decomposition). (Found: C, 50.19; H, 6.21; Cl, 8.75; N, 10.11; S, 3.89; M+, 353/355. C17H24ClN3O3.0.53 H2SO 4 requires; C, 50.31; H. 5.96; Cl, 8.74; N, 10.35; S, 4.17%; M(base), 353/355).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.Cl>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)=[O:27])=[CH:24][CH:23]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(C(F)(F)F)cc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Product: CN1CC=C(c2cn(C(=O)c3ccc(F)cc3)c3ccc(C(F)(F)F)cc23)CC1

Procedure:
(22.8 mg, 79%); from 3 -(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethyl-1H-indole (Example 4i, 20 mg, 0.071 mmol) and 4-fluorobenzoyl chloride (17.0 mg, 0.107 mmol), HRMS-FAB+ for C22H18N2OF4, calculated MH+ (--HCl): 403.14344; found: 403.14104.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CN1CCCC1=O.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>O>[C:22]([NH:26][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a mixture of 5.22 g of 4-fluoro-3-nitro-benzo trifluoride and 25 ml of N-methylpyrrolidone was added 3.88 g of tert-butylamine, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water, the deposited solid was collected by filtration. This solid was washed with water, then, dried under reduced pressure, to obtain 5.35 g of N-tert-butyl-2-nitro-4-trifluoromethylaniline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21](O)=[O:22])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=1.[CH:24]([NH:27][NH:28][C:29]([C:31]1[O:32][CH:33]=[CH:34][C:35]=1[CH3:36])=[O:30])([CH3:26])[CH3:25].C(NC(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([N:27]([CH:24]([CH3:26])[CH3:25])[NH:28][C:29]([C:31]2[O:32][CH:33]=[CH:34][C:35]=2[CH3:36])=[O:30])=[O:22])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=1
Reactant: Cc1ccoc1C(=O)NNC(C)C
Reactant: O=C(O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: Cc1ccoc1C(=O)NN(C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F)C(C)C
Yield: 56.9 %

Procedure:
A solution of (5-fluoro-2′-trifluoromethoxy-biphenyl-2-yloxy)-acetic acid (211 mg, 0.64 mmol) and 3-methyl-furan-2-carboxylic acid N′-isopropyl-hydrazide (140 mg, 0.768 mmol) in DMF (3 ml) was treated with diisopropyl amine (0.278 ml, 1.6 mmol) and PyBroP (448 mg, 0.96 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 50-100% ethyl acetate in hexanes gradient to afford the product as a white solid (180 mg, 57%). MS m/e 495.19 (M+H+)
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][N:35]3[C:43](=[O:44])[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:36]3=[O:45])=[CH:28][CH:27]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.[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>[F:15][C:14]([F:17])([F:16])[O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[N:6][C:2]([C:26]3[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][CH2:34][N:35]4[C:36](=[O:45])[C:37]5[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:43]4=[O:44])=[CH:30][CH:31]=3)=[N:3]2)=[CH:8][CH:9]=1
Reactant: CC1(C)OB(c2ccc(CCCN3C(=O)c4ccccc4C3=O)cc2)OC1(C)C
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 140 °C
Yield: 53.3 %

Procedure:
3-Bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (0.50 g, 1.6 mmol), 2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)isoindoline-1,3-dione (0.64 g, 1.6 mmol), sodium bicarbonate (0.27 g, 3.3 mmol), and tetrakis(triphenylphosphine) palladium(0) (0.19 g, 0.16 mmol) in dioxane (12 mL) and water (4.1 mL) was capped in a 10-20 mL vial and heated on a Biotage Initiator® microwave reactor for 30 minutes at 140° C., with external IR-sensor temperature monitoring from the side of the vessel. The mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography using 0-30% ethyl acetate/B, where B=1:1 dichloromethane/hexanes provided a solid which was dried under house vacuum overnight providing the title compound as a white solid (0.42 g, 53% yield): mp 145-148° C.; 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J=0.8 Hz, 1H), 8.08 (d, J=8.1 Hz, 2H), 7.84 (ddd, J=5.5, 3.0, 0.8 Hz, 2H), 7.82-7.77 (m, 2H), 7.69 (ddd, J=5.5, 3.0, 0.8 Hz, 2H), 7.38 (dt, J=9.0, 1.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 3.78 (t, J=7.2 Hz, 2H), 2.79-2.71 (m, 2H), 2.08 (p, J=7.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 493 ([M+H]+).
Reaction SMILES: [CH:1]1([N:4]([C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[O:22])=[C:16]3[N:15]=[C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)[CH:13]=2)C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[O:22])=[C:16]3[N:15]=[C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)[CH:13]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(c1cc(-c2cccc(O)c2)nc2c(C=O)cnn12)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1cnn2c(NC3CC3)cc(-c3cccc(O)c3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
To tert-butyl cyclopropyl(3-formyl-5-(3-hydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)carbamate (400 mg, 1.01 mmol) in methylene chloride (20 mL) was added TFA (10 mL). The reaction mixture was stirred at room temperature for 2 h. The volatiles were removed by rotary evaporation and the residue was purified by silica gel chromatography (0%-40% EtOAc/hexanes) to provide 103 mg of 7-(cyclopropylamino)-5-(3hydroxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. (35%). LCMS (M+1=295)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.C1C=[CH:13][C:14]2N(O)N=N[C:15]=2[CH:16]=1.CCN(C(C)C)C(C)C.C1(CO)CC1>O.C(Cl)CCl.CN(C=O)C>[CH:15]1([CH2:16][O:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N:6]=2)=[O:10])[CH2:13][CH2:14]1
Reactant: O=C(O)c1ccc(O)cn1
Reactant: On1nnc2ccccc21
Agent: OCC1CC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCC1CC1)c1ccc(O)cn1

Procedure:
To DMF (10 mL) was added 5-hydroxy-pyridine-2-carboxylic acid (1.0 g) followed by EDC (1.38 g), HOBt (971 mg) and DIPEA (1.22 mL). After 15 minutes cyclopropyl-methanol (520 mg) was added. After 12 hours the mixture was diluted with water and extracted three times with EA. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated to provide the title compound. MS ESI+: m/z=194 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:15])[CH2:3][NH:4][C:5]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:14][C:12]1[CH:11]=[CH:10][C:6]2[C:7](=[O:8])[NH:1][C@@H:2]([CH3:15])[CH2:3][NH:4][C:5]=2[CH:13]=1
Reactant: C[C@H](N)CNc1cc(Br)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1CNc2cc(Br)ccc2C(=O)N1
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
To a solution of the crude (S)-2-((2-aminopropyl)amino)-4-bromobenzoic acid (544 mg, 2.0 mmol) and Et3N (731 mg, 7.24 mmol) in DMF was added HATU (829 mg, 2.18 mmol). After 30 min, the reaction mixture was concentrated and purified by flash chromatography on silica gel (2-10% MeOH/DCM eluent) to provide (S)-8-bromo-3-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepin-5(2H)-one as a white oily solid (464 mg, 91% yield). This material was dissolved in dioxane (20 mL), then treated with Pd2(dba)3 (83 mg, 0.09 mmol), PCy3 (121 mg, 0.43 mmol), diboron pinacol ester (595 mg, 2.35 mmol) and KOAc (532 mg, 5.43 mmol), then heated at 90° C. for 2 h. At completion, the reaction was cooled to room temperature, then filtered and concentrated. The crude material was flashed over silica gel (2-10% MeOH/DCM eluent) to provide (S)-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-benzo[e][1,4]diazepin-5(2H)-one (527 mg, 96% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].[CH3:41][NH:42][CH2:43]C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:41][N:42]([CH3:43])[CH2:9][CH2:8][N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11]
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reactant: CCNC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CCN(C)C)c4)cc23)CC1
Yield: 40.3 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting [2-(dimethylamino)ethyl]methylamine (102 mg, 1.0 mmol) for N-methylethanamine to afford 26.0 mg of the title compound (40.3%).