Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)[CH:5]=[CH:6][C:7]=1[OH:8].C1C(=O)N([Cl:27])C(=O)C1>C1COCC1>[Cl:27][C:15]1[C:16]2[C:11](=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[OH:19]
Reactant: Oc1ccc2cc(-c3ccc(O)c(Cl)c3)ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Oc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)cc1Cl

Procedure:
The title compound was prepared by reacting 6-(3-chloro-4-hydroxyphenyl)-2-naphthol (500 mg, 1.85 mmol) and NCS (346 mg, 2.59 mmol) in THF (37 mL) according to method A to yield 380 mg (68%) of yellowish solid: mp 174–175° C.; 1H NMR (DMDO-d6): δ 7.09 (1H, d, 8.47 Hz), 7.31 (1H, d, J=8.89 Hz), 7.60 (1H, dd, J=8.20 Hz, J=2.26 Hz), 7.78 (1H, d, J=2.22 Hz), 7.84 (1H, d, J=8.99 Hz), 7.88 (1H, dd, J=9.00 Hz, J=1.80 Hz), 8.05 (1H, d, J=8.86 Hz), 8.14 (1H, d, J=1.60 Hz), 10.37 (1H, s), 10.49 (1H, s); MS (ESI) m/z 303/305/307 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:12][CH:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])=[CH:9][C:10]#[N:11].[CH:18]1([CH2:21][C:22](Cl)=[O:23])C[CH2:19]1.N1C=CC=CC=1>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:12][CH:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])=[C:9]([C:22](=[O:23])[CH2:21][CH2:18][CH3:19])[C:10]#[N:11]
Reactant: O=C(Cl)CC1CC1
Reactant: CC(C)C(C)NC(=CC#N)c1ccccc1Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CCCC(=O)C(C#N)=C(NC(C)C(C)C)c1ccccc1Cl
Temperature: 80 °C
Yield: 79 %

Procedure:
To a solution of 3-(2-chlorophenyl)-3-[(3-methylbutan-2-yl)amino]acrylonitrile (1 g, 4.02 mmol, 1 eq.) in 1,2-dichloroethane (2 ml) were added cyclopropylacetyl chloride (1.71 g, 16.08 mmol, 4 eq.) and pyridine (1.58 g, 20.1 mmol, Seq.) and the solution was heated to 80° C. for 8 h. The reaction was quenched with 1N aq. HCl (20 ml) and extracted with ethylacetate. The organic layers were combined and washed with 1N aq. NaOH (20 ml), dired over MgSO4 and concentration under vacuum. The residual oil was subjected to column chromatography to give 2-{(2-chlorophenyl)[(3-methylbutan-2-yl)amino]methylene}-3-oxohexanenitrile (1.012 g, 75% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][NH:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(F)cc3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-c2ccc(OCC3CCNC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
1.55 g (4.17 mmol) of tert-butyl 3-(4′-fluorobiphenyl-4-yloxymethyl)pyrrolidine-1-carboxylate are dissolved in 40 ml of dichloromethane and then, at 0° C., 6.00 ml (80.77 mmol) of trifluoroacetic acid are subsequently added. After stirring at ambient temperature for two hours, the mixture is concentrated to dryness and then the residue is taken up in water and dichloromethane. A saturated sodium hydrogencarbonate solution is added and then the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under vacuum. 0.98 g of product is obtained in the form of an oil, used as is in the following stage.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N:6]=1)(=[O:3])[CH3:2].C(O)(=[O:14])C.C(OO)(=O)C>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N+:6]=1[O-:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(Br)n1
Reactant: CC(=O)O
Agent: CC(=O)OO
Solvent: O
Product: CC(=O)Nc1cccc(Br)[n+]1[O-]
Yield: 83 %

Procedure:
23.4 gms (0.109 mole) of 2-acetamido-6-bromopyridine was dissolved in 200 ml. of glacial acetic acid containing 27.6 ml (0.218 mole) of 7.9M peracetic acid and the solution was heated at 70° C for 2 hours and at 55° C for 19 hours. The reaction mixture was diluted with 1600 ml water and the solution was then concentrated in vacuo to 550 ml. 8.6% of unreacted-2-acetamido-6-bromopyridine was removed by filtration. The solvent was evaporated from the filtrate giving an 83% yield of impure 2-acetamido-6-bromopyridine-1-oxide which was purified by treatment with activated charcoal to remove the yellow impurity and subsequently recrystallized from 2-propanol. A second recrystallization from 2-propanol gave fine white needles, m.p=180.0°-180.5° C.
Reaction SMILES: [ClH:1].Cl.[NH2:3]/[C:4](=[N:25]\[OH:26])/[C:5]1[CH:24]=[CH:23][C:8]2[CH:9]=[C:10]([C:12]([NH:14][C@@H:15]3[CH:20]4[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]4)[CH2:16]3)=[O:13])[S:11][C:7]=2[CH:6]=1.[H-].[Na+].[C:29](OC)(=O)[CH3:30].O>CN(C=O)C.C1COCC1>[ClH:1].[N:17]12[CH2:18][CH2:19][CH:20]([CH2:21][CH2:22]1)[C@@H:15]([NH:14][C:12]([C:10]1[S:11][C:7]3[CH:6]=[C:5]([C:4]4[N:3]=[C:29]([CH3:30])[O:26][N:25]=4)[CH:24]=[CH:23][C:8]=3[CH:9]=1)=[O:13])[CH2:16]2
Reactant: COC(C)=O
Reactant: N/C(=N\O)c1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
154 mg (0.37 mmol) of 6-[amino(hydroxyimino)methyl]-N-[(3R)-1-azabicyclo[2.2.2]-oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride (Example 27A) are dissoved in 2 ml of DMF and 0.75 ml of THF. 250 mg of 4 Å molecular sieves are added, and the mixture is stirred at room temperature for 30 min. Addition of 44.4 mg (1.11 mmol) of sodium hydride (60% suspension in mineral oil) is followed by heating at 60° C. for 20 min and then cooling to room temperature. A solution of 90 μl (1.11 mmol) of methyl acetate in 1 ml of THF is then added to the reaction mixture, after which it is heated at 80° C. for 14 h. Addition of a further 29.6 mg (0.74 mmol) of sodium hydride (60% suspension in mineral oil) and 0.88 ml (11.1 mmol) of methyl acetate in 1 ml of THF is followed by heating at 70° C. for a further 24 h. The reaction is stopped by adding water. Purification takes place by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 4N hydrogen chloride in dioxane, again concentrated. Drying under high vacum results in 41.9 mg (23.6% of theory) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[OH:26].[CH2:28](I)[CH3:29]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[O:26][CH2:28][CH3:29]
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: CCI
Product: CCOc1cc(-c2nc(CNC(=O)c3ncccc3C)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 97 and ethyl iodide, white powdery N-[2-(4-difluoromethoxy-3-ethoxyphenyl)-oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH2:14][CH2:15][C:16]([O:18]CC)=[O:17].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>ClC1C=CC=CC=1Cl>[CH3:8][C:6]1[CH:7]=[C:2]2[C:3](=[CH:4][CH:5]=1)[N:9]1[C:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:11][CH:12]=[C:13]1[C:21](=[O:22])[NH:1]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)CCc1nccn1-c1ccc(C)cc1N
Solvent: Clc1ccccc1Cl
Product: Cc1ccc2c(c1)[nH]c(=O)c1cnc(CCC(=O)O)n12

Procedure:
Ethyl 3-[1-(2-amino-4-methylphenyl)-1H-imidazol-2-yl]-propanoate as synthesized in above Example 181, 160 mg, 1,1′-carbonyldiimidazole 143 mg and 1,2-dichlorobenzene 6 mL were mixed and heated under reflux for 1.5 hours. The reaction liquid was allowed to cool off, and the precipitate was recovered by filtration and washed with ethyl acetate. After being dried under reduced pressure, the product was mixed with 3 mL of ethanol and 3.0 mL of 1N aqueous sodium hydroxide solution and heated under reflux for 20 minutes. Cooling the reaction liquid off, 3.0 mL of 1N hydrochloric acid was added. The precipitated crystals were recovered by filtration, washed with water and dried in flowing air under heating to provide 82 mg of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C@H:23]([CH2:35][CH:36]=O)[CH2:24][N:25]([CH3:34])[C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:19]=[CH:20][C:21]=1[Cl:22].ClCCl.CO>O>[ClH:15].[Cl:15][C:16]1[CH:17]=[C:18]([C@H:23]([CH2:35][CH2:36][N:12]2[CH2:13][CH2:14][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=3)[CH2:10][CH2:11]2)[CH2:24][N:25]([CH3:34])[C:26](=[O:33])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CSc1ccc(C2CCNCC2)cc1
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CSc1ccc(C2CCN(CC[C@H](CN(C)C(=O)c3ccccc3)c3ccc(Cl)c(Cl)c3)CC2)cc1
Product: Cl

Procedure:
Using a procedure similar to that described in Example 1 (alternative preparation), except using 4-(4-methylthiophenyl)piperidine and (S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide, the title compound was prepared. Chromatography with dichloromethane:methanol followed by conversion to the hydrochloride salt gave a white solid; mp 73-92(dec) °C.; MS: 541; NMR (CD3OD): 1.8-2.2 (m, 6), 2.4 (s, 1), 2.7 (s, 3), 2.6-3.2 (m, 6), 3.4-3.8 (m, 4), 6.9 (d, J=7, 1), 7.1-7.2 (m, 6), 7.3 (m, 5), 7.5(m, 1). Analysis for C30H34Cl2NO2S·1.0HCl·1.0 H2O: Calculated: C, 60.45; H, 6.26; N, 4.70; Found: C, 60.23; H, 5.85; N, 4.70.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:29])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:18][C:19]([CH3:27])=[C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21]=2[CH3:22])=[O:16])=[CH:8][C:7]=1[CH3:28].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[OH:29][CH:3]([CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:18][C:19]([CH3:27])=[C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21]=2[CH3:22])=[O:16])=[CH:8][C:7]=1[CH3:28])[CH2:2][NH:1][S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(CCC(=O)c2sc(C)c(CC(C)C)c2C)cc(C)c1OCC(O)CN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CCC(=O)c2sc(C)c(CC(C)C)c2C)cc(C)c1OCC(O)CNS(C)(=O)=O
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a solution of rac-3-[4-(3-amino-2-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(4-isobutyl-3,5-dimethyl-thiophen-2-yl)-propan-1-one (545 mg, 1.31 mmol) in DCM (27 mL), DIPEA (270 mg, 2.09 mmol) is added. The mixture is cooled to 0° C. before methanesulfonylchloride (180 mg, 1.51 mmol) is added. Stirring is continued at 0° C. for 1 h. The mixute is diluted with DCM, washed with water, dried over MgSO4, filtered and concentrated. The crude product is purified by chromatography on prep. TLC plates with DCM containing 4% of MeOH to give N-(2-hydroxy-3-{4-[3-(4-isobutyl-3,5-dimethyl-thiophen-2-yl)-3-oxo-propyl]-2,6-dimethyl-phenoxy}-propyl)-methanesulfonamide (545 mg) as a yellow oil; LC-MS: tR=1.06 min, [M+1]=496.24.
Reaction SMILES: C([Li])CCC.[F:6][C:7](F)([F:20])[CH2:8][O:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].C(O)(=O)C.C(OCC)(=O)C>C1COCC1>[F:20][C:7]([F:6])=[CH:8][O:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)OC=C(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
Add n-butyllithium (1.6 M in hexanes, 4.9 mL, 7.8 mmol) dropwise over 5 min to a solution of 2,2,2-trifluoroethyl-p-toluene sulfonate (1.0 g, 3.9 mmol) in THF (20 mL) at −78° C. Stir for 30 min, add acetic acid (225 μL, 3.9 mmol) and stir for 30 min. Warm to room temperature, add ethyl acetate and extract with saturated aqueous ammonium chloride, and saturated aqueous sodium bicarbonate. Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 15:85 ethyl acetate:hexanes) to give the title compound as an oil (430 mg, 47%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4]Br.ClC1C=CC(N[C:14]2[C:23]3[C:18](=[CH:19][C:20](O)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=C(F)C=1.C(=O)([O-])[O-:31].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][O:31][C:16]1[N:15]=[CH:14][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: O=C([O-])[O-]
Reactant: COC(CBr)OC
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2nc(OCC(OC)OC)ncc2c1
Temperature: 110 °C
Yield: 53.7 %

Procedure:
Bromoacetaldehyde dimethyl acetal (0.74 ml, 3.1 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.0 g, 3.13 mmol), (prepared as described for the starting material in Example 2), and anhydrous potassium carbonate (2.16 g, 15.6 mmol) in DMF (30 ml). The mixture was stirred and heated at 110° C. for 4 hours, then allowed to cool and the volatiles were removed by evaporation. Water was added to the residue and the aqueous mixture was extracted with methylene chloride (×4). The extracts were combined, washed with brine and dried by filtration through phase separating paper. The volatiles were removed by evaporation, the residue was triturated with ether, collected by filtration and dried to give 44-chloro-2-fluoroanilino)7-(2,2-dimethoxyethoxy6-methoxyquinazoline (440 mg, 35%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][N:9]=2)=[CH:3][CH:2]=1.C1(=O)OC(=[O:23])C2=CC=CC=C12.CC1C=CN=CC=1>>[CH:15]1[CH:16]=[C:17]2[C:8]([C:7]([C:11](=[O:18])[C:12]2=[CH:13][CH:14]=1)=[C:4]1[CH:5]=[CH:6][NH:1][CH:2]=[CH:3]1)=[O:23].[NH2:9][NH2:10]
Reactant: O=c1[nH]nc(Cc2ccncc2)c2ccccc12
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccncc1
Product: NN
Product: O=C1C(=C2C=CNC=C2)C(=O)c2ccccc21

Procedure:
The production of, for example, 4-(4-pyridylmethyl)-1(2H)-phthalazinone is carried out according to previously known methods by the reaction of phthalic acid anhydride and 4-methylpyridine at about 200° C. and subsequent reaction of the condensation product that is obtained (γ-pyrophthalone) with excess hydrazine at 130° C. (DE AS 1 061 788). Drawbacks of these methods are the low yield (<50%), low product quality and primarily the necessarily very high temperature of the condensation reaction, which makes very difficult an industrial-scale application of the methods.
Reaction SMILES: [F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]1[CH:19]=[N:20][C:21]([C:25](O)(O)[C:26]([F:29])([F:28])[F:27])=[CH:22][C:23]=1[CH3:24])[CH:12]=2)=[O:6].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]1[CH:19]=[N:20][C:21](/[C:25](=[N:39]/[CH2:38][C:37]3[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)/[C:26]([F:27])([F:29])[F:28])=[CH:22][C:23]=1[CH3:24])[CH:12]=2)=[O:6]
Reactant: Cc1cc(C(O)(O)C(F)(F)F)ncc1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Reactant: COc1ccc(CN)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(C/N=C(/c2cc(C)c(-c3ccc4cc(NC(=O)[C@@H]5C[C@@H]5F)ncc4c3)cn2)C(F)(F)F)cc1
Temperature: 100 °C

Procedure:
To a mixture of (1S,2S)-2-fluoro-N-(7-(4-methyl-6-(2,2,2-trifluoro-1,1-dihydroxyethyl)pyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (113.8 mg; 0.2614 mmol) and toluene (2 mL) was added a scoop of oven-dried 4 angstrom molecular sieves and a premixed solution of 4-methoxybenzylamine (54 μL; 0.393 mmol) and acetic acid (23 μL; 0.401 mmol) in toluene (1 mL). The reaction mixture was then heated at 100° C. for 3 days. The reaction mixture was cooled to room temperature and partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-10% methanol in dichloromethane) to yield 99.7 mg of a 1:1 mixture of the title compound and unreacted starting material. LCMS (ESI): M+H=419.2.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4](I)[C:3]=1[F:23].[CH3:24][C:25]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH:24]=[CH2:25])[C:3]=1[F:23]
Reactant: CCOC(=O)C(C)Oc1c(C2(C)OCCO2)cc(Cl)c(F)c1I
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: C=Cc1c(F)c(Cl)cc(C2(C)OCCO2)c1OC(C)C(=O)OCC
Temperature: 80 °C
Yield: 157.2 %

Procedure:
A mixture of ethyl 2-[4-chloro-3-fluoro-2-iodo-6-(2-methyl-1,3-dioxolan-2-yl)phenoxy]propanoate (1.83 g, 3.99 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.880 mL, 5.19 mmol), and potassium carbonate (1.65 g, 12.0 mmol) in 1,4-dioxane (15.6 mL) and water (7.8 mL) was degassed with nitrogen for 10 min. The reaction mixture was treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (163 mg, 0.199 mmol), degassed with nitrogen for another 10 min, and heated at 80° C. for 2 h. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was poured into water. The aqueous layer was separated and re-extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated give a crude residue. Purification by flash column chromatography (100% hexanes to 15% EtOAc/hexanes) gave the desired product (2.25 g, 57%) as a mixture of enantiomers. LCMS calculated for C17H21ClFO5 (M+H)+: m/z=359.1; found: 359.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[CH:8]([OH:27])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:41](OC(=O)C)([F:43])[F:42]>O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:41]([F:43])[F:42])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CC(=O)OC(F)(F)Cl
Reactant: CCC1=C(Cc2ccc(F)cc2)C(O)c2c(OCC(=O)OC)ccc(Cl)c2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of [8-chloro-2-ethyl-3-(4-fluorobenzyl)-4-hydroxy-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.25 g), N,N-dimethylformamide (1.1 mL), potassium carbonate (0.51 g) and acetic acid chlorodifluoromethyl ester (0.33 mL) was stirred at 70° C. for 16 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts dried over sodium sulfate and then the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane gave title compound, 0.06 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][N:12]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.ClCCl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][C:26]=1[F:34]>CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[O:9][CH2:10][CH2:11][N:12]([CH2:14][C@H:15]([O:20][C:32](=[O:33])[NH:31][C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[C:26]([F:34])[CH:27]=3)[C:16]([F:18])([F:19])[F:17])[CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(Cl)c(F)c1
Reactant: O[C@@H](CN1CCOC(c2cccc(Cl)c2)C1)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Cl
Product: O=C(Nc1ccc(Cl)c(F)c1)O[C@@H](CN1CCO[C@@H](c2cccc(Cl)c2)C1)C(F)(F)F
Temperature: 50 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
In a 50 mL round-bottom flask, (2S)-3-(2-(3-chlorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol (218 mg, 704 μmol) was combined with dichloromethane (12 ml) to give a colorless solution. TEA (71.2 mg, 98.1 μl, 704 μmol) was added. 1-Chloro-2-fluoro-4-isocyanatobenzene (157 mg, 915 μmol) was added. The reaction mixture was heated to 50° C. and stirred for 3 h and filtered. The solid was washed with dichloromethane (2×). The combined filtrate and washes were concentrated to a reduced volume and loaded onto a silica column. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 20% EtOAc in hexanes). The fractions that contained product were re-purified by flash chromatography (silica gel, 40 g, 10% to 20% (2:1 dichlormethane:EtOAc) in hexanes). The fractions from the back peak were pooled and concentrated and the resulting colorless film was dissolved in 2:1 hexanes ether and treated with 1M HCl in ether (1 mL). The resulting sticky solid was concentrated in vacuo to afford the salt, which was foamed to a white solid with ether (120 mg). The foam was triturated with ether/hexanes to afford ca. 90% pure (4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(S)-2-(3-chlorophenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochloride. LCMS: M+1=481;
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:14])=[C:8]([CH2:12][CH3:13])[C:9]=2[CH3:11])[S:4][C:3]=1[C:15]([OH:17])=O.N=C=N.[C:21]1([C:27]2NN=[N:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClC(Cl)C.CN(C=O)C>[CH2:12]([C:8]1[C:9]([CH3:11])=[C:10]2[C:2]([NH2:1])=[C:3]([C:15]3[O:17][C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:28][N:29]=3)[S:4][C:5]2=[N:6][C:7]=1[CH3:14])[CH3:13]
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: CCc1c(C)nc2sc(C(=O)O)c(N)c2c1C
Agent: N=C=N
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1c(C)nc2sc(-c3nnc(-c4ccccc4)o3)c(N)c2c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
To a solution of 3-amino-5-ethyl-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylic acid (0.16 g, 0.63 mmol) in a mixture of dichloroethane (8 mL) and DMF (2 mL) was added PS-carbodiimide (1.0 g, 1.26 mmol). The mixture was shaken for 15 min at room temperature, followed by the addition of 5-phenyltetrazole (0.042 g, 0.32 mmol). Then, the mixture was shaken at 80° C. overnight. The resin was then removed by filtration and washed with hot chloroform (2×5 mL). The filtrate was evaporated in vacuum to dryness and purified by chromatography (silica gel, dichloromethane/ethyl acetate, 9/1) to furnish the product 5-ethyl-4,6-dimethyl-2-(5-phenyl-[1,3,4]oxadiazol-2-yl)-thieno[2,3-b]pyridin-3-yl amine (0.063 g, 56%).