Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Br:5][C:6]1[CH:11]=[CH:10][N+:9](O)=[C:8](C)[C:7]=1C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[CH:8][N:9]=[C:2]([CH2:1][OH:4])[C:11]=1[CH3:10]
Reactant: Cc1c(Br)cc[n+](O)c1C
Reactant: CC(=O)[O-]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1c(Br)ccnc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To a stirred solution of 4-bromo-1-hydroxy-2,3-dimethyl-pyridin-1-ium acetate (which may be prepared as described in Description 5) (18120 mg, 69.13 mmol) in DCM (100 mL) was added trifluoroacetic anhydride (23.89 mL, 171.9 mmol) dropwise and the reaction was stirred at room temperature for 8 hours, then additional trifluoroacetic anhydride (23.89 mL, 171.9 mmol) was introduced. After 1 day, the reaction mixture was concentrated in vacuo to remove excess TFAA & DCM. The residue was then diluted with MeOH (200 mL) and a solution of saturated aqueous K2CO3 (approximately 100 mL) was added with caution [exotherms]. The resultant suspension was stirred for 3 hours and then concentrated in vacuo. The residue was then partitioned between DCM (200 mL) and water (200 mL). The organics were separated and dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in DCM (100 mL) and trifluoroacetic anhydride (23.89 mL, 171.9 mmol) was added dropwise and the reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, and the residue, diluted with MeOH (200 mL) and a solution of saturated aqueous K2CO3 (approximately 100 mL) was added with caution, and the resulting suspension was stirred for 3 hours. The reaction mixture was then concentrated in vacuo, and the residue was partitioned between DCM (200 mL) and water (200 mL). The organics were separated and dried over MgSO4, filtered and concentrated in vacuo. The residue was purified over silica (100 g SNAP), using the Isolera instrument, eluting with EtOAc: isohexane 0%-50%. Fractions containing desired product were combined and concentrated in vacuo to give (4-bromo-3-methyl-2-pyridyl)methanol (D6) (7055 mg, 34.917 mmol, 50.5% yield) as a yellow solid;
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3]1.[C:29](OC(=O)C)(=[O:31])C>C(O)=O>[CH:29]([NH:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3]1)=[O:31]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: O=CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](NC=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
3α-Aminocholestane (2.00 g, 5.15 mmol) was dissolved in 98-100% formic acid (10 ml) and acetic anhydride (3.6 ml) was added under ice cooling. After the mixture was stirred for 18 hours at room temperature, the precipitated solid was filtered off and recrystallized from methanol to obtain N-formyl-3α-aminocholestane (1.14 g, yield=53%). The N-formyl-3α-aminocholestane was dissolved in tetrahydrofuran (50 ml) and lithium aluminum hydride (415 mg) was added. The mixture was heated under reflux for 1.5 hours. After the completion of the reaction, saturated aqueous solution of sodium sulfate was added to the mixture to decompose an excess of lithium aluminum hydride. Ether (100 ml) was added, and the mixture was stirred and allowed to stand. After the organic layer was collected by decantation, ether (50 ml) was added to the aqueous layer. After the mixture was stirred and allowed to stand, the ether layer was collected again. The organic layers were combined, washed with saturated saline solution, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate (50 ml) and 4N hydrochloric acid-ethyl acetate (0.7 ml) was added. The resulting precipitate was filtered off. The precipitate was suspended in ether (500 ml) and 40% aqueous solution of potassium hydroxide (100 ml) was added. The suspension was vigorously stirred until the precipitate was dissolved. The ether layer was washed with saturated saline solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (1.04 g, yield=94%).
Reaction SMILES: C(=O)(OC1C=CC(C=C)=CC=1)[O:2][C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:12]([CH3:14])[CH3:13].C(C=C(C)C(O)=O)CC=C(C)C(O)=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>C1(C)C=CC=CC=1>[CH3:11][CH:9]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:12]([CH3:14])[CH3:13])[C:3]=1[OH:2])[CH3:10]
Reactant: C=Cc1ccc(OC(=O)Oc2c(C(C)C)cccc2C(C)C)cc1
Agent: CC(=CCCC=C(C)C(=O)O)C(=O)O
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1O

Procedure:
The polymerisation carried in a manner similar to that Whitcombe et al. The Molar ratio used was of (2,6-diisopropyl)phenyl (4-vinylphenyl) carbonate to crosslinker (ethylenedimethacrylic acid) to 1,1′-azobis(cyclohexanecarbonitrile) (ABCHC) was 1:19:0.125 for bulk and 1:1:0.125 for membranes, 2 ml/g monomers as porogen (toluene). The polymerisation took 48 hors to complete at 60–80° C. for bulk polymer and 24 hours for the membranes.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[C:34]([O:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=O)=[CH:43][CH:42]=1)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:45][C:44]1[CH:43]=[CH:42][C:41]([O:40][C:34](=[O:39])[C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:49][CH:48]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(C)C(=O)Oc1ccc(C(=O)Cl)cc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(OC(=O)C(C)(C)C)cc3)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 1-(3) and 4-pivaloyloxybenzoyl chloride were treated in a manner similar to Example 2-(4), (5) and 27-(3) to give 4-chloro-3-(4-pivaloyloxyphenylmethyl)-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole as a colorless powder. APCI-Mass m/Z 689/691 (M+NH4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[CH2:11]([NH2:14])[C:12]#[CH:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH:14][CH2:11][C:12]#[CH:13]
Reactant: C#CCN
Reactant: O=Cc1ccc(F)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: C#CCNCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.6 %

Procedure:
To a solution of 3,4-difluorobenzaldehyde (5 g, 35.2 mmol) in 200 mL dichloroethane was added mono-propargyl amine (4.85 mL, 70.7 mmol, 2 eq.) followed by Na(OAc)3BH (9 g, 42.5 mmol) and the mixture was stirred for 2 days at room temperature. The solution was diluted with 100 mL of dichloromethane, washed with 2×100 mL aq. NaHCO3, 100 mL brine, dried over Na2SO4, filtered and concentrated. The crude product was chromatographed with 20:80 ethyl acetate-hexanes to provide 3.8 g of (3,4-difluoro-benzyl)-prop-2-ynyl-amine as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([F:18])([F:17])[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH3:2].[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[C:5]([F:18])([F:17])[CH2:6][N:7]([C:23]1[C:24]([N+:28]([O-:30])=[O:29])=[CH:25][N:26]=[C:21]([Cl:20])[N:22]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(F)(F)CNCc1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)CN(Cc1ccc(OC)cc1)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.2 %

Procedure:
A solution of 1.2 g (0.0044 mole) of 2,2-difluoro-3-(4-methoxy-benzylamino)-propionic acid ethyl ester) in 4 mL of ethyl acetate was added over 5 minutes to a cooled (0 degrees) mixture of 0.85 g (0.0044 mole) of 2,4-dichloro-5-nitro-pyrimidine, 1.5 g (0.018 mole) of sodium bicarbonate and 10 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure to give 1.9 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(4-methoxy-benzyl)-amino]-2,2-difluoro-propionic acid ethyl ester (IV-291) as a yellow thick oil. This material was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](O)=O)[CH:5]=[CH:6][CH:7]=1.[Br:12]CCC1C=CC=CC=1F>>[Br:12][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: Fc1ccccc1CCBr
Product: Fc1cccc(CCBr)c1

Procedure:
1-(2-Bromoethyl)-3-fluorobenzene was prepared from 3-fluorophenylacetic acid as described above for 1-(2-bromoethyl)-2-fluorobenzene.
Reaction SMILES: [H-].[Na+].C1(C)C=CC=CC=1.[CH2:10]([C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[N:24][CH:25]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].FC(F)(F)S(O[CH2:39][C:40]([F:52])([F:51])[C:41]([F:50])([F:49])[C:42]([F:48])([F:47])[CH2:43][O:44][CH2:45][CH3:46])(=O)=O>O.CN(C)C=O>[CH2:10]([C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:39][C:40]([F:51])([F:52])[C:41]([F:49])([F:50])[C:42]([F:48])([F:47])[CH2:43][O:44][CH2:45][CH3:46])=[CH:30][CH:31]=2)=[N:24][CH:25]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCOCC(F)(F)C(F)(F)C(F)(F)COS(=O)(=O)C(F)(F)F
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCc1cnc(-c2ccc(OCC(F)(F)C(F)(F)C(F)(F)COCC)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
0.4 g of sodium hydride (97% pure), 15 ml of toluene and 15 ml of anhydrous N,N-dimethylformamide were placed in a 100 flask fitted with a magnetic stir bar and water-cooled condensor with a dry nitrogen inlet. Then 3.3 g (0.0106 moles) of 5-decyl-2-(4-hydroxyphenyl)pyrimidine was slowly added. After stirring for 30 minutes at room temperature, 3.9 g (0.0106 moles) of 5-ethoxy-2,2,3,3,4,4-hexafluoropentyl trifluoromethanesulfonate (made essentially as in Example 3) was added and the contents stirred overnight at room temperature. The contents then were poured into a separatory funnel containing 30 ml of water. The funnel was shaken and the two layers formed were allowed to separate. The aqueous layer was extracted twice with two 15 ml aliquots of toluene. The organic layers were combined, then washed four times with 20 ml aliquots of deionized water, dried with anhydrous sodium sulphate, and stripped of solvent using a rotary evaporator. The resulting oil was chromatographed on silica gel (chloroform) to obtain 2.07 g of 5-decyl-2-(4-(5-ethoxy-2,2,3,3,4,4-hexafluoropentoxy)phenyl)pyrimidine.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]([F:9])([F:8])[F:7])[CH3:3].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][S:23][C:24]3[C:29]([C:30]#[N:31])=[C:28]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][OH:41])=[CH:34][CH:33]=4)[C:27]([C:42]#[N:43])=[CH:26][N:25]=3)[N:21]=2)=[CH:13][CH:12]=1.Cl.FC(F)(F)CNC>CN(C=O)C.O.C1COCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][S:23][C:24]3[C:29]([C:30]#[N:31])=[C:28]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][OH:41])=[CH:34][CH:33]=4)[C:27]([C:42]#[N:43])=[C:26]([N:4]([CH2:2][CH3:3])[CH2:5][C:6]([F:9])([F:8])[F:7])[N:25]=3)[N:21]=2)=[CH:15][CH:16]=1
Reactant: CCNCC(F)(F)F
Reactant: N#Cc1cnc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: CNCC(F)(F)F
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCN(CC(F)(F)F)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
133 mg (0.81 mmol) of N-ethyl-2,2,2-trifluoroethanamine hydrochloride were dissolved in 2 ml of DMF, 130 mg Amberlyst A-21 were added and the mixture was stirred at RT for 30 min. The mixture was filtered off and added to 100 mg (0.14 mmol, purity about 74%) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-ylmethyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A), and the solution was stirred at RT overnight. The mixture was then warmed to 60° C. and stirred at this temperature overnight. In a separate flask, another 87 mg (0.54 mmol) of 2,2,2-trifluoro-N-methylethanamine hydrochloride were then dissolved in 0.5 ml of DMF, 88 mg of Amberlyst A-21 were added and the mixture was stirred at RT for 30 min. The mixture was filtered off and added to the first solution. The reaction mixture obtained was stirred at 100° C. for 4.5 h. The mixture was then diluted with a little water/THF and purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 37 mg (41% of theory) of the target compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][OH:28])=[CH:23][CH:22]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C.N1C=CC=CC=1>C1COCC1.O>[CH3:1][S:2]([O:28][CH2:27][CH2:26][O:25][C:24]1[CH:23]=[CH:22][C:21]([C:20]#[C:19][C:16]2[CH:15]=[CH:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=3)=[CH:18][N:17]=2)=[CH:30][CH:29]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.59 mL (7.55 mmol) methanesulphonic acid chloride are added dropwise to a solution, cooled to 0° C., of 2.2 g (6.29 mmol) 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethanol and 1.74 mL (12.58 mmol) triethylamine in 25 mL THF. The reaction mixture is heated to RT and stirred for 2 h. To complete the reaction 5 mL pyridine are added and kept at RT for a further 18 h. The solvent is eliminated i.vac., the residue is combined with water and triturated with diethyl ether. The product precipitated is suction filtered and dried.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH3:18][Mg]Br>O1CCCC1.C(OCC)C>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]([OH:17])[CH3:18])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(C)O)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.60 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde in 30 ml of dry tetrahydrofuran, cooled to 0° C. is added dropwise, 2.61 ml of a 3.0M solution of methylmagnesium bromide in diethyl ether. The reaction is stirred at 0° C. for 30 minutes and then quenched with 10 ml of aqueous ammonium chloride. After diluting with 10 ml of water, the reaction mixture is extracted with 9:1 chloroform-methanol. The combined extracts are dried with magnesium sulfate, filtered and concentrated to yield 0.64 g of the desired product. CI MASS SPEC 247(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5](=[O:14])[CH:4]=1.[Br:15]N1C(=O)CCC1=O>C1COCC1>[Br:15][C:4]1[C:5](=[O:14])[N:6]([CH3:13])[C:7]2[C:12]([C:3]=1[O:2][CH3:1])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(=O)n(C)c2ccccc12
Solvent: C1CCOC1
Product: COc1c(Br)c(=O)n(C)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of 4-methoxy-1-methylquinolin-2(1H)-one (2 g, 10.57 mmol) in THF (5 mL) at 0° C. under N2 atmosphere was added N-bromosuccinimide (2.26 g, 12.68 mmol) in portions over a period of 1 hour. The suspension was stirred at 0° C. for 1 hour then at room temperature for 2 hours. The solvent was removed in vacuo and CH2Cl2 was added to re-dissolve the residue. The solution was washed twice with a cold saturated NaHCO3 solution and with cold H2O then dried over anhydrous MgSO4. The solvent was removed in vacuo and the resulting solid residue was triturated several times with Et2O. The resulting solid was dried in vacuo to afford 3-bromo-4-methoxy-1-methylquinolin-2(1H)-one (2.7 g, MS: 269.9 [M+H+])
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:28]3[CH2:30][CH2:29]3)[C:15](=[O:27])[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:26][CH:25]=[N:24][CH:23]=4)=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:32]B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH:28]1([N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[C:4]([F:31])=[CH:3][C:2]([CH3:32])=[CH:7][N:6]=3)[CH2:9][CH2:10]2)[C:15](=[O:27])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:26][CH:25]=[N:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:30][CH2:29]1
Reactant: CB(O)O
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ncc(Br)cc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)c(F)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of N-(5′-Bromo-3′-fluoro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide (170 mg), methylboronic acid (126 mg), Na2CO3 solution (2 M; 385 μL), and Pd(PPh)4 (20 mg) in dioxane (3 mL) is stirred at 80° C. overnight under an argon atmosphere. Three more portions of methylboronic acid (42 mg each) as well as PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (14 mg) are added successively over the next day until the conversion is complete. The reaction mixture is filtered through a pad of aluminium oxide and washed with dioxane. The filtrate is concentrated in vacuo and the residue is purified by preparative HPLC. LC (method 1): tR=1.15 min; Mass spectrum (ESI+): m/z=421 [M+H]+.
Reaction SMILES: O.Cl.[CH3:3][C:4]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)=[CH:14][C:7]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[C:6]([N+:28]([O-])=O)[CH:5]=1.C(=O)(O)[O-].[Na+]>C(O)C.[Fe]>[NH2:28][C:6]1[CH:5]=[C:4]([CH3:3])[C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][CH:18]=2)=[CH:14][C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])c(C(=O)OC(C)C)cc1Oc1ccc(OC(F)(F)F)cc1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCO
Product: Cc1cc(N)c(C(=O)OC(C)C)cc1Oc1ccc(OC(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
An iron powder (372.9 g), 1290 ml of ethanol, 531 ml of water, and 2.8 g of a 35% hydrochloric acid were charged into a 2000-ml glass flask equipped with a stirring device, a thermometer, and a reflux condenser, and the mixture was heated to reflux. Isopropyl 4-methyl-2-nitro-5-(4-(trifluoromethoxy)phenoxy)benzoate (373 g) dissolved in 398 ml of ethanol was added dropwise thereto over a period of two hr. After reflux for 8 hr, 10 ml of a saturated aqueous sodium bicarbonate solution was added, and the mixture was filtered. The filtrate was concentrated, and 300 ml of ethyl acetate was added to the residue. The mixture was washed with brine, followed by separation. The ethyl acetate layer was concentrated under the reduced pressure. Isopropanol (320 ml) was added to the residue, and the mixture was heated at 70° C. for dissolution. Water (160 ml) was added to the solution to cool the solution. The precipitated solid was collected by filtration and was dried to give isopropyl 2-amino-4-methyl-5-(4-(trifluoromethoxy)phenoxy)benzoate (283.7 g, yield: 82.2%).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([OH:21])[C:12]([N:16]4[N:20]=[CH:19][CH:18]=[N:17]4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:22])=[O:5])[CH2:3][CH2:2]1.Br[CH:24]1[CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:24]1([O:21][C:11]2[C:12]([N:16]3[N:17]=[CH:18][CH:19]=[N:20]3)=[CH:13][CH:14]=[C:15]3[C:10]=2[CH2:9][CH2:8][C@H:7]([CH3:22])[N:6]3[C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[CH2:27][CH2:26][CH2:25]1
Reactant: C[C@H]1CCc2c(ccc(-n3nccn3)c2O)N1C(=O)C1CC1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@H]1CCc2c(ccc(-n3nccn3)c2OC2CCC2)N1C(=O)C1CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-cyclopropyl(5-hydroxy-2-methyl-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.055 g, 0.18 mmol), bromocyclobutane (0.050 g, 0.37 mmol), and cesium carbonate (0.150 g, 0.46 mmol) in acetonitrile (5 mL) stirred for 18 h at 80° C. The reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative-HPLC with the following conditions (Waters 1): Column, XBridge Prep C18 OBD Column, 5 um, 19×150 mm; mobile phase, water (0.03% aqueous ammonia) and acetonitrile (16% to 34% acetonitrile in 10 min, flow rate: 20 mL/min); Detector: UV 220&254 nm. This afforded (S)-(5-cyclobutoxy-2-methyl-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.030 g, 45%) as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.67-0.75 (m, 1H), 0.85-0.95 (m, 2H), 1.11-1.17 (m, 4H), 1.22-1.55 (m, 3H), 1.74-2.01 (m, 5H), 2.31-2.46 (m, 2H), 2.95-3.07 (m, 1H), 3.88-3.94 (m, 1H), 4.72-4.82 (m, 1H), 7.28 (d, J=8.40 Hz, 1H), 7.37 (d, J=8.40 Hz, 1H), 7.99 (s, 2H). MS (ESI, pos. ion) m/z 353 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.Br[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][S:12][C:10]2[N:11]=[C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]3[N:9]=2)=[CH:18][CH:19]=1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Reactant: Clc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)n2nc(SCCOc3ccc(Cl)cc3)nc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A mixture of 5,7-dimethyl-[1,2,4]-triazolo[1,5-a]pyrimidine-2-thiol (1.0 g, 5.6 mmol), 1-(2-bromoethoxy)-4-chlorobenzene (1.19 g, 5.1 mmol), potassium carbonate (1.75 g, 12.6 mmol), and anhydrous N,N-dimethylformamide (6 mL) was added to a 20 mL scintillation vial with a magnetic stirring bar. The vial was capped loosely and the mixture allowed to stir at room temperature for 30 minutes. Progress of the reaction was monitored by analytical HPLC with UV detection (Rt=8.28 min). The mixture contained solids starting at 30 minutes and was stopped stirring at 1 hour. The mixture was transferred into an Erlenmeyer flask with a total of 70 mL of water, and allowed to stir for 10 min. The resulting solid was isolated by filtration, rinsed with 100 mL of water, and allowed to dry under reduced pressure. The off-white powder was >90% pure by analytical HPLC with UV detection at 215 nm. The solid was dissolved in 25 mL of ethanol with gentle warming, diluted with 5 mL of water and allowed to cool. The fine white needles that formed were isolated by filtration, washed with 20 mL of cold ethanol, and dried to afford the title compound (1.43 g, 85% yield). EM (calc.): 334.1; MS (ESI) m/e: 335.1 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.31 (d, 2H), 7.12 (s, 1H), 7.03 (d, 2H), 4.33 (t, 2H), 3.60 (t, 2H), 2.68 (s, 3H), 2.55 (s, 3H).