Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.[Cl:12][S:13](O)(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[Cl:12][S:13]([C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([CH3:11])([CH3:1])[CH2:6][C:5]=2[CH:7]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: CC1(C)Cc2ccccc2O1
Solvent: ClC(Cl)Cl
Product: CC1(C)Cc2cc(S(=O)(=O)Cl)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
To a stirred solution of 22.2 g (0.15 mole) of 2,3-dihydro-2,2-dimethylbenzofuran in 190 mL of chloroform was added dropwise 20 mL (0.3 mole) of chlorosulfonic acid. After complete addition, the reaction mixture was stirred at room temperature for two hours. The reaction mixture was poured into a separatory funnel with ice water and shaken. The organic layer was separated from the aqueous phase and dried over anhydrous magnesium sulfate. The dried organic phase was filtered and the filtrate was evaporated under reduced pressure to leave 14.5 g of 5-chlorosulfonyl-2,3-dihydro-2,2-dimethylbenzofuran as a solid (mp 75°-77° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][NH2:11]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[N:11]/[CH3:10])[CH:7]=[CH:8][CH:9]=1
Reactant: CN
Reactant: O=Cc1cccc(Cl)c1
Solvent: ClCCl
Product: C/N=C/c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A mixture of 3-chloro-benzoaldehyde (Aldrich, 97%) (4.21 g, 30.0 mmol) and methyl amine (2.0 M in THF, Aldrich, 22.5 mL, 45.0 mmol) in CH2Cl2 (50 mL) was stirred at rt overnight. The reaction mixture was concentrated and the residue was dried under reduced pressure to afford [[1-(3-chloro-phenyl)-meth-(E)-ylidene]-methyl-amine (4.60 g, 100%) as colorless oil which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([F:11])=[C:4](C#N)[C:3]=1[F:14].FC1C(C=O)=C(F)C(F)=C(C=O)C=1F.FC1C(F)=CC(F)=C(F)C=1.FC1C(F)=CC(F)=C(F)C=1C#N>>[F:1][C:2]1[C:3]([F:14])=[CH:4][C:5]([F:11])=[C:6]([F:10])[C:7]=1[CH2:8][NH2:9]
Reactant: N#Cc1c(F)c(F)c(C#N)c(F)c1F
Agent: Fc1cc(F)c(F)cc1F
Agent: N#Cc1c(F)c(F)cc(F)c1F
Agent: O=Cc1c(F)c(F)c(C=O)c(F)c1F
Product: NCc1c(F)c(F)cc(F)c1F

Procedure:
From the toluene extract, a small amount of a sample was withdrawn, and it was subjected to GC analysis. As a result of the analysis, a peak of the tetrafluoroterephthalonitrile as a raw material was below the detection limit, the amount of tetrafluoroterephthalaldehyde was 89.4 mol %, the amount of 2,3,5,6-tetrafluorobenzene was 1.31 mol %, and the amount of 2,3,5,6-tetrafluorobenzonitrile was 1.03 mol %. On the other hand, the aqueous phase was neutralized and then subjected to GC analysis. As a result of the analysis, presence of 2.35 mol % of 2,3,5,6-tetrafluorobenzylamine was confirmed. The results are set forth in Table 1.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:14])[CH:8]=2)[N:3]=1.Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2cc(O)ccc2nc1Cl
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc2nc(Cl)c(C=O)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
To a solution of 2-chloro-6-hydroxyquinoline-3-carbaldehyde (2.35 g, 11.3 mmol) in N,N-dimethylformamide (15 mL) was added tert-butyl 2-bromoacetate (2.0 mL, 13.6 mmol) and potassium carbonate (3.13 g, 22.6 mmol). The reaction was stirred at room temperature for 1.5 hours. The reaction was diluted with water (100 mL) and allowed to stir for 1 hour. The resulting solid was collected by filtration, washed with water, and dried under vacuum to give the title compound (3.62 g, 99%) as an off-white solid. +ESI (M+H) 322.1; 1H NMR (400 MHz, CDCl3, δ): 10.54 (s, 1 H), 8.60 (s, 1 H), 7.99 (d, J=9.36 Hz, 1 H), 7.59 (dd, J=9.17, 2.93 Hz, 1 H), 7.11 (d, J=2.73 Hz, 1 H), 4.65 (s, 2 H), 1.49 (s, 9 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:23]=[CH:22][C:13]([O:14][CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH2:18]([N:17]([CH2:20][CH3:21])[CH2:16][CH2:15][O:14][C:13]1[CH:22]=[CH:23][C:10]([C:9]#[C:8][C:5]2[CH:4]=[CH:3][C:2]([C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)=[CH:7][N:6]=2)=[CH:11][CH:12]=1)[CH3:19]
Reactant: CCN(CC)CCOc1ccc(C#Cc2ccc(Br)cn2)cc1
Reactant: COc1ccc(OB(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN(CC)CCOc1ccc(C#Cc2ccc(-c3ccc(OC)cc3)cn2)cc1
Temperature: 110 °C

Procedure:
A mixture of 200 mg (0.54 mmol) {2-[4-(5-bromo-pyridin-2-ylethynyl)-phenoxy]-ethyl}-diethyl-amine, 163 mg (1.07 mmol) 4-methoxy-phenylboric acid, 31 mg (0.03 mmol) tetrakis-triphenylphosphane-palladium and 0.27 mL of a 2 M aqueous Na2CO3 solution in 5 mL 1,4-dioxane is heated for 20 h at 110° C. under a nitrogen atmosphere. The solvent is distilled off i.vac., the residue is taken up in water, exhaustively extracted with EtOAc and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 95:5:0.5). The product fractions are evaporated down, the residue is triturated with diethyl ether, suction filtered and washed with diisopropylether.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]2[CH:10]=[CH:11][O:12][C:6]=2[C:5]=1[OH:13])([O-])=O.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([CH2:24]O)=[N:22][N:23]=2)[N:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>Cl.[Fe].CCO.C1COCC1>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([CH2:24][O:13][C:5]3[C:6]4[O:12][CH:11]=[CH:10][C:7]=4[CH:8]=[N:9][C:4]=3[NH2:1])=[N:22][N:23]=2)[N:20]=1
Reactant: O=[N+]([O-])c1ncc2ccoc2c1O
Reactant: OCc1nnc2ccc(Cl)nn12
Agent: [Fe]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ncc2ccoc2c1OCc1nnc2ccc(Cl)nn12
Temperature: 40 °C

Procedure:
To a mixture of 6-nitrofuro[3,2-c]pyridin-7-ol (50.0 mg, 0.278 mmol), (6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanol (102 mg, 0.555 mmol), triphenylphosphine (191 mg, 1.11 mmol) and THF (10 mL) under nitrogen at rt was added diisopropyl azodicarboxylate (0.219 mL, 1.11 mmol) dropwise. The solution was heated to 40° C. for 2 h. The solvent was removed in vacuo, and EtOH (20 mL), iron powder (200 mg, 3 mmol) and conc. HCl (8 drops) were added. The mixture was heated to 75° C. for 1 h. The material was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo to afford the title compound as a dark orange solid, and was used in the next step without further purification. MS (ES+): m/z 317.02 (100) [MH+]. HPLC: tR=1.83 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[C:21]([C:22](O)=[O:23])[C:16]=4[N:15]=[C:14]3[C:31](=[O:42])[NH:32][CH:33]3[CH2:38][CH2:37][N:36]([CH:39]([CH3:41])[CH3:40])[CH2:35][CH2:34]3)[CH:8]=2)=[CH:4][CH:3]=1.[NH:43]1[CH2:46][CH:45]([OH:47])[CH2:44]1>>[CH:39]([N:36]1[CH2:37][CH2:38][CH:33]([NH:32][C:31]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:17]3[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]([F:30])([F:28])[F:29])=[C:21]([C:22]([N:43]4[CH2:46][CH:45]([OH:47])[CH2:44]4)=[O:23])[C:16]=3[N:15]=2)=[O:42])[CH2:34][CH2:35]1)([CH3:41])[CH3:40]
Reactant: OC1CNC1
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)c(OCC(F)(F)F)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)N4CC(O)C4)c(OCC(F)(F)F)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1

Procedure:
1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-4-(3-hydroxy-azetidine-1-carbonyl)-5-(2,2,2-trifluoro-ethoxy)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 50.0 mg (0.08 mmol) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-5-(2,2,2-trifluoro-ethoxy)-1H-benzoimidazole-4-carboxylic acid and 8.7 mg (0.12 mmol) azetidin-3-ol. The title compound was obtained as its formiate in form of a white amorphous solid.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:3]1.[C:32]([O:36][C:37](=[O:45])[C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)([CH3:35])([CH3:34])[CH3:33].CC(C)([O-])C.[Na+].C(C1C=C(C(C)C)C=C(C(C)C)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1)(C)C>O1CCOCC1>[C:32]([O:36][C:37](=[O:45])[C:38]1[CH:43]=[CH:42][C:41]([N:2]2[CH2:6][CH2:5][C@H:4]([O:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]4[N:18]=[C:19]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:20][C:21]=4[C:22]([F:25])([F:23])[F:24])=[O:16])=[CH:10][CH:9]=3)[CH2:3]2)=[CH:40][CH:39]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: O=C(Nc1ccc(O[C@H]2CCNC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](Oc3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)C2)cc1
Temperature: 105 °C
Yield: 68.3 %

Procedure:
To a mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-((S)-pyrrolidin-3-yloxy)-phenyl]-amide hydrochloride (180 mg, 0.37 mmol), 4-bromobenzoic acid tert-butyl ester (114 mg, 0.44 mmol), sodium tert-butoxide (118 mg, 1.23 mmol) and (2′,4′,6′-triisopropyl-1,1′-biphenyl-2-yl)dicyclohexylphosphine (X-PHOS, 40 mg) in dioxane (5 mL) bubbled with argon was added tris(dibenzylideneacetone)dipalladium Pd2(dba)3 (24 mg). The mixture was heated at 105° C. for 2 hrs. Solvents were evaporated and the residue was extracted with ethyl acetate and 0.1N hydrochloric acid. The organic layer was dried and concentrated. The residue was purified through ISCO column chromatography (silica gel, ethyl acetate in hexane, 5% to 60% linear gradient) to give a white solid as 4-((S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-pyrrolidin-1-yl)-benzoic acid tert-butyl ester (150 mg, yield 69%).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][OH:4].CCN(C(C)C)C(C)C.[S:18](Cl)([C:21]1[C:33]([CH3:34])=[C:32]2[C:26]([O:27][C:28]([CH2:31]2)([CH3:30])[CH3:29])=[C:24]([CH3:25])[C:22]=1[CH3:23])(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[NH:1]([S:18]([C:21]1[C:33]([CH3:34])=[C:32]2[C:26]([O:27][C:28]([CH2:31]2)([CH3:30])[CH3:29])=[C:24]([CH3:25])[C:22]=1[CH3:23])(=[O:19])=[O:20])[C@H:2]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][OH:4]
Reactant: COC(=O)[C@@H](N)CO
Reactant: Cc1c(C)c(S(=O)(=O)Cl)c(C)c2c1OC(C)(C)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CO)NS(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2
Reaction time: 8 h
Yield: 82.7 %

Procedure:
H-Ser-OMe, 3.5 g (22.6 mmol), was suspended in (40 mL) of chloroform. Under ice cooling, DIEA (8.7 mL, 49.7 mmol) and Pbf-Cl (5.86 g, 20.3 mmol) were sequentially added and stirred overnight while gradually elevating to room temperature. After the reaction was stopped by adding satd. citric acid aqueous solution, chloroform was distilled off under reduced pressure and the whole was extracted with AcOEt. The organic layer was washed sequentially with satd. citric acid aqueous solution, satd. sodium bicarbonate aqueous solution and satd. sodium chloride aqueous solution, and then dried over anhydrous MgSO4. After concentration under reduced pressure, flash chromatography was performed using AcOEt: n-hexane=1:1 to give Pbf-Ser-OMe (6.94 g, 82.7%).
Reaction SMILES: O[C:2]1[N:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C1(OC)C=CC=CC=1.P(Br)(Br)([Br:23])=O>>[Br:23][C:2]1[N:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: O=P(Br)(Br)Br
Reactant: COc1cnc(O)c2[nH]ccc12
Solvent: COc1ccccc1
Product: COc1cnc(Br)c2[nH]ccc12
Temperature: 160 °C
Yield: 27.4 %

Procedure:
To a flask containing 7-hydroxy-4-methoxy-6-azaindole (0.200 g, 1.22 mmol) was added anisole (3 mL) and then POBr3 (1.57 g, 6.09 mmol). The system was purged with Ar and then it was heated at 160° C. (oil bath temperature) for 1 h. The reaction mixture was then allowed to cool to room temperature, quenched with 2M HBr (5 mL) and extracted with methyl t-butyl ether. The aqueous phase was separated and the pH was adjusted to 6-7, after which it was extracted with EtOAc. The resulting organic phase was dried (MgSO4) and evaporated to give a solid residue which was chromatographed (SiO2/5% MeOH-DCM) to afford the title compound (0.076 g, 27%) as a white solid:
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccc(F)c1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1c([N+](=O)[O-])ccc(F)c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
In a 1 L, three necked flask fitted with a dropping funnel and a thermometer were charged 2-bromo-3-fluorobenzoic acid (Example 134g) (28.23 g, 0.13 mol) and concentrated H2SO4 (200 mL). After cooling to 0° C., HNO3 (70%, 16.0 mL) was added dropwise over 30 min, keeping the temperature between 0 to 10° C. After 1 h, the reaction mixture was poured into the crushed ice keeping the temperature below 20° C. The mixture was extracted with EtOAc (2×200 mL), the combined extract was washed with brine and dried with MgSO4. The filtrate was evaporated to give 27.27 g (77%) of a mixture of 2-bromo-3-fluoro-6-nitrobenzoic acid and 2-bromo-3-fluoro-5-nitrobenzoic acid (1:0.4) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (dd, J=9.6, 4.8 Hz, 1H), 7.21 (dd, J=10.0, 8.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:13]3[CH2:14][CH2:15][CH:9]2[CH2:10][NH:11][CH2:12]3)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>ClCCl>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:11]2[CH2:12][CH:13]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[CH:9]([CH2:15][CH2:14]3)[CH2:10]2)=[O:28])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: Clc1cccnc1N1C2CCC1CNC2
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)N2CC3CCC(C2)N3c2ncccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-(3-Chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane (102 mg, 456 μmol) and 1-tert-butyl-4-isocyanatobenzene (80 mg, 456 μmol) were combined in dry dichloromethane (4.5 mL) and stirred overnight at room temperature. The mixture was concentrated and the residue was purified by chromatography on silica gel (7:3, hexanes:ethyl acetate) to provide the title compound. MS (ESI) m/z: 399 (M+H)+;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1.Br[CH:28]([CH2:30][CH2:31][CH3:32])[CH3:29]>>[CH3:29][CH:28]([O:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:13][CH2:12][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])([CH2:14][CH2:15]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCC(C)Br
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(O)c3)(CC1)OC2
Product: CCCC(C)Oc1cccc(C23CCC(CCOCC(=O)O)(CC2)CO3)c1
Reaction time: 0.33 h
Yield: 88 %

Procedure:
The title compound was prepared by an analogous sequence to that used to synthesize Example 51 from 7F (tert-butyl 2-(2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate) except that 2-bromopentane instead of (bromomethyl)cyclobutane was used as the alkylating agent. The crude product was purified by preparative LC/MS (Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 MeCN:water with 10 mM NH4OAc; Mobile Phase B: 95:5 MeCN:water with 10 mM NH4OAc; Gradient: 30-70% B over 20 min, then a 5-min hold at 100% B; Flow rate: 20 mL/min) to give the title compound (11.5 mg, 88% yield; 96% purity by LC/MS) as a light yellow oil. LCMS, [M−H]−=375. 1H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.96-6.83 (m, 2H), 6.74 (d, J=8.3 Hz, 1H), 4.41 (sxt, J=5.9 Hz, 1H), 3.95 (s, 2H), 3.76 (s, 2H), 3.50 (t, J=6.7 Hz, 3H), 2.09-1.96 (m, 2H), 1.87-1.75 (m, 2H), 1.71-1.57 (m, 5H), 1.56-1.47 (m, 1H), 1.46-1.32 (m, 3H), 1.21 (d, J=6.1 Hz, 3H), 0.90 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Na].S(O)(O)(=O)=O.[CH3:7][O:8][C:9](=[NH:11])[NH2:10].[C:12]([CH2:20][C:21](OCC)=[O:22])(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH3:7][O:8][C:9]1[N:10]=[C:21]([OH:22])[CH:20]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:11]=1
Reactant: COC(=N)N
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CO
Product: COc1nc(O)cc(-c2ccccc2)n1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 8.2 %

Procedure:
Sodium (4.14 g, 180 mmol) was dissolved in dry methanol (120 ml) and the solution was cooled to 0-5° C. O-Methylisourea sulfat (10.3 g, 60 mmol) and ethyl benzoylacetate (11.5 g, 60 mmol) was added and the mixture was stirred for two hours at room temperature and then refluxed for twelve hours. The mixture was evaporated, acidified with 2M HCl and extracted three tines with ethyl acetate and three times with DCM. The organic phase was dried and evaporated and the residue was suspended in diethyl ether, the solid filtered off, washed and dried which gave the title compound, (1.0 g) MS+1=203.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])=[O:12])=[CH:5][CH:4]=1)#[N:2].[Al](Br)(Br)Br.[Cl:23][C:24]([Cl:28])([Cl:27])[C:25]#[N:26]>>[Cl:23][C:24]([Cl:28])([Cl:27])[C:25]1[N:26]=[C:25]([C:24]([Cl:28])([Cl:27])[Cl:23])[N:26]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([S:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])=[O:12])=[CH:7][CH:8]=2)[N:2]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CCOCCOC(=O)CSc1ccc(C#N)cc1
Agent: Br[Al](Br)Br
Product: CCOCCOC(=O)CSc1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Reaction time: 24 h
Yield: 86 %

Procedure:
A mixed solution containing 10 g of 2-ethoxyethyl 2-(4-cyanophenylthio)acetate (37.7 mmol), 0.8 g of AlBr3 and 50 g of trichloroacetonitrile was bubbled with dry HCl at room temperature. The process of reaction was checked by TLC. The reaction product was formed gradually with the lapse of time while precipitation was formed. After 24 hours, the reaction mixture was quenched and extracted with 500 mL of chloroform. The resultant product was washed with deionized water and dried over anhydrous magnesium sulfate. Volatile substances were removed from the dried product under vacuum and the target product was separated by column chromatography using hexane/ethyl acetate (3/1) as eluent (yield: 86%). Then, the product was subjected to structural analysis by NMR, FT-IR and UV-Vis. spectrophotometers.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]([C:6]1[CH2:7][O:8][C:9]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:12][C:10]=2[CH:11]=1)=O>C(O)C.N1C=CC=CC=1>[CH:4](=[N:2][OH:3])[C:6]1[CH2:7][O:8][C:9]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:12][C:10]=2[CH:11]=1
Reactant: O=CC1=Cc2cc(Cc3cccnc3)ccc2OC1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=CC1=Cc2cc(Cc3cccnc3)ccc2OC1
Reaction time: 2.5 h
Yield: 84.1 %

Procedure:
Hydroxylamine hydrochloride was added to a mixed solution of 3.88 g (15.5 mmol) of 3-formyl-6-(3-pyridylmethyl)-2H-1-benzopyran in ethanol (35 ml) and pyridine (35 ml) at room temperature. The mixture was stirred for 2.5 hours was evaporated in vacuo and the residue was dispersed in chloroform-methanol (10:1). Then, after the organic layer was washed with water and brine, the solvent was evaporated in vacuo. The crystal precipitated during the evaporation of the solvent, was collected by filtration to obtain 3.46 g (yield=84.1%) of the desired compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[N:9]1([C:14](N2C=CN=C2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1>C(Cl)Cl>[N:9]1([C:14]([O:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: OCc1ccncc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(OCc1ccncc1)n1ccnc1
Yield: 80.7 %

Procedure:
A solution of (pyridin-4-yl)methanol (2.0 g, 18.3 mmol) and di(1H-imidazol-1-yl)methanone (5.94 g, 36.6 mmol) in 20 mL CH2Cl2 was heated overnight at 50° C. The reaction was quenched with water, extracted with CH2Cl2, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 10-70% EtOAc in CH2Cl2 gave (pyridin-4-yl)methyl 1H-imidazole-1-carboxylate (3 g, 81%). LC/MS: m/z 204.3 (M+H)+ at 0.38 min (v). 1H NMR (400 MHz, CDCl3) δ 8.69 (dd, J=4.4, 1.6 Hz, 2H), 8.20 (t, J=0.9 Hz, 1H), 7.47 (t, J=1.5 Hz, 1H), 7.34 (dd, J=4.4, 1.6 Hz, 2H), 7.11 (dd, J=1.6, 0.8 Hz, 1H), 5.45 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][O:10][C:11]1[CH:16]=[C:15]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Nc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2cc(N)ncn2)c1
Temperature: 125 °C
Yield: 69.6 %

Procedure:
A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol), 3-methoxyphenylboronic acid (0.475 g, 3.13 mmol), Na2CO3 (0.795 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) was suspended in DME/EtOH/water (15:2:3 mL), heated in the microwave synthesizer at 125° C. for 20 min and concentrated. The residue was purified by silica gel chromatography (10-60% ethyl acetate-hexanes) to afford 6-(3-methoxyphenyl)pyrimidin-4-amine (0.35 g, 1.74 mmol, 70% yield) as an off-white solid. LCMS R.T.=1.28; [M+H]+=201.98.