Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:15][CH2:16][CH3:17])[NH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:4])[CH3:3].[C:18]([NH:22][C:23]([C:25]1[C:26]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=2)=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CC(C)([O-])C.[K+]>>[C:18]([NH:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][N:8]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:2]([OH:1])([CH3:4])[CH3:3])[N:6]=[C:7]2[CH2:15][CH2:16][CH3:17])=[CH:33][CH:32]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Reactant: CC(C)(C)NC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)NC(C)(C)C)cc1
Yield: 67.1 %

Procedure:
Following a procedure similar to that described in Example 68(a), but using 4.16 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9), 6.00 g of N-t-butyl-4'-bromomethylbiphenyl-2-carboxamide (prepared as described in Preparation 38) and 2.14 g of potassium t-butoxide, 5.87 g of the title compound was obtained as crystals, melting at 145°-146° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:30][CH3:31])=[C:21]([NH:23][C:24](=[O:29])[C:25](F)(F)F)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Li+].[OH-].C1COCC1.[CH:39]1[CH:43]=[C:42](CC(Cl)=O)[S:41][CH:40]=1>O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:30][CH3:31])=[C:21]([NH:23][C:24](=[O:29])[CH2:25][C:40]4[S:41][CH:42]=[CH:43][CH:39]=4)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)Cc1cccs1
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A solution of N-[5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (250 mg, 0.56 mmol) and 1M LiOH (1.30 mL, 1.39 mmol) in 10:1 THF:H2O (5 mL) was heated at 50° C. overnight. After removal of THF by rotary evaporation, the reaction mixture was redissolved in EtOAc and washed with water (25 mL) and brine (25 mL). The organic layer was dried over MgSO4. Following filtration, the solvent was removed by rotary evaporation. After high vacuum removal of the residual solvent, the crude mixture was dissolved in THF (5 mL) and to this was added thiophene-2-acetylchloride (0.10 mL, 0.84 mmol). After overnight stirring, water (0.5 mL) was added and THF removed by rotary evaporation. The reaction mixture was redissolved in DCM (25 mL) washed with saturated NaHCO3 (10 mL), water (10 mL) and brine (10 mL). Organics were dried over MgSO4, filtered and filtrate concentrated under reduced pressure to afford the desired amide (210 mg, 79%) as an off-white solid. ES-LC/MS m/z=476 [M+H]−.
Reaction SMILES: C(OC([CH2:8][NH:9][CH2:10][C:11]1[S:15][CH:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([O:28][CH2:29][CH3:30])[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=2)[CH:12]=1)=O)(C)(C)C.O>ClCCl.FC(F)(F)C(O)=O>[CH2:29]([O:28][C@@H:23]([CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:12]=[C:11]([CH2:10][NH:9][CH3:8])[S:15][CH:14]=2)=[CH:17][CH:18]=1)[C:24]([O:26][CH3:27])=[O:25])[CH3:30]
Reactant: CCO[C@@H](Cc1ccc(-c2csc(CNCC(=O)OC(C)(C)C)c2)cc1)C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCO[C@@H](Cc1ccc(-c2csc(CNC)c2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.5 %

Procedure:
5 g (11.5 mmol) of methyl 3-(4-{5-[(tert-butoxycarbonylmethylamino)methyl]thiophen-3-yl}phenyl)-2(S)-ethoxypropanoate are placed in 80 ml of dichloromethane and 4.4 ml of trifluoroacetic acid. After stirring at room temperature for 24 hours, water is added and the reaction medium is extracted with dichloromethane. The dichloromethane phase is washed with aqueous 30% sodium hydroxide solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with a 50/50 heptane/ethyl acetate mixture. 3.2 g (84%) of methyl 2(S)-ethoxy-3-[4-(5-methylaminomethylthiophen-3-yl)phenyl]propanoate are obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:16])COC)=[CH:8][CH:7]=2)[CH2:3]1.[OH2:17].[OH-].[Li+].Cl>O.CO.C1COCC1>[OH:1][CH:2]1[CH2:3][N:4]([C:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:16])=[O:17])=[CH:10][CH:11]=2)[CH2:5]1
Reactant: COCC(=O)c1ccc(N2CC(O)C2)cc1
Reactant: O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(N2CC(O)C2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A mixture of 1-[4-(3-hydroxyazetidin-1-yl)phenyl]-2-methoxyethanone (1.33 g, 6.00 mmol) and lithium hydroxide monohydrate (504 mg, 12.0 mmol) in water (4 mL), methanol (3 mL) and THF (6 mL) was stirred at 40° C. overnight. The mixture was neutralized with 3 N HCl aqueous solution (˜4 mL) to pH about 7, extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product (1.10 g, 94.9%) which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=194.1.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:14]([CH2:16][NH2:17])[OH:15]>>[OH:15][CH2:14][CH2:16][NH:17][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCO
Product: O=C(O)c1ccc(S(=O)(=O)NCCO)cc1

Procedure:
Procedure H was performed to couple 4-(chlorosulfonyl)benzoic acid with ethanolamine to produce 4-(2-hydroxyethylsulfamoyl)benzoic acid which was purified by reverse phase HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([CH:19]([OH:22])[CH:20]=[CH2:21])[CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([C:19](=[O:22])[CH:20]=[CH2:21])[CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC(O)c1cc(OCCCNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: C=CC(=O)c1cc(OCCCNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Yield: 62.6 %

Procedure:
1-(5′-(3″-t-butoxycarbonylaminopropyloxy)-2′-nitrophenyl)-2-propen-1-ol (9.66 g) is dissolved in chloroform (300 ml) and thereto is added activated manganese dioxide (7.2 g), and the mixture is heated with reflux. After completion of the reaction, inorganic materials are filtered off with celite, and the filtrate is concentrated, and thereto is added ethyl acetate. The organic layer is separated, washed with an aqueous saturated saline solution, dried over sodium sulfate. After distilling off the solvent, the residue is purified with a silica gel column chromatography to give 1-[5′-(3″-t-butoxycarbonylaminopropyloxy)-2′-nitrophenyl]-2-propen-1-one (6.01 g) as yellow color crystal.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[I-:17].[K+].II.N(OC(C)(C)C)=O>C(#N)C.[Cu](I)I>[I:17][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: Nc1ccc(-c2ccco2)c2c1C(=O)NC2
Reactant: [I-]
Agent: I[Cu]I
Agent: CC(C)(C)ON=O
Agent: II
Solvent: CC#N
Product: O=C1NCc2c(-c3ccco3)ccc(I)c21
Yield: 57.8 %

Procedure:
In a similar manner to Step 4 of Example 140, 7-amino-4-(furan-2-yl)isoindolinone (43.0 mg, 0.201 mmol) was dissolved in acetonitrile (4.3 mL), and the solution was treated with potassium iodide (40.0 mg, 0.241 mmol), copper iodide (46.0 mg, 0.241 mmol), iodine (61.0 mg, 0.241 mmol) and tert-butyl nitrite (0.072 mL, 0.60 mmol), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=6/1) to obtain 7-iodo-4-(furan-2-yl)isoindolinone (37.8 mg, yield 58%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][C:10]([C:13](Cl)=[O:14])=[CH:9][N:8]=1.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([NH2:26])[CH:21]=[CH:20]2.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([NH:26][C:13]([C:10]1[CH:9]=[N:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:12][CH:11]=1)=[O:14])[CH:21]=[CH:20]2
Reactant: O=C(Cl)c1cnc(-c2ccccn2)nc1
Reactant: Nn1ccc2cc(F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nn1ccc2cc(F)ccc21)c1cnc(-c2ccccn2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
A solution of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid chloride (1 mmol) in EtOAc (20 mL) is added to a stirred solution of 5-fluoro-indol-1-ylamine (1 mmol) and K2CO3 (2 mmol) in EtOAc (10 mL) and H2O (20 mL) at rt, and the reaction mixture is stirred at rt overnight. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration. The solid is purified by silica gel chromatography eluting with 0-10% MeOH in DCM to afford 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (65 mg, 20%) as a solid. MS: 334 (M+H); 1H NMR (300 MHz, CD3OD): δ 6.56 (m, H) 7.04 (m, H), 7.28-7.79 (m, 3H), 8.04 (m, H), 8.49 (m, H), 8.81 (m, H), 9.48 (s, 2H), 12.22 (s, N—H). IC50=18 nM.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:14][C:15]1[CH:16]=[C:17]([S:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)(=[O:26])=[O:25])[CH:18]=[CH:19][C:20]=1[CH2:21][CH2:22][CH3:23]>C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:30]2[CH2:29][CH2:28][N:27]([S:24]([C:17]3[CH:18]=[CH:19][C:20]([CH2:21][CH2:22][CH3:23])=[C:15]([F:14])[CH:16]=3)(=[O:25])=[O:26])[CH2:32][CH2:31]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCc1ccc(S(=O)(=O)N2CCNCC2)cc1F
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: CCCc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)cc1F

Procedure:
In the manner given in Example 1A, p-nitrobenzenesulfonyl chloride, 1-[(3-fluoro-4-propylphenyl)sulfonyl]piperazine and triethylamine are stirred at reflux to give 1-[(p-nitrophenyl)sulfonyl]-4-[(3-fluoro-4-propylphenyl)sulfonyl]piperazine.
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[CH:3][C:2]=1[CH3:9].OO.[C:12]([OH:15])(=[O:14])[CH3:13]>C(OC(=O)C)(=O)C>[C:12]([O:15][CH2:9][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[C:6]([CH3:7])[N:1]=1)(=[O:14])[CH3:13]
Reactant: Cc1cc(C)nc(C)c1
Reactant: CC(=O)O
Agent: OO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCc1cc(C)cc(C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 24 %

Procedure:
To a stirred solution of 2,4,6-collidine (3.22 g, 26.6 mmol) in glacial acetic acid (21 mL) at room temperature was added 30% H2O2 (3.0 mL) and the resultant solution was heated to 70° C. After 6 hours, the reaction mixture was cooled to room temperature, additional H2O2 (3.0 mL) was added, and the solution was heated at 70° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CHCl3 (50 mL) and treated with solid Na2CO3 (9.9 g). After 1 hour, the supernatant was decanted and the residue was washed with warm CHCl3 (3×75 mL). The combined supernatants were filtered and concentrated to provide 2.43 g as a yellow oil. The oil was dissolved in acetic anhydride (22.5 mL) and heated at 90° C. overnight. The mixture was cooled to room temperature and concentrated. The crude product was purified by flash chromatography (40 g silica gel, 2:1 hexanes/ethyl acetate) to give 1.05 g (24%) of 2-acetoxymethyl-4,6-dimethylpyridine: 1H NMR (CDCl3) □ 2.31 (s, 3H), 2.35 (s, 3H), 2.51 (s, 3H), 5.14 (s, 2H), 6.92 (s, 1H), 6.97 (s, 1H); and 0.35 g (8%) of 4-acetoxymethyl-2,5-dimethylpyridine: 1H NMR (CDCl3) □ 2.15 (s, 3H), 2.53 (s, 6H), 5.04 (s, 2H), 6.92 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](CC#N)[CH:5]=[C:6]([CH3:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.OS(O)(=O)=O.[C:29]([OH:32])(=[O:31])[CH3:30]>>[CH3:20][C:6]1[CH:5]=[C:4]([CH2:30][C:29]([OH:32])=[O:31])[CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:18])[CH3:19])[CH:10]=1
Reactant: CC(=O)O
Reactant: COc1ccc(Oc2c(C)cc(CC#N)cc2C)cc1C(C)C
Agent: O=S(=O)(O)O
Product: COc1ccc(Oc2c(C)cc(CC(=O)O)cc2C)cc1C(C)C
Temperature: 105 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a stirred solution of 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)phenylacetonitrile (0.75 g, 2.42 mmol) in acetic acid (7 mL) was added a 50% solution of H2SO4 (14 mL). The reaction mixture was heated at 105° C., for 3 h, cooled to room temperature and poured into ice water (100 mL). The mixture was stirred for 1 h and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)phenylacetic acid as a brownish solid (0.62 g, 85%, m.p.: 118-120° C.): 1H NMR (300 MHz, CDCl3): δ 7.11 (s, 2 H), 6.82 (d, J=2.7 Hz, 1 H), 6.80 (d, J=8.7 Hz, 1 H), 6.37 (dd, J=3.3, 8.7 Hz, 1 H), 3.80 (s, 3 H), 3.61 (s, 2 H), 3.38-3.25 (m, 1 H), 2.11 (s, 6 H), 1.17 (d, J=7.2 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:1); Rf=0.2.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].O[C:23]1[CH:24]=[C:25]([C:35]([O:37][CH3:38])=[O:36])[CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:28]=1.[Cl-].[NH4+]>C(Cl)(Cl)Cl>[F:7][C:8]([F:21])([F:20])[S:9]([O:12][C:23]1[CH:24]=[C:25]([C:35]([O:37][CH3:38])=[O:36])[CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:28]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc(O)cc(-c2ccccc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccccc2)c1
Reaction time: 0.5 h

Procedure:
With cooling with ice, pyridine (1.2 mL) and trifluoromethanesulfonic acid anhydride (1.2 mL) were added to a CHCl3 (40 mL) solution of methyl 5-hydroxybiphenyl-3-carboxylate, and stirred for 30 minutes with cooling with ice. Aqueous ammonium chloride was added to the reaction liquid, extracted with ethyl acetate, and the organic layer was washed with water, aqueous saturated sodium bicarbonate solution and saturated saline water. This was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound as a yellow oil. Not purified, this was used in the next step.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:35][CH2:36][C@H:37]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([F:14])[C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:38][CH2:39]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)cc1F
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A80) and trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:32][O:33][C@@H:34]([CH3:37])[CH2:35]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl>C1COCC1.CCOC(C)=O.O>[CH3:32][O:33][C@@H:34]([CH3:37])[CH2:35][O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1ccc2ccc(O)cc2n1
Reactant: CO[C@@H](C)CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CO[C@@H](C)COc1ccc2ccc(C)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
To a stirred solution of 2-methylquinolin-7-ol (1.00 g, 6.28 mmol), PPh3 (4.12 g, 15.7 mmol) and (S)-2-methoxypropan-1-ol (0.679 g, 7.54 mmol) in THF (60 mL) was added dropwise diisopropyl azodicarboxylate (2.05 mL, 10.1 mmol) at 0° C. under nitrogen. The reaction mixture was stirred at ambient temperature overnight. The reaction was then heated at 50° C. for additional 2 hours. After cooling, to the reaction were added 4N HCl (3.1 mL), water (100 mL) and EtOAc (200 mL). The aqueous layer was separated and washed with EtOAc (100 mL). The aqueous was neutralized with ammonium hydroxide to about pH 9, extracted with EtOAc, washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1:1 hexane/EtOAc) to give (S)-7-(2-methoxypropoxy)-2-methylquinoline (0.738 g, 51%).
Reaction SMILES: [BH4-].[Li+].[CH3:3][O:4][C:5]([N:7]1[CH2:12][CH:11]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=2)[NH:10][CH:9]([C:22](OCC)=[O:23])[CH2:8]1)=[O:6].[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[OH:23][CH2:22][CH:9]1[NH:10][CH:11]([C:13]2[CH:14]=[C:15]([F:21])[C:16]([F:20])=[C:17]([F:19])[CH:18]=2)[CH2:12][N:7]([C:5]([O:4][CH3:3])=[O:6])[CH2:8]1
Reactant: CCOC(=O)C1CN(C(=O)OC)CC(c2cc(F)c(F)c(F)c2)N1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)N1CC(CO)NC(c2cc(F)c(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Lithium borohydride (187 mg) was added to a solution of 5-(3,4,5-trifluorophenyl)piperazine-1,3-dicarboxylic acid 3-ethyl ester 1-methyl ester (991 mg) in THF (20 mL), and the reaction solution was stirred at room temperature for two hours. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 867 mg of a crude product of the title compound. The property value of the compound is as follows.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[N:3]=1.BrC1C=CC(S([N:19]2[CH2:24][CH2:23][N:22]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:20]2)(=O)=O)=CC=1.C(N(CC)CC)C.CCOCC>C1COCC1>[CH3:8][C:4]1[N:3]=[C:2]([N:30]2[CH2:31][CH2:32][CH:27]([C:25]([N:22]3[CH2:23][CH2:24][NH:19][CH2:20][CH2:21]3)=[O:26])[CH2:28][CH2:29]2)[CH:7]=[CH:6][N:5]=1
Reactant: Cc1nccc(Cl)n1
Reactant: O=C(C1CCNCC1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nccc(N2CCC(C(=O)N3CCNCC3)CC2)n1
Yield: 52.7 %

Procedure:
4-Chloro-2-methylpyrimidine (135 mg) was added to a solution of 1-(4-bromophenylsulphonyl)-4-(piperidin-4-ylcarbonyl )piperazine (415 mg) in THF (15 ml) containing triethylamine (0.2 ml). The mixture was heated at reflux for 16 hours. After cooling, the THF was evaporated. The residue was treated with H2O (20 ml) and the aqueous extracted with EtOAc (3×20 ml). The combined organic phases were washed with saturated brine (1×20 ml) dried and evaporated to give an oil which was purified by chromatography on silica gel. Elution with CH2Cl2 /MeOH/0.88NH3 (96:3:1) gave an oil. Trituration with Et2O (10 ml) gave, as a colourless solid, 1-(4-bromophenylsulphonyl) 4-(4-(1-(2-methylpyrimidyl)piperidin-4-ylcarbonyl)piperazine (152 mg), mp 200-202° C.;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[K+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)c1ccc(F)cc1
Yield: 88.1 %

Procedure:
A solution of ethyl 3-(4-fluorophenyl)butyrate (45.3 g, 0.215 mol), 85% potassium hydroxide (14.22 g, 0.215 mol, Mallinckrodt) in 200 ml of deionized water was refluxed for 2 h, concentrated by spin evaporation in vacuo, made acidic (pH 3) with 12 N hydrochloric acid (Mallinckrodt), and extracted with dichloromethane (4×200 ml). The dichloromethane layers were combined, washed with deionized water (50 ml), and concentrated by spin evaporation in vacuo. The residue was crystallized from dichloromethane-hexanes to give 34.5 g (88%) of 3-(4-fluorophenyl)butyric acid as a white crystalline solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][C:3]=1[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14].CO.C[Si]([N:22]=[N+:23]=[N-:24])(C)C>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:24][N:23]=[N:22][CH:9]=2)=[CH:4][C:3]=1[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc(Cl)c(CNC(=O)OC)c1
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)NCc1cc(-c2cnn[nH]2)ccc1Cl
Temperature: 100 °C

Procedure:
To a solution of methyl N-[(2-chloro-5-ethynylphenyl)methyl]carbamate (i.e. the product of Step D) (0.43 g, 1.92 mmol) in N,N-dimethylformamide (3.9 mL) and methanol (0.4 mL) was added trimethylsilyl azide (0.38 mL, 2.89 mmol) and copper(I) iodide (0.019 g, 0.1 mmol). The reaction mixture was heated in a CEM Discover microwave apparatus at 100° C. for 8 h and then allowed to cool to room temperature. The reaction mixture was partitioned between ethyl acetate and aqueous sodium chloride, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with water (3×), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound, a compound of the present invention, as a brown solid (0.30 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15]C)=[O:14])[C:7]([CH3:17])=[C:6]2[C:18]1[C:27]2[C:22](=[C:23]([CH3:28])[CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1)#[N:2].[OH-].[Li+]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=[O:14])[C:7]([CH3:17])=[C:6]2[C:18]1[C:27]2[C:22](=[C:23]([CH3:28])[CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1)#[N:2]
Reactant: COC(=O)Cn1c(C)c(-c2ccnc3c(C)cccc23)c2cc(C#N)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2c(-c3c(C)n(CC(=O)O)c4ccc(C#N)cc34)ccnc12
Reaction time: 1 h

Procedure:
The product from step b) was taken up in THF (10 ml) treated with a solution of lithium hydroxide (252 mg) in water (10 ml) and stirred for 1 hour. The solution was concentrated to remove the THF and acidified with saturated aqueous potassium hydrogen sulphate. The solid was collected by filtration, washed with water, washed with a little cold propan-2-ol, washed with a little cold ether and dried to give the title compound as a yellow/orange solid (606 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12]Br.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:12][CH:11]([O:14][CH3:15])[O:10][CH3:9])[CH:3]=1
Reactant: Sc1cccc(Cl)c1
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(CSc1cccc(Cl)c1)OC
Reaction time: 16 h
Yield: 95.8 %

Procedure:
To a solution of 3-chlorothiophenol (2.4 g, 16.6 mmol) in THF (200 mL) at 0° C. is added bromoacetaldehyde dimethyl acetal (2.8 g, 16.6 mmol). To the solution is added sodium hydride (0.70 g, 17.4 mmol, 60% mineral oil dispersion). The reaction is stirred for 16 hours, then quenched by the addition of saturated NH4Cl (aq.). The solution is diluted with EtOAc. The organic layer is washed with saturated NaCl (aq.). The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with hexanes. The title compound (3.7 g, 15.9 mmol) is obtained as an oil.