Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5](C)=[C:6]([CH2:8]P(=O)(OCC)OCC)[N:7]=1)[CH3:2].[H-].[Na+].[CH3:20][O:21][CH2:22][O:23][C:24]1[C:28]([CH:29]=O)=[CH:27][N:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[N:25]=1.O>O1CCCC1>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:29]/[C:28]2[C:24]([O:23][CH2:22][O:21][CH3:20])=[N:25][N:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])[CH:27]=2)[N:7]=1)[CH3:2]
Reactant: COCOc1nn(-c2ccccc2C)cc1C=O
Reactant: CCOP(=O)(Cc1nc(CC)sc1C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(/C=C/c2cn(-c3ccccc3C)nc2OCOC)cs1
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To a solution of diethyl [(2-ethyl-5-methyl-1,3-thiazol-4-yl)methyl]phosphonate (1.26 g) in tetrahydrofuran (40 mL) was added sodium hydride (60% in oil, 0.192 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-(2-methylphenyl)-1H-pyrazole-4-carbaldehyde (0.99 g) was added to the reaction mixture, and the mixture was heated under reflux for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:20-1:3, v/v) to give 2-ethyl-4-{(E)-2-[3-(methoxymethoxy)-1-(2-methylphenyl)-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole as a pale-yellow oil (0.81 g, yield 57%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CCCC=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CCCCN1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Prepared from butanal and piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:18])[C:8](=[O:17])[N:9]2[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[N+:19]([O-])=O>CN(C)C=O.[Ni]>[NH2:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[Cl:1])[N:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:8](=[O:17])[C:7](=[O:18])[NH:6]2
Reactant: COC(=O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(Cl)cc21
Agent: [Ni]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)c(=O)[nH]c2cc(N)c(Cl)cc21
Yield: 99.4 %

Procedure:
10 g (30.5 mmol) of 7-chloro-1-(methoxy-carbonylmethyl)-6-nitro-2,3(1H,4H)-quinoxalinedione were dissolved in 300 ml of dimethylformamide and, after addition of 5 g of Raney nickel, hydrogenated under 1 bar at room temperature. The mixture was then filtered and the filtrate was concentrated under reduced pressure to yield 8.6 g (95%) of the product. Melting point >260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[N:3]=1.B(O)(O)[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[N:3]=1
Reactant: COc1ccc(Cl)cc1-c1cc(N)cc(Cl)n1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(C)cc2)cc(Cl)n1
Reaction time: 60 h
Yield: 71.4 %

Procedure:
A mixture of 2-chloro-6-(5-chloro-2-methoxy-phenyl)-pyridin-4-yl-amine (715 mg, 2.65 mmol), p-tolylboronic acid (722 mg, 5.3 mmol), copper (II) acetate (962 mg, 5.3 mmol), triethylamine (1.5 ml, 10.6 mmol) and molecular sieves (4 angstrom) in dichloromethane (40 ml) was stirred under oxygen atmosphere for 60 hours. The mixture was filtered through a pad of celite under suction. The filtrate was purified by flash chromatography eluting with ethyl acetate-hexane (1:3 followed by 2:5) to provide the title compound (680 mg, 72% yield). 1H NMR (DMSO-d6) δ 2.32 (s, 3H, CH3), 3.91 (s, 3H, CH3), 6.73 (d, 1H, J=1.9 Hz, Ar), 7.14 (d, 2H, J=8.4 Hz, Ar), 7.18 (d, 1H, J=8.9 Hz, Ar), 7.22 (d, 2H, J=8.2 Hz, Ar), 7.44–7.48 (m, 2H, Ar), 7.75 (d, 1H, J=2.8 Hz, Ar), 9.1 (s, 1H, NH).
Reaction SMILES: [F:1][C:2]([F:17])([N:8]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[N:9]1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[Cl:18][C:19]1[C:28](Cl)=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Cl:18][C:19]1[C:28]([NH:14][S:13]([C:10]2[CH:11]=[CH:12][N:8]([C:2]([F:1])([F:17])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])[N:9]=2)(=[O:15])=[O:16])=[N:27][C:26]2[C:21]([N:20]=1)=[CH:22][CH:23]=[CH:24][CH:25]=2
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: CN(C)C(=O)C(F)(F)n1ccc(S(N)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CN(C)C(=O)C(F)(F)n1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)n1
Temperature: 0 °C
Yield: 69 %

Procedure:
1.30 g of 2,2-difluoro-N,N-dimethyl-2-(3-sulfamoylpyrazol-1-yl)acetamide, 1.16 g of 2,3-dichloroquinoxaline and 670 mg of potassium carbonate in about 16 ml of dried DMA are heated at 100° C. (bath temperature) under nitrogen in a flask until the sulfonamide has reacted virtually completely (HPLC check, about 3 hours). The cooled reaction solution is poured into about 200 ml of ice-water, with a precipitate depositing after some time. This is filtered off with suction and discarded. The filtrate is adjusted to pH 4-5 using saturated citric acid solution. A further precipitate deposits, which is filtered off, washed with water and dried, giving 1.44 g of 2-[3-(3-chloroquinoxalin-2-ylsulfamoyl)pyrazol-1-yl]-2,2-difluoro-N,N-dimethylacetamide as pale-beige solid (yield 69%, content 99.8%). MS-FAB (M+H+)=431.0. Rf (polar method): 1.98 min. This is employed without further purification for the next step.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[N:7][CH:8]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39][CH2:38][C:24]=3[N:25]([S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:26]=2[CH:27]=1>>[O:15]=[C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][N:7]=2)[CH:14]=[CH:13][N:12]1[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39][CH2:38][C:24]=3[N:25]([S:28]([C:31]3[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=3)(=[O:30])=[O:29])[C:26]=2[CH:27]=1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cn2)cc[nH]1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CN(C(=O)OC(C)(C)C)CC3)cc1
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(-n5ccc(-c6ccc(C(F)(F)F)cn6)cc5=O)cc42)CN(C(=O)OC(C)(C)C)CC3)cc1
Yield: 37.2 %

Procedure:
4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (131 mg, 0.545 mmol) and tert-butyl 7-bromo-5-tosyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (255 mg, 0.505 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (125 mg, 34%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 9.01 (s, 1H), 8.29 (d, J=1.6 Hz, 1H), 8.08 (dd, J=8.3, 1.9 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.33 (dd, J=8.2, 1.6 Hz, 1H), 7.29-7.23 (m, 4H), 7.09 (dd, J=7.2, 1.8 Hz, 1H), 4.52 (s, 2H), 3.80-3.73 (br m, 2H), 3.18-3.09 (br m, 2H), 2.35 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]=[CH:7]2)([O-:3])=[O:2].[F-].[Cs+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9](=[O:14])[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=c1ccc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: ClCc1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: O=c1ccc2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
Compound 46B (50 mg, 0.26 mmol) was dissolved in DMF (1 mL), CsF (120 mg, 0.79 mmol) and benzyl chloride (0.09 mL, 0.79 mmol) were added, and the reaction was stirred at rt for 16 h. The reaction mixture was then concentrated under reduced pressure and subsequently purified by silica gel flash chromatography eluting with 0-5% EtOAc/CH2Cl2 (gradient) to give the title compound (57 mg, 77%). LC/MS m/z 281 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28]([OH:30])=O)=[CH:25][CH:26]=3)[C:21]([CH3:31])=[C:20]2[CH3:32])[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].[N+:33]([C:36]1[CH:41]=[CH:40][C:39]([C@@H:42]([NH2:44])[CH3:43])=[CH:38][CH:37]=1)([O-:35])=[O:34]>>[CH3:32][C:20]1[N:19]([CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=2)[C:27]2[C:22]([C:21]=1[CH3:31])=[CH:23][C:24]([C:28](=[O:30])[NH:44][C@H:42]([C:39]1[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:41][CH:40]=1)[CH3:43])=[CH:25][CH:26]=2
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)c1cccc(-c2ccccc2Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Product: CCOC(=O)c1cccc(-c2ccccc2Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4ccc([N+](=O)[O-])cc4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using the 1-((3′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and the (S)-1-(4-nitrophenyl)ethanamine instead of the (S)-1-(4-bromophenyl)ethanamine.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[CH:9]=[CH:10][C:11]([NH2:17])=[CH:12][C:13]=32)[CH2:6]1)(=[O:4])=[O:3].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:35][CH3:36])(=[O:34])=[O:33])[C:22]([Cl:37])=[CH:21][N:20]=1.C(O)(C)C.C(=O)(O)[O-].[Na+]>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:35][CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:17][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]2[CH2:16][CH:14]3[CH2:15][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6]2)=[N:20][CH:21]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CS(=O)(=O)N1CC2CC(C1)c1cc(N)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CC3CN(S(C)(=O)=O)C2)ncc1Cl
Temperature: 130 °C

Procedure:
Into a microwave tube was dissolved 10-methanesulfonyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (50 mg, 0.2 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (64.5 mg, 0.194 mmol) in isopropyl alcohol (1 mL, 10 mmol). The tube was heated in the microwave at 130° C. for 20 minutes. The reaction solution was poured into saturated sodium bicarbonate solution and was extracted with methylene chloride (6×20 ml). The reaction was dried over magnesium sulfate filtered and was rotovaped to a clear oil. Upon addition of ethyl acetate and hexanes 2-[5-Chloro-2-(10-methanesulfonyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide crashed out as a white solid 63.03 mg, 60%). MP: 207° C. dec.; 1H-NMR (CDCl3) δ 9.09 (s, 1H), 8.43 (d, J=8.3 Hz, 1H), 8.14 (s, 1H); 7.96 (d, J=7.8 Hz, 1H), 7.64-7.58 (m, 2H) 7.17 (d, J=7.8 Hz, 1H), 6.98 (m, 1H), 4.62 (br s, 1H), 3.67-3.53 (m, 2H), 3.38-3.39 (m, 2H), 3.20 (br s, 1H), 3.14 (br s, 1H), 2.66 (d, J=5.3 Hz, 3H), 2.42-2.35 (m, 1H), 2.03 (s, 3H), 1.84 (d, J=11.1 Hz, 1H), 1.57 (s, 3H), LC/MS (ESI+): 549 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5](I)[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1.[CH3:33][O:34][CH2:35][CH2:36][OH:37]>>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:37][CH2:36][CH2:35][O:34][CH3:33])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1
Reactant: Nc1ncnc2c1nc(I)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: COCCO
Product: COCCOc1nc2c(N)ncnc2n1-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be prepared from 1-[4-(6-amino-8-iodopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea and 2-methoxyethanol by using the same techniques as in Example 136.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]=O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20](=[O:21])[CH:22]=[CH:13][C:10]1[S:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1nc(-c2ccc(F)cc2)cs1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=Cc1nc(-c2ccc(F)cc2)cs1

Procedure:
2 g (10.57 mmol) of 4-(4-fluoro-phenyl)-thiazole-2-carbaldehyde and 4.177 g (11.09 mmol) of (tert-butoxycarbonylmethylene)triphenylphosphorane in 25 ml of THF were stirred at room temperature for 2 h. The reaction mixture was evaporated, and the residue was used in the subsequent step without purification.
Reaction SMILES: [F:1][C:2]([F:26])([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1)[C:3]1[N:12]=[C:11](SC)[C:10]2[C:5](=[C:6]([NH:15][C:16](=[O:18])[CH3:17])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+].[CH3:50][C:51]1[NH:55][N:54]=[C:53]([NH2:56])[CH:52]=1>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:26])([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1)[C:3]1[N:12]=[C:11]([NH:56][C:53]2[CH:52]=[C:51]([CH3:50])[NH:55][N:54]=2)[C:10]2[C:5](=[C:6]([NH:15][C:16](=[O:18])[CH3:17])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(NC(C)=O)cccc12
Reactant: Cc1cc(N)n[nH]1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)Nc1cccc2c(Nc3cc(C)[nH]n3)nc(C(F)(F)c3ccc(F)cn3)nc12
Reaction time: 0.67 h
Yield: 36.1 %

Procedure:
To N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)acetamide (90 mg, 0.24 mmol) in DCM (5 mL) at 0° C. was added 3-chloroperbenzoic acid (70%, 77 mg, 0.3 mmol) and the mixture stirred for 40 min. The mixture was diluted with DCM and then aq sodium thiosulfate and saturated aq sodium bicarbonate were added. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. To the residue were added THF (3 mL) and 5-methyl-1H-pyrazol-3-amine (107 mg, 1.1 mmol) and the mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-8-yl)acetamide (37 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.17 (s, 3H) 2.24 (s, 3H) 5.93 (s, 1H) 7.59 (t, J=8.10 Hz, 1H) 7.92-8.12 (m, 2H) 8.34 (d, J=8.29 Hz, 1H) 8.57-8.75 (m, 2H) 9.52 (s, 1H) 10.76 (br s, 1H) 12.20 (br s, 1H); LC-MS (ESI) m/z 428 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23](O)[CH3:24].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:1][CH:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([O:12][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])=[O:11]
Reactant: CCCCCCCCCCC(C)O
Reactant: NC(Cc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)C(N)Cc1ccccc1
Yield: 99.1 %

Procedure:
To a stirred solution of DL-phenylalanine 38 (5 g, 30.26 mmol) in toluene (100 mL) was added dodecanol 2 (5.08 g, 27.24 mmol) in one lot, followed by pTSA (6.33 g, 33.29 mmol). The temperature of the reaction mixture was slowly raised to reflux temperature, and the water was separated azeotropically The reaction mixture was monitored by TLC. The reaction mixture was concentrated under vacuum. The obtained residue was taken in ethyl acetate (200 mL) and washed with aqueous 5% Na2CO3 (3×50 mL) followed by brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 39 (9 g, yield: 89.1%) as a liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>>[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])=[O:16]
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Product: O=C(NS(=O)(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1Cl

Procedure:
A mixture of 4-chlorophenylsulfonamide (0.1 mol; 19.0 g) and 2,4-dichlorobenzoyl chloride (0.12 mol; 16.8 mL); the title compound was prepared essentially as described in Example 110.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:22])[NH:13][C:14]3[C:19]([C:20]=2[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:10])=[CH:4][CH:3]=1.[CH3:23][N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](Cl)=[O:26]>>[OH:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12](=[O:22])[C:11]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][C:25](=[O:26])[N:24]([CH3:23])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:3][CH:4]=1)=[O:10]
Reactant: O=C(Nc1ccc(O)cc1)c1c(O)c2ccccc2[nH]c1=O
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(NC(=O)c2c(O)c3ccccc3[nH]c2=O)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-hydroxy-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid (4-hydroxy-phenyl)-amide and N-methyl-N-phenylcarbamoyl chloride (5%,). HPLC-MS: m/z=430.1 (M+1); Rt: 4.80 min, purity: 70%.
Reaction SMILES: [F:1][S:2]([F:18])([F:17])([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)[C:6]([OH:8])=[O:7].[H][H]>CO.[Ni]>[NH2:12][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([S:2]([F:18])([F:1])([F:15])([F:16])[F:17])[CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(S(F)(F)(F)(F)F)c1
Agent: [Ni]
Solvent: CO
Product: Nc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reaction time: 3 h
Yield: 86.9 %

Procedure:
Subsequently, the 3-pentafluorosulfanyl-5-nitrobenzoic acid (5 g) was dissolved in methanol (300 ml), Raney nickel (about 750 mg) was added and hydrogenation was effected under a hydrogen atmosphere (hydrogen balloon). After 3 h, the catalyst was filtered off and the filter residue was washed thoroughly with methanol. The filtrate was concentrated and dried. The residue was purified using silica gel (2×50 g cartridge, n-heptane/EA gradient of 0-100% within 60 min). 3.9 g of the title compound were obtained.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[CH2:18][CH:17]([CH2:19][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:22][CH2:21]3)[C:15](=[O:16])[C:10]2=[CH:11][C:12]=1[O:13][CH3:14]>C(OCC)(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[CH2:18][CH:17]([CH2:19][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25]3)[C:15](=[O:16])[C:10]2=[CH:11][C:12]=1[O:13][CH3:14].[N+:1]([O-:4])([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: O=[N+]([O-])[O-]
Temperature: 25 °C

Procedure:
Nitric acid (0.45 ml, dissolved in 35 ml of absolute ethanol) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 213.7° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.C[Si](C)(C)[C:34]#[C:35][CH3:36].C(NCC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I.CN(C=O)C>[F:24][C:23]([F:26])([F:25])[C:22]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[C:2]([C:34]#[C:35][CH3:36])[CH:3]=1)([OH:31])[C:27]([F:30])([F:29])[F:28]
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Reactant: CC#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1
Temperature: 120 °C
Yield: 23.8 %

Procedure:
A glass microwave reaction vessel was charged with 2-(3-bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (128 mg, 0.23 mmol, Example 69, step 2), 1-(trimethylsilyl)-1-propyne (0.173 mL, 1.16 mmol, Sigma-Aldrich, St. Louis, Mo.), diethylamine (48 μL, 0.46 mmol, Sigma-Aldrich, St. Louis, Mo.), bis(triphenylphosphine) palladium(II) dichloride (15 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.), triphenylphosphine (12 mg, 0.05 mmol, Sigma-Aldrich, St. Louis, Mo.), copper iodide (9 mg, 0.05 mmol, Strem Chemical Inc, Newburyport, Mass.), and DMF (1 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 30 min. The reaction was diluted with EtOAc (about 10 mL) and water (about 10 mL). The organic layer was separated and washed with water (10 mL), dried (Na2SO4), concentrated and purified column chromatography (12 g silica, 0 to 20% EtOAc in hexanes to afford 1,1,1,3,3,3-hexafluoro-2-(3-(1-propyn-1-yl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (28 mg) as a white solid.
Reaction SMILES: CC1(C)C[O:35][C:5]2([CH2:9][C@@H:8]([CH2:10][C@H:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[C:28]([CH3:34])[CH:27]=3)[C:12](N([C@H](C)[C@H](O)C3C=CC=CC=3)C)=[O:13])[CH2:7][CH2:6]2)OC1.S(=O)(=O)(O)[OH:39]>O1CCOCC1.O>[CH3:34][C:28]1[CH:27]=[C:26]([C@@H:11]([CH2:10][C@H:8]2[CH2:7][CH2:6][C:5](=[O:35])[CH2:9]2)[C:12]([OH:39])=[O:13])[CH:31]=[CH:30][C:29]=1[S:32][CH3:33]
Reactant: O=S(=O)(O)O
Reactant: CSc1ccc([C@@H](C[C@H]2CCC3(C2)OCC(C)(C)CO3)C(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)cc1C
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)O)cc1C
Temperature: 110 °C
Yield: 90 %

Procedure:
A solution of (R)-3-((R)-8,8-dimethyl-6,10-dioxa-spiro[4.5]dec-2-yl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-methyl-4-methylsulfanyl-phenyl)-propionamide (1.35 g, 2.57 mmol) in dioxane (14 mL) was treated with a 9 N aqueous sulfuric acid solution (8 mL). The resulting solution was then heated at 110° C. for 16 h. The reaction was then cooled and diluted with water (150 mL) and extracted with a chloroform/methanol solution (3:2, 2×50 mL) and then combined the organic extracts and concentrated. The resulting residue was then dissolved in acetonitrile and concentrated with silica gel (3 g) and purified on Biotage Flash chromatography system (40 L column, silica gel, 60% ethyl acetate/hexanes) to afford (R)-2-(3-methyl-4-methylsulfanyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionic acid (674 mg, 90%) as a pale yellow gum: [α]28958−115.4° (c=0.35, methanol); ES-HRMS m/e calcd for C16H20O3S (M+Na)+ 315.1025, observed 315.1025; 1H NMR (300 MHz, DMSO-d6) δ 1.46 (m, 1H, CH), 1.76-2.32 (m, 8H, 4×CH2), 2.22 (s, 3H, ArCH3), 2.44 (s, 3H, SCH3), 3.48 (m, 1H, ArCHCO), 7.14 (m, 3H, Ar), 12.31 (s, 1H, CO2H).