Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29]3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:37])[CH:3]=1.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29]3)[CH2:27][CH2:28]2)=[O:22])=[C:4]([CH3:37])[CH:3]=1
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC3(C=Cc4ccccc43)CC2)cnc2c(C(=O)O)cnn12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC4(C=Cc5ccccc54)CC3)cnc12
Yield: 36.8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-2-methylphenylamino)-6-(spiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.03 g, 0.06 mmol) obtained in step 2 and ethanesulfonamide (0.032 g, 0.30 mmol), the title compound (0.013 g, 37%) was obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.Br.[C:23]12[CH2:30][NH:29][CH2:28][C:27]=1[CH2:26][NH:25][CH2:24]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:25]4[CH2:26][C:27]5[CH2:28][NH:29][CH2:30][C:23]=5[CH2:24]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1NCC2=C1CNC2
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 66.4 %

Procedure:
The solution of 0.4 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.8 g of 3,7-diazabicyclo[3.3.0]oct-1(5)-ene dihydrobromide, and 0.8 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 30 ml of acetonitrile was refluxed in oil bath at the temperature of 100° C. for 8 hours, and this reaction mixture was kept overnight at the room temperature. The product precipitate was filtered off and then the residue was washed with methanol, to obtain 0.35 g of the title compound (yield 67%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]2[CH2:32][CH:31]([NH:33][CH2:34][CH2:35][OH:36])[CH2:30][CH2:29][CH2:28][C:27]=2[C:37]=1[O:38][CH3:39]>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]3[CH2:32][CH:31]([NH:33][CH2:34][CH2:35][OH:36])[CH2:30][CH2:29][CH2:28][C:27]=3[C:37]=2[O:38][CH3:39])=[N:3][CH:4]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCCC(NCCO)C2
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)ccc2c1CCCC(NCCO)C2

Procedure:
The title compound was prepared from (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (100 mg, 0.30 mmol) and 2-(2-Amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamino)-ethanol (75 mg, 0.30 mmol) in an analagous manner to Example 946 to afford an off-white foam (97 mg, 58%). Mp: 80-1° C. LCMS (m/e) 560 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.60 (s, 1H), 8.60 (d, J=8 Hz, 1H), 8.19 (s, 1H), 7.94 (d, J=8 Hz, 1H), 7.68 (d, J=8 Hz, 1H), 7.65 (m, 1H), 7.52 (s, 1H), 7.30 (m, 1H), 6.87 (d, J=8 Hz, 1H), 3.75 (s, 3H), 3.66 (m, 2H), 3.00-2.82 (m, 5H), 2.76 (m, 2H), 2.09 (m, 1H), 1.86 (m, 4H), 1.60 (m, 1H), 1.35 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([CH2:8][C@@H:9]([N:11]=[N+]=[N-])[CH3:10])[CH:7]=1>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([CH2:8][C@@H:9]([NH2:11])[CH3:10])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1C[C@H](C)N=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1C[C@H](C)N
Yield: 48 %

Procedure:
To a solution of (1S)-2-(5-chloro-2-methylphenyl)-1-methylethyl azide (500 mg, 2.38 mmol) in 50 mL of EtOAc was added Pd/C (150 mg of 10% Pd) and the mixture was hydrogenated under hydrogen balloon for 20 min. The catalyst was removed by filtration through celite, then passed through silica gel plug eluting first with EtOAc (40 mL), then MeOH/EtOAc/NH4OH 20:75:5 (120 mL). The fraction with product was evaporated to give (1S)-2-(5-chloro-2-methylphenyl)-1-methylethylamine (210 mg, 48%) as pale oil. ESI-MS: m/z (MH+) 184.4. 1H NMR (300 MHz, CDCl3): δ 7.12 (s, 1H), 7.08 (s, 2H), 3.16 (m, 1H), 2.48-2.70 (m, 2H), 2.28 (s, 3H), 1.23 (s, 2H), 1.13 (d, J=6.21 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:33][C:32]5[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=5)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3ccc(F)cc3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-fluoro-benzyl bromide following a procedure analogous to that described for Intermediate 7. LC (method 6): tR=1.18 min; Mass spectrum (ESI+): m/z=458 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20]2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C=O>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:20]2[Br:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
A solution of N-bromosuccinimide (7.83 g, 44.0 mmol) in N,N-dimethylformamide (30 mL) was added dropwise (40 min) to a cooled (0 ° C.) and stirred solution of ethyl 5-(benzyloxy)-1H-indole-2-carboxylate (10.0 g, 39.2 mmol) in N,N-dimethylformamide (20 mL). The cold bath was removed and stirring was continued for an additional 1.5 h. The reaction was poured over ice water (600 mL) and the resulting precipitate was collected by vacuum filtration. The precipitate was washed with water and dried to give 12.9 g (98%) of crude product. This material was used in the next reaction without further purification or analysis.
Reaction SMILES: [CH3:1][C@H:2]([NH2:11])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>>[CH3:1][C@H:2]([NH2:11])[C@H:3]([OH:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](N)[C@@H](O)c1ccccc1
Agent: Cl
Product: C[C@H](N)[C@H](O)c1ccccc1
Yield: 105.7 %

Procedure:
61 grams of this salt were split in a manner analogous to that described in example 1. There were obtained 33 grams of L-3-formyl-2,2,5,5-tetramethyl-thiazolidine-4-carboxylic acid melting at 179° - 180°C.; [α]D20 - 54.4° as well as 26.5 grams of d-phenylpropanolamine.HCl melting point 173°C.; [α]D20 + 33°. From the mother liquor of the racemate splitting by evaporation to dryness and treatment with isopropanolic HCl there were obtained 28 grams (77%) of l-phenylpropanolamine.HCl, melting point 179°C.; [α]D20 - 31.4°.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[CH:25]=[C:24]([C:26]2[O:30][N:29]=[C:28]([CH3:31])[N:27]=2)[CH:23]=[CH:22][C:21]=1[C:32]1[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][N:15]([C:38]([C:35]5[CH:34]=[CH:33][C:32]([C:21]6[CH:22]=[CH:23][C:24]([C:26]7[O:30][N:29]=[C:28]([CH3:31])[N:27]=7)=[CH:25][C:20]=6[CH3:19])=[CH:37][CH:36]=5)=[O:39])[C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:6][CH2:7]1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: Cc1noc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)n1
Product: Cc1noc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)n1

Procedure:
The title compound was prepared from 1'-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (D8) and 2'-methyl-4'-(3-methyl-1,2,4-oxadiazol-5-yl)biphenyl-4-carboxylic acid (D29) using a similar procedure to Example 1. This was converted to its oxalate salt, which was obtained as a yellow solid (3%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.CS([C:19]1[N:20]=[CH:21][C:22]2[N:27]=[C:26]([C:28]3[CH:48]=[C:47]([CH3:49])[C:31]([O:32][CH:33]4[CH2:36][CH:35]([C:37]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])[CH2:34]4)=[C:30]([CH3:50])[CH:29]=3)[O:25][C:23]=2[N:24]=1)(=O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:19]1[N:20]=[CH:21][C:22]2[N:27]=[C:26]([C:28]3[CH:29]=[C:30]([CH3:50])[C:31]([O:32][CH:33]4[CH2:36][CH:35]([C:37]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])[CH2:34]4)=[C:47]([CH3:49])[CH:48]=3)[O:25][C:23]=2[N:24]=1
Reactant: Cc1cc(-c2nc3cnc(S(C)(=O)=O)nc3o2)cc(C)c1OC1CC(C(=O)OCc2ccccc2)C1
Reactant: Oc1cccc(Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cnc(Oc4cccc(Cl)c4)nc3o2)cc(C)c1OC1CC(C(=O)OCc2ccccc2)C1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
48 mg of potassium carbonate and 20 mg of 3-chlorophenol were added to a solution of 70 mg of benzyl 3-[4-(5-methanesulfonyloxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]cyclobutanecarboxylate in 5 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 1.5 h and at 60° C. for a further 4 h. For work-up, 10% strength aqueous citric acid solution was added, and the reaction was extracted with dichloromethane. The combined organic phases were concentrated and dried under reduced pressure. This gave 77 mg (100%) of the title compound, which was reacted further without any purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C([O:14][C@@H:15]1[C@@H:28]([O:29]C(=O)C)[C@H:27]([O:33]C(=O)C)[CH2:26][S:25][C@H:16]1[O:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22](Br)[CH:23]=1)(=O)C>>[O:17]([C:18]1[CH:19]=[N:20][CH:21]=[C:22]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:23]=1)[C@@H:16]1[S:25][CH2:26][C@@H:27]([OH:33])[C@H:28]([OH:29])[C@H:15]1[OH:14]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: OB(O)c1cccc(F)c1
Product: O[C@@H]1[C@@H](O)[C@H](Oc2cncc(-c3cccc(F)c3)c2)SC[C@H]1O

Procedure:
By following a procedure analogous to Example 122 starting from 3-fluoro-phenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 5-(3-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=67%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][CH2:5]2.[Br-].[CH2:13]([Zn+])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH2:13]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][CH2:5]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: O=C1OCc2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1OCc2cc(Cc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 40 h
Yield: 43.6 %

Procedure:
A mixture of 5-bromo-3H-isobenzofuran-1-one (14 mmol, 3.04 g), benzylzinc bromide solution (0.5 M in THF, 28 mmol, 56 mL), [1,1′bis(diphenylphosphino)-ferrocene]dichloropalladium(II) 1:1 complex with CH2Cl2 (0.07 mmol, 57 mg), and anhydrous 1,4-dioxane (70 mL) was refluxed with stirring under nitrogen for 40 h. After cooling to ambient temperature silica gel was added and the mixture was concentrated in vacuo. The residue was added on top of a chromatography column filled with silica gel. Elution with hexanes:ethyl acetate=9:1 gave a yellow solid. Further purification by recrystallization from ethyl acetate/hexanes gave the title compound (1.37 g) as white needles; 1H NMR (CDCl3, 200 MHz): δ=7.83 (d, 1H), 7.16 to 7.39 (m, 7H), 5.26 (s, 2H), 4.11 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:19][C:18]3[CH:17]=[N:16][N:15]([CH3:20])[C:14]=3[NH:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH:35]=O)[CH2:31][CH2:30]1)=[O:28].[CH2:37]([NH:41][CH3:42])[CH2:38][CH2:39][CH3:40].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CN(C=O)C>[CH2:37]([N:41]([CH2:35][CH:32]1[CH2:31][CH2:30][N:29]([C:27](=[O:28])[CH2:26][CH2:25][C:3]2[CH:4]=[CH:5][C:6]([C:8]([N:10]3[CH2:19][C:18]4[CH:17]=[N:16][N:15]([CH3:20])[C:14]=4[NH:13][C:12]4[CH:21]=[CH:22][CH:23]=[CH:24][C:11]3=4)=[O:9])=[CH:7][C:2]=2[CH3:1])[CH2:34][CH2:33]1)[CH3:42])[CH2:38][CH2:39][CH3:40]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(C=O)CC1
Reactant: CCCCNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCN(C)CC1CCN(C(=O)CCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4ccccc43)cc2C)CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A solution of 1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidine-4-carbaldehyde from Example E58.1 (2.43 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of butyl-methyl-amine (0.43 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and the mixture was heated at 50° C. for 3 h then stirred at room temperature for 2 days. A solution of sodium tri-acetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added and the mixture was stirred for 20 h at room temperature. Solvents were removed in vacuo to yield the title compound. MS: (ESI)+:[M+H]+=557.6
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].N1C=CC=CC=1.[CH2:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[C:19]([F:26])[CH:18]=1)[CH3:16]>C1C=CC=CC=1>[CH2:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])=[O:22])=[C:19]([F:26])[CH:18]=1)[CH3:16]
Reactant: CCc1ccc(C(=O)Cl)c(F)c1
Reactant: Nc1ccccc1O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCc1ccc(C(=O)Nc2ccccc2O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 13.08 gm. of o-aminophenol in 150 cc. of dry pyridine which is cooled in ice water is added a solution of 4-ethyl-2-fluorobenzoyl chloride (prepared from 20.0 gm. of acid and thionyl chloride) in 30 cc. of dry benzene. The mixture is stirred at room temperature overnight and then concentrated in vacuo. The residue is treated with water and the precipitate collected by filtration to give crude 4-ethyl-2-fluoro-2'-hydroxybenzanilide which was characterized by infra red spectra and then used in the following step.
Reaction SMILES: [BH4-].[Na+].[Br:3]/[CH:4]=[CH:5]/[C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl/C=C/C(=O)CCCCC>C(O)C>[Br:3]/[CH:4]=[CH:5]/[CH:6]([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(=O)/C=C/Br
Agent: CCCCCC(=O)/C=C/Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC(O)/C=C/Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cooled mixture of 14.29 g. (0.378 mole) of sodium borohydride in 400 ml. of anhydrous ethanol is added the crude 1-bromo-trans-1-octen-3-one (Example 725), from 0.424 mole of 1-chloro-trans-1-octen-3-one) over 30 minutes. The mixture is stirred for 2 hours with ice cooling and is then partitioned between ice water and benzene. The organic phase is washed with water and saturated brine, dried (Na2SO4), and evaporated to an oil. Fractional distillation yields the title compound as a colorless oil, b.p. 66°-68° C. (0.025 torr).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:28]1[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N:30]=[C:29]1[CH3:37])=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.NC1C=CC=CC=1NC1N=C2C(N=C(CN3CCC(C([OH:66])(C)C)CC3)N2C)=C(N2CCOCC2)N=1.C(O)(=O)CO>>[OH:66][CH2:37][C:29]1[N:28]([C:5]2[N:4]=[C:3]3[C:8]([N:9]=[C:10]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]4)[N:2]3[CH3:1])=[C:7]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:6]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Agent: O=C(O)CO
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(CO)nc4ccccc43)nc21

Procedure:
Following the procedures for synthesis of 157, 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and glycolic acid were reacted to give 178. LCMS: M+H+=521.3. 1H-NMR (400 MHz, DMSO-d6): δ 8.17 (d, 1H), 7.68 (d, 1H), 7.31 (m, 2H), 5.28 (t, 1H), 5.08 (d, 2H), 4.27 (s, br, 4H), 4.02 (s, 1H), 3.82 (s, 3H), 3.78 (m, 4H), 3.73 (s, 2H), 2.90 (d, 2H), 2.01 (m, 2H), 1.66 (d, 2H), 1.21 (m, 3H), 1.02 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:22][CH3:23])=[C:8]([S:10]([C:13]2[CH:18]=[C:17]([Br:19])[C:16]([NH2:20])=[C:15]([NH2:21])[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[C:24]([O-])(O)=O.[Na+]>C(O)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:22][CH3:23])=[C:8]([S:10]([C:13]2[CH:18]=[C:17]([Br:19])[C:16]3[N:20]=[CH:24][NH:21][C:15]=3[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(N)c(N)c(Br)c2)c(SC)s1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c3nc[nH]c3c2)c(SC)s1
Temperature: 100 °C
Yield: 57 %

Procedure:
4-(3,4-Diamino-5-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 38, step d) 170 mg, 0.39 mmol) was dissolved in formic acid (2.5 mL) and heated to 100° C. for 2 hours. The resulting solution was cooled to room temperature, poured over ice-water slurry, and basified to pH 8 with NaHCO3. This aqueous solution was extracted with ethyl acetate (75 mL, 3×). The organic layer was separated and washed with water, brine, and dried over MgSO4. Solvents were removed in vacuo to afford 100 mg (57%) of 4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester as a brown oil. ESI-MS (m/z): Calcd. for C14H11BrN2O4S3: 447 (M+H); found: 447.1 and 449.1.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C:13]2[C:22]([CH3:23])=[C:21]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30](I)[CH:31]=4)[C:26]([CH3:35])([CH3:34])[CH2:25]3)[C:20]3[C:15](=[CH:16][C:17]([F:36])=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C:13]2[C:22]([CH3:23])=[C:21]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)[CH:31]=4)[C:26]([CH3:35])([CH3:34])[CH2:25]3)[C:20]3[C:15](=[CH:16][C:17]([F:36])=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(I)cc21
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 105 °C
Reaction time: 1 h

Procedure:
Prepared according to procedure N using 2-(3,5-bis(trifluoromethyl)phenyl)-7-fluoro-4-(6-iodo-3,3-dimethylindolin-1-yl)-3-methylquinoline (in a mixture with the 5-F regioisomer; described herein) (160 mg, 0.25 mmol), morpholine (43 μL, 0.50 mmol), Pd2dba3 (34.1 mg, 0.037 mmol), 2-(dicyclohexylphosphino)-2,4,6-tri-i-propyl-1,1-biphenyl (35.5 mg, 0.074 mmol), and sodium tert-butoxide (71.6 mg, 0.745 mmol) in toluene (2.5 mL). The reaction was stirred at 105° C. for 1 h. Purification afforded 2-(3,5-bis(trifluoromethyl)phenyl)-4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-7-fluoro-3-methylquinoline as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 8.12 (2H, s), 8.00 (1H, s), 7.84-7.92 (1H, m), 7.80 (1H, ddd, J=9.5, 2.1, 1.0 Hz), 7.28-7.31 (1H, m), 7.10 (1H, dd, J=8.1, 1.1 Hz), 6.31-6.39 (1H, m), 5.57-5.64 (1H, m), 3.69-3.84 (6H, m), 2.93-3.00 (4H, m), 2.30 (3H, s), 1.53 (3H, s), 1.47 (3H, s). Mass Spectrum (ESI) m/e=604 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12](N)=[O:13].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][OH:23])=[CH:18][CH:17]=1>>[OH:23][N:22]([C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)[C:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:13]
Reactant: ONc1ccc(Cl)cc1
Reactant: NC(=O)c1cnc2ccccc2c1O
Product: O=C(c1cnc2ccccc2c1O)N(O)c1ccc(Cl)cc1

Procedure:
Using the procedure of Step A of Example 6, 9.45g of 4-hydroxy-3-quinoline carboxamide and N-(4-chlorophenyl)-hydroxylamine acid were reacted to obtain 14.4 g of crude N,4-dihydroxy-N-(4-chlorophenyl)-3-quinoline carboxamide
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:36].O>C(Cl)(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:36])=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A solution of tert-butyl 2-{2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (15.47 g, 37.3 mmol) in 150 mL of CHCl3 was treated with 3-chloroperoxybenzoic acid (MCPBA, 70%, 15.12 g, 61.3 mmol). After stirring for 1.5 h, the reaction mixture was treated with water (100 mL) and CHCl3 (50 mL) and the layers were separated. The organic portion was washed with 2% Na2CO3 solution (2×), H2O and brine then dried over Na2SO4 and concentrated to give 16.06 g of tert-butyl 2-{2-[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a yellow solid.