Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5](Cl)=[O:6].C(N(CC)CC)C.[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([NH:32][CH3:33])[CH:26]=1>ClCCl>[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([N:32]([CH3:33])[C:5](=[O:6])[CH2:4][CH2:3][N:2]([CH3:1])[C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:26]=1
Reactant: CNc1cc(C)cc(C)n1
Reactant: CN(CCC(=O)Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(N(C)C(=O)CCN(C)c2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
A solution of 3-[methyl-(4-nitro-phenyl)-amino]-propionyl chloride (550 mg, 4.04 mmol) in dichloromethane (5 mL) was cooled to 0° C., triethylamine (1.12 mL, 8.08 mmol) was added followed, after 5 min, by (4,6-dimethyl-pyridin-2-yl)-methyl-amine (1.14 g, 4.73 mmol). The reaction mixture was warmed to room temperature and stirred for 30 min then partitioned between water and dichloromethane. The organic phase was separated, washed with saturated bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue which was purified by column chromatography over silica gel (60-120 mesh) using 20% ethyl acetate in hexane as eluent to afford N-(4,6-dimethyl-pyridin-2-yl)-N-methyl-3-[methyl-(4-nitro-phenyl)-amino]-propionamide (600 mg, 43%) as a yellow solid.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=O.[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][NH:16][CH3:17])=[CH:11][C:10]=1[F:18]>C(O)(=O)C>[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:17])[C:2]2[CH2:4][O:5][C:6](=[O:7])[CH:1]=2)=[CH:11][C:10]=1[F:18]
Reactant: CNCc1cnc(Cl)c(F)c1
Reactant: O=C1COC(=O)C1
Solvent: CC(=O)O
Product: CN(Cc1cnc(Cl)c(F)c1)C1=CC(=O)OC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
24.80 g (248 mmol) of tetronic acid are added slowly to 41.40 g (225.3 mmol) of N-[(6-chloro-5-fluoropyridin-3-yl)methyl]methanamine (III-1) in 64 ml of acetic acid, and the mixture is stirred at room temperature for about 16 hours. The reaction mixture is concentrated under reduced pressure, the residue is taken up in ethyl acetate and the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by recrystallization from ethyl acetate gives 30.0 g (52% of theory) of 4-[[(6-chloro-5-fluoropyridin-3-yl)methyl](methyl)amino]furan-2(5H)-one.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:31][O:32]CC)[N:18]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>ClCCl>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:31][OH:32])[N:18]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)C1CCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc(CO)n2CCCCNC(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 144 h
Yield: 21.7 %

Procedure:
Boron tribromide (2.5 equivalents, 14.6 mL of 1 M solution in dichloromethane) was added dropwise to a cooled (ice bath) suspension of N-{4-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}cyclopentanecarboxamide (2.4 g, 5.8 mmol) in dichloromethane (25 mL). The reaction mixture was allowed to slowly warm to ambient temperature and then stirred for 6 days. Additional boron tribromide (5 equivalents, 29 mmol, 29 mL) was added and the reaction was stirred at ambient until starting material was consumed. The reaction was quenched slowly with methanol (100 mL) and then concentrated under reduced pressure. The residue was combined with 6 M hydrochloric acid (100 mL), heated to 50° C., and stirred for 2 hours. The resulting solution was cooled (ice bath) and then free-based (pH 9) with the addition of 6 M aqueous sodium hydroxide. A brown gummy solid formed in the basic aqueous solution. The aqueous liquid was decanted from the solid and acetonitrile was added (30 mL). A white precipitate formed and was isolated by filtration. The white precipitate was then triturated with hot acetonitrile, allowed to cool, isolated by filtration, washed with ether, and dried under vacuum to provide N-{4-[4-amino-2-(hydroxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}cyclopentanecarboxamide (0.48 g) as a fine white solid, mp 183-186° C.; MS (ESI) m/z 382 (M+H)+; Anal. Calcd for C21H27N5O2: C, 65.35; H, 7.18; N, 18.14; Found C, 65.06; H, 6.90; N, 18.13.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([OH:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:34][C:35]=2[CH3:36])=[N:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:20][CH2:22][C:23]2[CH:28]=[N:27][C:26]([O:29][CH2:30][C:31]3[N:32]=[C:33]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[O:34][C:35]=3[CH3:36])=[CH:25][CH:24]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Reactant: CCOC(=O)CCc1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
A mixture of ethyl 3-(1-benzyl-3-hydroxy-1H-pyrazol-4-yl)propionate (411 mg), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (472 mg), potassium carbonate (414 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-benzyl-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]propionate (748 mg, yield 91%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:15]1([CH:21]([NH2:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:29][CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[O:12])=[CH:13][CH:14]=1
Reactant: Cc1ccccc1C(N)c1ccccc1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Product: Cc1ccccc1C(NC(=O)CNC(=O)c1ccc(F)cc1)c1ccccc1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-phenyl-C-o-tolyl-methylamine (CA [2936-62-1]).
Reaction SMILES: Cl.Cl.[CH:3]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.[Cl:21][C:22]1[N:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1>>[ClH:21].[CH:3]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([C:22]4[N:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=4)[CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: O=C(C1CCNCC1)N1CCN(C2CCC2)CC1
Agent: Cl
Product: O=C(C1CCN(c2ccc(C(F)(F)F)nn2)CC1)N1CCN(C2CCC2)CC1

Procedure:
The title compound (E190) was prepared from 1-cyclobutyl-4-(piperidine-4-carbonyl)-piperazine (free base compound from D7) and 3-chloro-6-trifluoromethyl-pyridazine (A. J. Goodman, S. P. Stanforth and B. Tarbit, Tetrahedron, 1999, 55(52), 15067-15070) using the method described in Example 88. LCMS electrospray (+ve) 398 (MH+). 1H NMR δ [MeOH-d4]: 1.86-2.02 (6H, m), 2.33-2.37 (4H, m), 2.78-2.89 (1H, m), 2.91-3.12 (2H, m), 3.23.3.28 (1H, m), 3.44-3.54 (6H, m), 3.71-3.75 (1H, m), 4.30-4.42 (2H, m), 4.67-4.70 (2×m, 1H), 7.95 (1H, d, J=10 Hz) and 8.00 (1H, d, J=10 Hz).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([F:36])[C:29]=1B(O)O>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:29]2[C:28]([F:27])=[CH:33][C:32]([O:34][CH3:35])=[CH:31][C:30]=2[F:36])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: COc1cc(F)c(B(O)O)c(F)c1
Product: COc1cc(F)c(-c2cncc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)c(F)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 2,6-difluoro-4-methoxyphenylboronic acid, 5-(2,6-difluoro-4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=30%).
Reaction SMILES: C([C@:8]([CH2:39][NH2:40])([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[C:25]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10])(OC(C)(C)C)=O.[ClH:41].O1CCOCC1>O1CCOCC1>[ClH:38].[ClH:41].[NH2:40][CH2:39][C@H:8]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[C:25]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)[C@](CN)(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3[nH]cc(-c4cccs4)c23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3[nH]cc(-c4cccs4)c23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a solution of (2S)-2-Boc-aminomethyl-3-(4-chlorophenyl)-1-[4-(5-thiophen-2-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-pip-erazin-1-yl]-propan-1-one in 1.5 mL dioxane was added 1.5 mL 4M HCl/dioxane. The resulting suspension was stirred at room temperature 16 hours, after which it was concentrated to dryness. The solids were dissolved in minimal MeOH, and the product was triturated by the addition of ether. The solids were isolated by filtration through a fritted funnel with nitrogen pressure, rinsed with ether, and dried in vacuo to give (2S)-2-aminomethyl-3-(4-chlorophenyl)-1-[4-(5-thiophen-2-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride (37 mg, 67%) a pale yellow powder. 1H NMR (D2O, 400 MHz) δ 8.18 (1H, s), 7.41 (1H, d, J 5.4 Hz), 7.30 (1H, s), 7.19 (2H, d, J 8.6 Hz), 7.06 (1H, dd, J 5.0 and 3.5 Hz), 7.01 (2H, d, J 8.0 Hz), 6.88 (1H, d, J 3.5 Hz), 3.47-3.14 (5H, m), 3.08-3.00 (3H, m), 2.86-2.77 (3H, m), 2.59 (1H, t, J 12.0 Hz), 2.13-2.06 (1H, m). LCMS (APCI+) m/z 481 [M+H]+; Rt: 1.87 min.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:10]([CH2:23][CH2:24][CH3:25])[N:11]=[C:12]3[C:21]=2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=[C:13]3[NH2:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O.[Pt](=O)=O>[CH:1]1([CH2:7][CH2:8][C:9]2[N:10]([CH2:23][CH2:24][CH3:25])[N:11]=[C:12]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[N:14]=[C:13]3[NH2:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCc1ccccc1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CCCn1nc2c(N)nc3c(c2c1CCC1CCCCC1)CCCC3
Reaction time: 18 h
Yield: 52.7 %

Procedure:
A mixture of 1-(2-phenylethyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 42, 400 mg, 1.21 mmol) and platinum (IV) oxide (200 mg) in trifluoroacetic acid (8 mL) was shaken under hydrogen pressure (50 psi, 3.4×105 Pa) on a Parr apparatus for 18 hours and worked up using the method described in Example 58 to afford 217 mg of 1-(2-cyclohexylethyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine as a white powder, mp 173-174.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[C:20]([N:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(C2CCCN2)c1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(C2CCCN2C(=O)c2ccccc2)c1
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 2-(3-methoxyphenyl)pyrrolidine (1.0 g) in dry acetonitrile (50 ml) was added milled potassium carbonate (2.0 g) followed by benzoyl chloride (0.73 ml) at ambient temperature, under nitrogen. The reaction mixture was stirred for 2 hrs, filtered through a pad of celite, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated, and the residue was purified by flash column chromatography (silica gel, 0-25% ethyl acetate/dichloromethane). The appropriate fractions were collected and concentrated to give 1.2 g (75%) of 1-benzoyl-2-(3-methoxyphenyl)pyrrolidine.
Reaction SMILES: COC1C=C(OC)C=CC=1C([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[N:18]([CH:24]([CH:29]([CH3:31])[CH3:30])[C:25]([O:27][CH3:28])=[O:26])[C:17]3=[O:32])=[CH:10][CH:9]=1)=O.[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[N:46]=[C:47]=[O:48]>O1CCCC1>[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[NH:46][C:47](=[O:48])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[N:18]([CH:24]([CH:29]([CH3:30])[CH3:31])[C:25]([O:27][CH3:28])=[O:26])[C:17]3=[O:32])=[CH:12][CH:13]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: COC(=O)C(C(C)C)N1C(=O)c2ccc(-c3ccc(NC(=O)c4ccc(OC)cc4OC)cc3)cc2C1=O
Solvent: C1CCOC1
Product: COC(=O)C(C(C)C)N1C(=O)c2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The compound of example 665 (100 mg. 0.284 mmol) was dissolved in tetrahydrofuran (10 mL) and to this solution, 2-chloro phenylisocyanate (65 mg. 0.426 mmol) was added. The reaction mixture was stirred at room temperature for 24 h. The solvent was removed completely to obtain a residue which was purified by column chromatography (silicagel, 30% ethyl acetate in chloroform) to afford the title compound.
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1.C([Li])(CC)C.Br[C:36]1[C:37]([Cl:43])=[N:38][CH:39]=[C:40]([F:42])[CH:41]=1.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[NH4+].[OH-]>CC(OC)(C)C.[Cl-].[Zn+2].[Cl-].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:43][C:37]1[C:36]([C@H:2]2[CH2:3][CH2:4][CH2:5][N:1]2[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:41][C:40]([F:42])=[CH:39][N:38]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1
Reactant: Fc1cnc(Cl)c(Br)c1
Agent: [Pd+2]
Agent: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Agent: CC(=O)[O-]
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc(F)cnc1Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
A solution of tert-butyl pyrrolidine-1-carboxylate (1 mL 5.70 mmol) and (−)-sparteine (1.31 mL, 5.70 mmol) in anhydrous MTBE (30 mL) was first cooled to −78° C. under nitrogen, followed by addition of sec-butyl lithium (4.07 mL, 1.4M, 5.70 mmol) drop-wise over 15 minutes with a syringe, maintaining the temperature below −75° C. The pale yellowish solution was stirred at −78° C. for 3 hours before being treated with zinc chloride (3.80 mL, 1.0 M, 3.80 mmol) dropwise over 15 minutes while maintaining the temperature below −73° C. The mixture was stirred at −78° C. for 30 minutes, then placed into an ambient temperature water bath and stirred for another hour. At this point a large amount of white precipitate was present. The mixture was treated with 3-bromo-2-chloro-5-fluoropyridine (1.00 g, 4.75 mmol) in MTBE (5 mL), followed by addition of palladium acetate (53 mg, 0.24 mmol) and tri-t-butylphosphine tetrafluoroborate (83 mg, 0.28 mmol). The mixture was allowed to stir at ambient temperature overnight to reach completion. The mixture was treated with NH4OH (1 mL), stirred for 30 minutes and filtered through GF/F paper, washing with MTBE. The filtrate was washed with 10% citric acid (30 mL) and the aqueous layer was back-washed with MTBE (2×30 mL). The combined organic phases were washed with brine (20 mL), dried (MgSO4), and concentrated to afford the crude product as dark yellowish oil. This crude material was purified on a silica 50 g Biotage SNAP cartridge eluting with 10% EtOAc in hexanes to afford the desired product as colorless oil (0.5 g, 35%). MS (apci pos) m/z=201.1 (M+H-Boc).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][C:9]=1[NH:17][C:18](=[O:34])[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH:32]=[CH:31][N:30]=[C:29]2[CH3:33])[CH:23]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:14]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH3:33])[CH:23]=3)[CH2:19][C:18](=[O:34])[NH:17][C:9]=2[CH:10]=1)([CH3:16])[CH3:15]
Reactant: Cc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(C(C)C)ccc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nccn1-c1cccc(C2=Nc3ccc(C(C)C)cc3NC(=O)C2)c1

Procedure:
Prepared from (4-isopropyl-2-{3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert.-butyl ester (Example K88) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light brown solid (94 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:6]([CH3:14])[C:7](=[O:13])[NH:8]2.C1C(=O)N([Br:28])C(=O)C1>C(Cl)Cl>[Br:28][C:12]1[C:3]([O:2][CH3:1])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:13])[N:6]([CH3:14])[CH:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc2c1C(c1ccccc1)N(C)C(=O)N2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1c(Br)ccc2c1C(c1ccccc1)N(C)C(=O)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-Methoxy-3-methyl-4-phenyl-3,4-dihydro-1H-quinazolin-2-one (1.38 g, 0.005 mol) and NBS (0.82 g, 0.0046 mol) in DCM (150 mL) is stirred at r.t. for 4 h. The mixture is extracted with DCM from water and purified by column chromatography on silica gel using an ethylacetate and petrol ether gradient to give the desired product.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[Cl:20]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C=O)C>[Cl:20][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:1][C:2]=1[NH:10][S:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:12])=[O:13]
Reactant: O=S(=O)(Nc1cc2cccnc2s1)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1sc2ncccc2c1Cl)c1ccccc1
Reaction time: 16 h
Yield: 34.5 %

Procedure:
To compound 147-F (0.26 g, 0.643 mmol) in DMF (1 mL) under argon at ambient temperature was added N-chlorosuccinimide (94.4 mg, 0.707 mmol) and the reaction mixture was stirred for 16 h. Ethyl acetate was added, the mixture washed with H2O (2×), brine, evaporated under reduced pressure and purified by reverse phase pHPLC (C18) to afford 0.072 g of compound 813-A as a tan solid. 1H-NMR (DMSO-d6): δ 7.50 (dd, 1H), 7.56-7.65 (m, 2H), 7.65-7.74 (m, 1H), 7.81-7.89 (m, 2H), 8.00 (dd, 1H), 8.58 (dd, 1H).
Reaction SMILES: [NH2:1][C:2](=[O:22])[C@H:3]([NH:14]C(=O)OC(C)(C)C)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1>Cl.O1CCOCC1>[NH2:14][C@H:3]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[C:2]([NH2:1])=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)[C@H](N)Cc1c[nH]c2ccccc12

Procedure:
A solution of (R)-tert-butyl 1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-ylcarbamate (0.963 g, 3.18 mmol) in 4N HCl in dioxane (8 mL) was stirred at room temperature for 1 h. It was then concentrated in vacuo. The residue was partitioned between nBuOH and aq. 5% NaHCO3. The nBuOH phase was separated, washed with water, concentrated in vacuo to give (R)-2-amino-3-(1H-indol-3-yl)propanamide as free base (0.324 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1([C:24]2[CH:29]=[CH:28][C:27]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][OH:15])=[CH:4][CH:3]=3)=[CH:26][CH:25]=2)[CH2:22][CH2:23]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CO
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CO)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 4, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: S1C=CN=C1.C[O:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH:16](Br)[F:17])=[CH:11][CH:10]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28](=[S:30])[NH2:29])[CH2:24][CH2:23]1>>[F:17][C:16]1[S:30][C:28]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[N:29][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([C:8]([OH:7])=[O:20])=[CH:10][CH:11]=1
Reactant: CN1CCN(C(N)=S)CC1
Reactant: COC(=O)c1ccc(C(=O)C(F)Br)cc1
Agent: c1cscn1
Product: CN1CCN(c2nc(-c3ccc(C(=O)O)cc3)c(F)s2)CC1

Procedure:
The starting material, methyl 4-acetylbenzoate, is commercially available. Bromination at the α-position to the ketone is achieved with bromine in acetic acid to provide the desired 4-(2-bromo-acetyl)-benzoic acid methyl ester. Subsequent treatment of 4-(2-bromo-acetyl)-benzoic acid methyl ester with potassium fluoride in the presence of 18-crown-6 at 90° C., provides 4-(2-fluoro-acetyl)-benzoic acid methyl ester after column chromatography. Repeated bromination at the α-position to the ketone is achieved with bromine in acetic acid to provide the desired 4-(2-bromo-2-fluoro-acetyl)-benzoic acid methyl ester. Formation of the thiazole is typically carried out by heating 4-(2-bromo-2-fluoro-acetyl)-benzoic acid methyl ester with 4-methylpiperazine-1-carbothioamide at 70° C. for 2 hours. On cooling, the desired 4-[5-fluoro-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzoic acid methyl ester precipitates out. Deprotection of the methyl ester is carried out using a lithium hydroxide solution and the desired acid, 4-[5-fluoro-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzoic acid is generally obtained in good yield as the dihydrochloride salt on workup with hydrochloric acid.