Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][C:17]1=[O:28].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20]([N:19]=[CH:18][C:17](=[O:28])[N:16]2[CH2:15][CH2:14][CH2:13][CH:12]=[O:11])=[CH:21][CH:22]=1
Reactant: COc1ccc2ncc(=O)n(CCCCO)c2c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc2ncc(=O)n(CCCC=O)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.1 %

Procedure:
A solution of oxalyl chloride (0.171 ml, 1.99 mmol) in dichloromethane (5 ml) was cooled to −78° C., a solution of dimethyl sulfoxide (0.283 ml, 3.99 mmol) in dichloromethane (5 ml) was added dropwise under a stream of argon and the reaction mixture was stirred at the same temperature for 15 minutes. A solution of 1-(4-hydroxybutyl)-7-methoxyquinoxalin-2(1H)-one (198 mg, 0.797 mmol) in dichloromethane (5 ml) was added dropwise and the reaction mixture was further stirred at the same temperature for 1 hour. Triethylamine (0.833 ml, 5.98 mmol) was added thereto, the temperature was raised to room temperature and a saturated ammonium chloride aqueous solution and dichloromethane were added. After stirring, the organic layer was separated, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to yield 114 mg (58%) of the title compound in the form of a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH:36]=O)=[C:32]([F:38])[CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[C:32]([F:38])[CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13]
Reactant: CCN(c1cc(-c2ccc(C=O)c(F)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)c(F)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.5 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3′-fluoro-4′-formyl-4-methyl-[1,1′-biphenyl]-3-carboxamide (285 mg, 0.55 mmol) and morpholine (149 mg, 1.64 mmol) in dichloroethane (5 mL), acetic acid (0.2 mL, 3.29 mmol) was added and reaction stirred at room temperature for 30 minutes. Then sodium triacetoxyborohydride (349 mg, 1.64 mmol) was added to the reaction mixture at 0° C., allowed to attain room temperature and stirring continued for overnight. On completion, reaction mixture was diluted with dichloromethane, washed with water, saturated aqueous sodium bicarbonate solution and dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic and prep. HPLC purification afforded the title compound (70 mg, 20%). LCMS: 591.45 (M+1)+; HPLC: 98.96% (@ 254 nm) (Rt; 4.034; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.5 (bs, 1H), 10.1 (bs, 1H), 8.24 (s, 1H), 7.66-7.73 (m, 3H), 7.54 (s, 1H), 7.36 (s, 1H), 5.88 (s, 1H), 4.44 (s, 2H), 4.30 (m, 5H), 3.96 (m, 2H), 3.66-3.86 (m, 6H), 3.17-3.34 (m, 4H), 2.27 (s, 3H), 2.22 (s, 3H), 2.11 (s, 3H), 1.57-1.67 (m, 4H), 0.84 (t, 3H, J=6 Hz).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[CH:18][C:17]2=[O:30])[C:8]([NH:10][C:11]2SC=C[N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.NC1[CH:36]=[CH:35][N:34]([CH2:37][C:38]([CH3:41])([OH:40])[CH3:39])N=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1([CH2:6][C@H:7]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[CH:18][C:17]2=[O:30])[C:8]([NH:10][C:11]2[CH:36]=[CH:35][N:34]([CH2:37][C:38]([OH:40])([CH3:41])[CH3:39])[N:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2nccs2)C1
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.6 %

Procedure:
A solution of (S)-3-cyclopentyl-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (prepared as in Example 26, 150 mg, 0.43 mmol) in dichloromethane (10 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 75 mg, 0.48 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (230 mg, 0.52 mmol) and N,N-diisopropylethylamine (170 mg, 1.30 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (47 mg, 22%) as a white solid: LR-ES-MS m/z calculated for C26H34N4O5 [M]+ 482, observed [M+H]+ 483; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00-1.94 (m, 11H) 1.04 (br. s., 3H) 1.06 (br. s., 3H) 3.81 (s, 3H) 3.89 (s, 2H) 4.13 (d, J=18.4 Hz, 1H) 4.52 (d, J=18.4 Hz, 1H) 4.68 (s, 1H) 4.70 (s, 1H) 4.81 (dd, J=10.4, 4.7 Hz, 1H) 6.44 (d, J=2.2 Hz, 1H) 6.95-7.05 (m, 1H) 7.18-7.24 (m, 1H) 7.25-7.36 (m, 2H) 7.53 (d, J=2.2 Hz, 1H) 10.79 (s, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@@H:13]([NH2:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45](O)=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[F:2][C:3]1[CH:4]=[C:5]([C@@H:13]([NH:15][C:45]([C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][CH:42]=2)[N:36]([CH2:35][C:32]2[CH:31]=[CH:30][C:29]([C:24]4[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:34][CH:33]=2)[C:37]([CH3:49])=[C:38]3[CH3:48])=[O:46])[CH3:14])[CH:6]=[CH:7][C:8]=1[C:9]([F:11])([F:12])[F:10]
Reactant: C[C@H](N)c1ccc(C(F)(F)F)c(F)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(C(F)(F)F)c(F)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-fluoro-4-(trifluoromethyl)phenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 589 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([S:13]([F:18])([F:17])([F:16])([F:15])[F:14])[CH:12]=1)[C:6](OC)=[O:7].Cl.[CH3:20][NH:21][O:22][CH3:23].C([Mg]Br)(C)C.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([S:13]([F:16])([F:18])([F:17])([F:14])[F:15])[CH:12]=1)[C:6]([N:21]([O:22][CH3:23])[CH3:20])=[O:7]
Reactant: COC(=O)c1cc(OC)cc(S(F)(F)(F)(F)F)c1
Reactant: CNOC
Agent: CC(C)[Mg]Br
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)N(C)OC)cc(S(F)(F)(F)(F)F)c1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
Methyl 3-methoxy-5-(pentafluorosulfanyl)benzoate (81 mg) was dissolved in absolute THF (5 ml), and N,O-dimethylhydroxylamine hydrochloride (42 mg) was added. Then the mixture was cooled to −15° C., and isopropylmagnesium bromide solution (0.21 ml, 2 M in THF) was added dropwise. After 20 min, the cooling bath was removed and the mixture was stirred at RT for 1 h. To complete the reaction, the mixture was twice more cooled to −15° C., isopropylmagnesium bromide solution (0.1 ml each time) was added dropwise and the mixture was stirred at RT for 1 h. Then ammonium chloride solution was added (10 ml) and the aqueous phase was extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 70 mg of the desired compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Cl)=[CH:4][CH:3]=1.[O:10]=[C:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.Cl>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2([OH:10])[CH2:12][CH2:13][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: Cl[Mg]c1ccc(Cl)cc1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C1CCC(O)(c2ccc(Cl)cc2)CC1
Reaction time: 1 h

Procedure:
Slowly add 4-chlorophenylmagnesium chloride (5.9 mL of 1M solution) to a solution of ethyl 4-oxo-cyclohexanecarboxylate (1.0 g) in Et2O at 0° C. After 1 h, pour the reaction mixture into 1N HCl and extract with Et2O. Separate the organic layer, wash with water, brine and concentrate to give ethyl 4-(4-chlorophenyl)-4-hydroxy-cyclohexanecarboxylate (1.75 g) which is used without purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:35])[C:5]([CH3:34])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:30]C(=O)C)=[C:17]([CH:29]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:35])[C:5]([CH3:34])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:30])=[C:17]([CH:29]=2)[C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Yield: 64.7 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-methoxyaniline (0.073 g, 0.152 mmol) was dissolved in methanol (2 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.043 g, 0.0983 mmol, 65%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=O.N1CCCCC1>C(O)C>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[NH:11][C:10]1=[O:16]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2cccnc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccnc4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 70 °C

Procedure:
A mixture of 4-pyridin-3-yl-1,3-dihydroindol-2-one (42 mg, 0.2 mmol), 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (50 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol was heated in a sealed tube at 70° C. for 5 hours. The reaction was concentrated and the residue was crystallized from ethyl acetate/hexane to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]([F:39])([F:38])[C:22]([C:24]1[S:28][C:27]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])=[CH:26][CH:25]=1)=[O:23]>>[C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH:19][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([C:27]5[S:28][C:24]([C:22](=[O:23])[C:21]([F:20])([F:38])[F:39])=[CH:25][CH:26]=5)[CH:30]=4)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Reactant: O=C(O)c1cccc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Product: O=C(NCC1(c2nc(-c3ccccc3)cs2)CCOCC1)c1cccc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Yield: 15 %

Procedure:
This compound was synthesized from (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoic acid as described in example 118 step 3 (0.022 g, yield 15%). 1H NMR (400 MHz, DMSO) δ 8.650-8.681 (t, 1H), δ 8.132 (s, 2H), δ 8.071 (s, 1H), δ 7.973-7.991 (d, 1H), δ 7.897-7.915 (d, 1H), 7.826-7.846 (d, 1H), 7.786-7.797 (d, 1H), 7.532-7.571 (t, 1H), 7.320-7.357 (t, 2H), 7.254-7.272 (d, 1H), 3.814-3.843 (d 2H), 3.553-3.568 (d, 2H), 3.282-3.409 (d, 2H), 2.22-2.26 (d, 2H), 1.936-2.006 (m, 2H); MS (ESI+) m/z 555.1 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[CH:3]=1.[NH2:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:38]C(OC(C)(C)C)=O)[C:35]([OH:37])=[O:36])=[CH:29][CH:28]=2)[CH:24]=[C:23](Cl)[N:22]=1.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[NH2:38][C@@H:34]([CH2:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH:24]=[C:23]([O:13][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[N:14]3[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]3)[C:9]([F:12])([F:11])[F:10])[N:22]=[C:21]([NH2:20])[N:26]=2)=[CH:28][CH:29]=1)[C:35]([OH:37])=[O:36]
Reactant: Cc1ccn(-c2cc(Cl)ccc2C(O)C(F)(F)F)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1ccn(-c2cc(Cl)ccc2C(Oc2cc(-c3ccc(C[C@H](N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
1-[4-Chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethanol (0.120 g, 0.41 mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (0.176 g, 0.45 mmol), 1,4-dioxane (4 ml), and Cs2CO3 (0.533 g, 1.64 mmol) were combined in a 20 ml sealed tube, and the mixture was heated at 100° C. for 12 h. The mixture was concentrated. To the residue, 10% methanol in DCM (50 ml) was added and the mixture was filtered. The filtrate was concentrated to give a crude product, which was taken in THF/3N HCl (30 ml/15 ml) and the resulting mixture was stirred at 40-45° C. for 12 h. LCMS indicated the completion of reaction with desired product. The mixture was concentrated to give a crude product, which was dissolved in MeOH and H2O (1:1) and purified by preparative HPLC using MeOH/H2O/TFA as solvent system to give (S)-2-amino-3-[4-(2-amino-6-{1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidine-4-yl)-phenyl]-propionic acid as a TFA salt. LCMS: M+1=547. 1H-NMR (400 MHz, CD3OD): δ (ppm) 2.30 (s, 3H), 3.10-3.30 (m, 2H), 4.20 (t, 1H), 6.32 (d, 1H), 6.74 (s, 1H), 7.0 (q, 1H), 7.38 (d, 2H), 7.50 (m, 2H), 7.72 (m, 1H), 7.90 (m, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[C:12]([NH2:14])[N:11]3[N:15]=[CH:16][C:17]([C:18]4[CH:19]=[N:20][C:21]5[C:26]([CH:27]=4)=[CH:25][CH:24]=[CH:23][CH:22]=5)=[C:10]3[N:9]=2)[CH2:3][CH2:2]1.[Br:28]N1C(=O)CCC1=O>CC#N>[Br:28][C:13]1[C:8]([CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:9][C:10]2[N:11]([N:15]=[CH:16][C:17]=2[C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=1[NH2:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(CN2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Solvent: CC#N
Product: Nc1c(Br)c(CN2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To crude 5-(morpholinomethyl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine (44 mg) in CH3CN (8 mL) was added N-bromosuccinimide (22 mg, 0.12 mmol), followed by additional CH3CN (4 mL). The reaction was then stirred at room temperature for 30 minutes, at which time LC/MS analysis confirmed full conversion of the starting material to the product. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give 6-bromo-5-(morpholinomethyl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine as a yellow solid (8.7 mg, 0.02 mmol, 7% over three steps). LCMS: 0.82 mins, m/z=439.0 and 441.0 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:16][CH2:17][C:18](=O)[C:19]3[CH:28]=[CH:27][C:22]4[NH:23][C:24](=[O:26])[S:25][C:21]=4[CH:20]=3)=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:41]2)=CC=1>O1CCOCC1.CCOC(C)=O>[F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[S:41][C:18]([C:19]4[CH:28]=[CH:27][C:22]5[NH:23][C:24](=[O:26])[S:25][C:21]=5[CH:20]=4)=[CH:17][N:16]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)NCC(=O)c1ccc2[nH]c(=O)sc2c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(-c3cnc(CN4CCC(Cc5ccc(F)cc5)CC4)s3)cc2s1
Yield: 18 %

Procedure:
To a stirred solution of 2-[4-(4-fluorobenzyl)piperidin-1-yl]-N-[2-oxo-2-(2-oxo-2,3-dihydrobenzothiazol-6-yl)ethyl]acetamide (0.50 g, 1.13 mmol) in 1,4-dioxan (30 mL) was added [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (Lawesson's reagent) (0.69 g, 1.70 mmol). The resulting suspension was heated at reflux for 24 hours. The reaction mixture was condensed to dryness in vacuo, redissolved in EtOAc, and washed with saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic phase was dried (MgSO4) and condensed to dryness in vacuo. The material was then subject to column chromatography [silica gel, EtOAc/Heptanes (0-50% EtOAc over 60 min)] gave 6-{2-[4-(4-fluorobenzyl)piperidin-1-ylmethyl]thiazol-5-yl}-3H-benzothiazol-2-one (0.087 g, 18%) as an off-white solid:
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[CH2:5]1.[CH3:17][CH:18]1[CH2:22][CH2:21][CH2:20][NH:19]1>C(O)C>[CH3:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[CH2:5]1
Reactant: CN1CC(CCCl)Cc2ncccc2C1=O
Reactant: CC1CCCN1
Solvent: CCO
Product: CC1CCCN1CCC1Cc2ncccc2C(=O)N(C)C1

Procedure:
To a solution of 8-(2-chloroethyl)-6,7,8,9-tetrahydro-6-methyl-5H-pyrido[3,2-c]azepin-5-one in ethanol was added 2-methylpyrrolidine. The solution is heated to reflux for several hours and ethanol is removed by evaporation. The residue is partitioned between dilute aqueous base and chloroform and the chloroform layer concentrated and the title compound isolated by an appropriate technique, e.g., distillation.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7](=[N:9][OH:10])[CH3:8].CO[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:26]([S:27]([NH:30][C:31]3[C:36]([O:37][CH3:38])=[N:35][C:34]([CH3:39])=[CH:33][N:32]=3)(=[O:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1)=O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CCCCC.C1COCC1.O>[CH3:38][O:37][C:36]1[C:31]([NH:30][S:27]([C:26]2[C:21]([C:18]3[CH:17]=[CH:16][C:15]([C:13]4[O:10][N:9]=[C:7]([CH3:8])[CH:6]=4)=[CH:20][CH:19]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:29])=[O:28])=[N:32][CH:33]=[C:34]([CH3:39])[N:35]=1
Reactant: COC(=O)c1ccc(-c2ncccc2S(=O)(=O)Nc2ncc(C)nc2OC)cc1
Reactant: CC(C)=NO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(-c2cc(C)no2)cc1
Yield: 8.5 %

Procedure:
n-Butyl lithium (1.63 ml of a 1.6M solution in pentane) was added to a stirred solution of acetone oxime (95 mg) in dry THF (5 ml) at 0° C. After 1 hour a solution of 2-(4-methoxycarbonylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (414 mg) in THF (5 ml) was added. The solution was allowed to warm up over 17 hours. The mixture was poured into a stirred solution of concentrated sulphuric acid (0.6 g) in THF (2.8 ml) and water (0.7 ml) and heated under reflux for 1 hour. The cooled solution was treated with saturated sodium carbonate solution to pH 5 then extracted three times with ethyl acetate. The organic extracts were washed with water and saturated sodium chloride solution then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column, eluting with 0-45% ethyl acetate/hexane to give N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[3-methylisoxazol-5-yl]phenyl)pyridine-3-sulphonamide (37 mg) as a solid; 1H NMR (DMSO-d6 at 373K); 2.2 (s, 3H), 2.3 (s, 3H), 3.8 (s, 3H), 6.7 (s, 1H), 7.4 (br s, 1H), 7.5-7.7 (m, 4H), 7.8 (d, 2H), 8.5 (dd, 1H), 8.8 (dd, 1H); mass spectrum (+ve ESP): 438 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](Cl)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].N1C=CC=CC=1>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)Nc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 175.6 %

Procedure:
To a stirred solution of (4-nitro-phenyl)-acetyl chloride (2.20 g, 11.05 mmol) in anhydrous dichloromethane (50 mL) was added 2-aminobenzoic acid (0.76 g, 5.50 mmol) followed by the addition of pyridine (3 mL). After stirring for 5 hours at rt, the cloudy solution was diluted with dichloromethane and thoroughly washed with 3 M HCl solution, then with brine and dried over Na2SO4. The solvent was removed and the solid crystallized from ethyl acetate to provide the title compound (2.9 g, 88% yield).
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH2:4]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19]OS(C)(=O)=O)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[CH2:4]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][S:2][CH3:1])=[O:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[S-]
Reactant: CS(=O)(=O)OCC1CCCN1C(=O)OCc1ccccc1
Agent: [Na+]
Solvent: CO
Product: CSC[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 78.9 %

Procedure:
To a suspension of 1.81 g (25.8 mmol) sodium methanethiolate in 25 ml methanol was added a solution of 1.35 g (4.31 mmol) 2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid benzyl ester in 25 ml methanol. Conversion was monitored by thin layer chromatography. After complete consumption of the starting material the reaction mixture was diluted with ethyl acetate and washed with two portions of water. The organic layer was dried over sodium sulfate. Flash chromatography gave 0.89 g (3.4 mmol, 78%) (S)-2-methylsulfanylmethyl-pyrrolidine-1-carboxylic acid benzyl ester as a light yellow oil.