Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:14][CH:13]2[CH2:15][CH2:16][CH:6]([C:7]3[CH:8]=[CH:9][C:10]([N+:17]([O-])=O)=[CH:11][C:12]=32)[CH2:5]1)([CH3:3])[CH3:2]>CO.[Pd]>[CH:1]([N:4]1[CH2:14][CH:13]2[CH2:15][CH2:16][CH:6]([C:7]3[CH:8]=[CH:9][C:10]([NH2:17])=[CH:11][C:12]=32)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CC2CCC(C1)c1cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CO
Product: CC(C)N1CC2CCC(C1)c1cc(N)ccc12
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
10-Isopropyl-4-nitro-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-triene (62 mg, 0.238 mmol) was placed in methanol (4 mL) and 10% palladium on carbon (6.2 mg) was added. The reaction was hydrogenated at 15 psi for 30 minutes. The mixture was then filtered through celite and concentrated under reduced pressure to obtain 10-isopropyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-trien-4-ylamine as a yellow oil (54.7 mg, 100%). LCMS (m/e) 231 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 6.85 (dd, 1H, J=0.7 and 7.2 Hz), 6.50-6.45 (m, 2H), 3.52 (bs, 2H), 2.87-2.78 (m, 5H), 2.33-2.26 (m, 2H), 2.18-2.09 (m, 2H), 1.60-1.50 (m, 2H), 0.93 (d, 6H, J=6.6 Hz).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[C:7]([CH2:12][N:13]=[N+]=[N-])=[CH:6][C:5]=1[O:16][CH2:17][CH3:18]>O1CCCC1.N.C(P(CC)CC)C>[CH3:1][NH:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][C:5]=1[O:16][CH2:17][CH3:18])[CH2:12][N:13]=[C:10]2[NH2:11])=[O:19]
Reactant: CCOc1cc(CN=[N+]=[N-])c(C#N)cc1C(=O)NC
Agent: CCP(CC)CC
Agent: N
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1C(=O)NC)C(N)=NC2
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
After dissolving N1-methyl-4-(azidomethyl)-5-cyano-2-ethoxybenzamide (931 mg) in tetrahydrofuran (10 ml), 28% aqueous ammonia (2 ml) and triethylphosphine (0.4 ml) were added in that order. The mixture was stirred at 50° C. for 15 minutes. The precipitated crystals were filtered off, washed with tetrahydrofuran, water and ethyl acetate in that order and dried to yield the title compound (365 mg).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]5[C:29](O)=[O:30])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].CC[N:34]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]5[C:29]([NH2:34])=[O:30])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCCCC3C(=O)O)cc1OCC2
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCCCC3C(N)=O)cc1OCC2
Reaction time: 18 h
Yield: 7 %

Procedure:
A mixture of 1-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-2-carboxylic acid (1.15 g, 2.73 mmol), EDCI (0.58 g, 3.0 mmol), HOBt (0.41 g, 3.0 mmol) and DIPEA (2.34 mL, 13.65 mmol) in DMF was stirred at RT (2 mL) for 5 min before ammonium chloride (0.44 g, 8.18 mmol) was added and the reaction mixture stirred for 18 h. The reaction mixture was concentrated in vacuo and the resultant residue triturated with water before being subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 459 as a white solid (0.08 g, 6%). LCMS: RT=3.48 min, [M+H]+=422. 1H NMR 400 MHz (DMSO-d6) δ: 8.18 (1 H, d, J=9.06 Hz), 7.89 (1 H, d, J=0.63 Hz), 7.80 (1 H, s), 7.31 (1 H, br, s), 7.01 (1 H, br, s), 6.72 (1 H, dd, J=9.16, 2.60 Hz), 6.40 (1 H, d, J=2.54 Hz), 5.92-5.91 (1 H, m), 4.44-4.43 (4 H, m), 4.39 (1 H, m), 3.60 (1 H, d, J=12.44 Hz), 3.39-3.32 (1 H, m), 2.06 (1 H, d, J=13.57 Hz), 1.75 (2 H, m), 1.58 (3 H, m), 1.48 (6 H, dd, J=6.60, 2.59 Hz)
Reaction SMILES: C([NH:9][C:10]([NH:20][CH2:21][CH:22]([OH:31])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[N:11][CH2:12][CH2:13][CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)(=O)C1C=CC=CC=1>Cl>[OH:31][CH:22]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:21][NH:20][C:10]([NH:11][CH2:12][CH2:13][CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)=[NH:9]
Reactant: O=C(NC(=NCCCc1c[nH]cn1)NCC(O)COc1ccccc1)c1ccccc1
Agent: Cl
Product: N=C(NCCCc1c[nH]cn1)NCC(O)COc1ccccc1

Procedure:
0.5 g (1.2 mmol) of N-benzoyl-N'-(2-hydroxy-3-phenoxypropyl)-N"-[3-(imidazol-4-yl)propyl]-guanidine are heated under reflux in 30 ml of 20% hydrochloric acid for 6 hours. The reaction mixture is worked up by a method analogous to that of Example 4. The dihydrochloride crystallises from isopropyl alcohol/acetone in the form of colourless crystals melting at 165°-166° C.
Reaction SMILES: [C:1]([O:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(O)(=[O:17])C>>[C:1]([O:7][CH:8]1[CH2:13][CH2:12][C:11]([OH:17])([CH3:14])[CH2:10][CH2:9]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC1CCC(OC(=O)C(C)(C)C)CC1
Reactant: CC(=O)O
Product: CC1(O)CCC(OC(=O)C(C)(C)C)CC1

Procedure:
FIG. 2 represents chemical structures, reaction schemes and reaction yields for an example of an oxidation of the substrate 4-methylcyclohexyl pivalate in the presence of two different complexes. Experimental details are provided in Examples 3 and 4. Reaction of the substrate with complex 4 in the presence of acetic acid (AcOH) yielded 38% (by GC) of the mono-oxidized product 4-hydroxy-4-methylcyclohexyl pivalate (entry 4). This yield was amplified by using a three-fold reagent addition procedure, in which each addition of the complex included 5 mol % complex 4 and 0.5 equivalent AcOH, and each addition of oxidant included 1.2 equivalents H2O2. The three-fold reagent addition procedure was carried out over a period of 30 minutes, providing diastereomerically pure hydroxylated product 2 in 51% isolated yield (entry 5).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl-].[NH4+].O>CO.[Fe]>[NH2:13][C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([Br:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(N)c1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
To a solution of methyl 5-bromo-2-methyl-3-nitrobenzoate (6.3 g, 21 mmol) in methanol (150 ml) was added ammonium chloride (11.0 g, 209 mmol) followed by deionized water (75 ml). The mixture was heated to 70° C. before the addition of iron (7.0 g, 125 mmol). The reaction mixture was stirred at 70° C. for 2 hours, before being allowed to cool to room temperature and filtered through Kieselgel. The filter pad was washed with MeOH (150 ml) and the filtrate concentrated in-vacuo. The residue was dissolved in saturated NaHCO3 (aq) (50 ml) and EtOAc (150 ml). The phases were separated and the organic phase was washed with saturated NaHCO3 (aq) (3×50 ml), dried over MgSO4, filtered and concentrated in-vacuo. The residue was purified by flash column chromatography (50 g silica Isolute cartridge, 5-20% EtOAc:Heptanes) to give the title compound (3.0 g, 51%) as a thick pale yellow oil. LC-MS 87%, 1.89 min (3.5 minute LC-MS method), m/z=243.9, 244.9, 245.9, 246.9; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.34 (d, J=1.89 Hz, 1H) 6.95 (d, J=1.89 Hz, 1H) 3.88 (s, 3H) 3.80 (br. s., 2H) 2.29 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]([NH2:22])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[N:39]1([C:46](Cl)=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>C1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C@@H:17]([NH:22][C:46]([N:39]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:47])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][CH2:15]2)=[CH:5][CH:4]=1
Reactant: CC(C)C[C@H](N)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: O=C(Cl)N1CCCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NC(=O)N1CCCCCC1
Temperature: 25 °C
Yield: 19.8 %

Procedure:
To a solution of (S)-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-ylmethyl}-3-methyl-butylamine monohydrochloride (189 mg, 0.46 mmol) in benzene (2 mL) were added sequentially N,N-diisopropylethylamine (0.26 mL, 1.5 mmol), 4-dimethylaminopyridine (20 mg), and azepane-1-carbonyl chloride (0.13 mL, 0.78 mmol) under nitrogen atmosphere. The resulting reaction mixture was refluxed for 16 hours, then cooled to ambient temperature. The reaction mixture was filtered to remove the white solid formed during the reaction; the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (25 mL) and washed successively with saturated aqueous NaHCO3 solution (25 mL), brine (2×25 mL), and dried over Na2SO4. The solution was concentrated in vacuo affording a slightly amber colored oil. The crude product was purified first by flash chromatography (50% EtOAc in hexanes), then by preparative plate (50% EtOAc in hexanes) affording 46.6 mg (20%) of the pure titled compound as a clear oil. APCI-MS m/z 513.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:9]=[CH:8]2.C(OC([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:33][CH2:32]1)=O)(C)(C)C.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC.O>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH2:37][CH:34]1[CH2:35][CH2:36][NH:31][CH2:32][CH2:33]1)[N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:9]=[CH:8]2
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(O)cc21
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(OCC3CCNCC3)cc21
Temperature: 70 °C
Yield: 39.3 %

Procedure:
To a solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-ol (0.06 g, 0.19 mmol) and 4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.08 g, 0.20 mmol) in DMF (3 mL) was added Nal (0.014 g, 0.009 mmol) and K2CO3 (0.08 g, 0.56 mmol). The reaction mixture was heated to 70° C. for 20 hours. The mixture was diluted with ether and water and the layers were separated. The aqueous layer was extracted with ether (2×) and the combined organic layers were washed with water and brine, and dried over Na2SO4. The crude mixture was concentrated under reduced pressure and purified by reverse phase HPLC. The desired fraction was concentrated to 0.037 g that was then treated with HCl (4N in dioxane) for 7 hours. The solvent was removed under reduced pressure and the final product was dried under high vacuum to obtain 0.031 g solid (37% yield). MS (APCI+) m/z 416(M+1) detected.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[C:19]([Cl:26])=[C:20]([OH:25])[C:21]([CH3:24])=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[NH2:17][C:18]1[C:19]([Cl:26])=[C:20]([C:21]([CH3:24])=[CH:22][CH:23]=1)[O:25][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Cc1ccc(N)c(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N)c(Cl)c1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Temperature: 140 °C
Reaction time: 12 h
Yield: 64.1 %

Procedure:
To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (2.0 g, 6.1 mmol) in N,N-dimethylformamide (20 mL) were added 3-amino-2-chloro-6-methylphenol (1.9 g, 12 mmol) and potassium carbonate (2.1 g, 15 mmol), and the mixture was stirred at 140° C. for 12 hr. After cooling the mixture to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=50/50→80/20) and precipitated from methanol/diisopropyl ether to give the title compound (1.4 g, 64%) as a pale-yellow powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:36])=[C:23]([N:25]4[CH2:34][CH2:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][C:31]=5[Cl:35])[CH2:26]4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.CCOCC>[Cl:35][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:32]=1[CH2:33][CH2:34][N:25]([C:23]1[C:22]([NH2:36])=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:18]=3)[CH:24]=1)[CH2:26]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(N4CCc5c(Cl)cccc5C4)c3)cn2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1N1CCc2c(Cl)cccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{4-[6-Amino-5-(5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (26 mg, 0.051 mmol) was dissolved in MeOH (20 mL), 1.0 M of HCl in Et2O (20 mL) was added, and the mixture was stirred at rt overnight. The solvent was removed in vacuo to give the title compound as a brown solid. 1H NMR (400 MHz, CD3OD): δ=2.32-2.39 (m, 4H), 3.11 (t, J=6.0 Hz, 2H), 3.22-3.32 (m, 2H), 3.42 (t, J=6.0 Hz, 2H), 3.59 (d, J=13.2 Hz, 2H), 4.27 (s, 2H), 4.58-4.68 (m, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.98 (s, 1H), 8.33 (s, 1H). MS(ES+): m/z=409.10/411.08 (46/18) [MH+]. HPLC: tR=2.25 min (ZQ2, polar—5 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[CH:16]1[O:20][CH2:19][CH2:18][O:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C([Li])CCC.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:11][C:10]=1[CH:16]1[O:20][CH2:19][CH2:18][O:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: Brc1ccc(OCc2ccccc2)c(C2OCCO2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OCc2ccccc2)c(C2OCCO2)c1
Temperature: -60 °C
Yield: 55.1 %

Procedure:
A solution of 2-(2-benzyloxy-5-bromophenyl)-1,3-dioxolane (7.8 g, 23.2 mmol) in freshly distilled THF (160 ml) was cooled to -75° C. with stirring under an argon atmosphere. To this solution was added n-butyl lithium (25.6 ml, 1.6 M in hexane) keeping the temperature below -70° C. The reaction mixture was stirred at -70° C. for 1 hour. The reaction was allowed to warm to -60° C. and added to a cooled (-60° C.) solution of ethyl chloroformate (5.05 g, 46.5 mmol) in freshly distilled THF (70 ml). The reaction was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was diluted with ethyl ether (100 ml), washed with ice/water (1×50 ml), saturated aqueous NaHCO3 (1×35 ml), brine (1×35 ml) dried over MgSO4 and evaporated. The product was purified by chromatography (eluant: ethyl ether/hexane) to give 2-(2-benzyloxy-5-ethoxycarbonylphenyl)-1,3-dioxolane as a colourless gum (4.2 g, 55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:30]=[C:29]([CH:38]([CH3:40])[CH3:39])[CH:28]=1)=[O:25].[CH3:41][NH2:42].C1COCC1>>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14]([NH:42][CH3:41])[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:30]=[C:29]([CH:38]([CH3:40])[CH3:39])[CH:28]=1)=[O:25]
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)C)nn4-c4ccccc4)c(F)cc3C)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)C)nn4-c4ccccc4)c(F)cc3C)c(=O)n(C)c2n1
Yield: 52 %

Procedure:
Using a procedure analogous to Example A1, 1-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea (0.24, 0.43 mmol) and 2 M methylamine in THF (3 eq) were combined to provide 1-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea as a white solid (0.12 g, 52% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.90 (s, 1H), 8.82 (s, 1H), 8.68-8.60 (m, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.82-7.79 (m, 1H), 7.66 (s, 1H), 7.55-7.47 (m, 4H), 7.43-7.39 (m, 1H), 7.12 (d, J=12.4 Hz, 1H), 6.30 (s, 1H), 3.59-3.52 (m, 3H), 2.91-2.80 (m, 4H), 2.05 (s, 3H), 1.18 (d, J=7.2 Hz, 6H); MS (ESI) m/z: 541.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])=[O:8].BrC1SC=CC=1.[C-:21]#[N:22].[Na+]>CN(C)C=O>[C:21]([C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])=[O:8])#[N:22]
Reactant: [C-]#N
Reactant: CC(C)(C)NS(=O)(=O)c1sccc1Br
Agent: Brc1cccs1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)NS(=O)(=O)c1sccc1C#N
Temperature: 25 °C

Procedure:
A mixture of 197.7 g of 3-bromo-N-(1,1-dimethylethyl)thiophene-2-sulfonamide, 195.9 g of cuprous cyanide and 500 mL of dimethylformamide was heated to 150° for two and one half hours at which time none of the bromothiophene remained as indicated by thin layer chromatography. The reaction was cooled to room temperature and poured into 1500 mL of 10% aqueous sodium cyanide. The aqueous mixture was extracted with five, 200 mL portions of ethyl ether and the combined extracts were washed with five, 150 mL portions of water followed by one, 200 mL aqueous sodium chloride wash. After drying over magnesium sulfate, filtration and evaporation of the solvent 140.8 g of the desired product was obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([N:30]2[CH2:40][C:39]([CH3:42])([CH3:41])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][C:47]=2[O:55][CH3:56])=[N:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[NH2:66][CH:67]1[CH2:72][CH2:71][N:70]([CH2:73][CH2:74][O:75][CH3:76])[CH2:69][CH2:68]1>CC(N(C)C)=O>[CH:25]1([N:30]2[CH2:40][C:39]([CH3:41])([CH3:42])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([NH:66][CH:67]4[CH2:72][CH2:71][N:70]([CH2:73][CH2:74][O:75][CH3:76])[CH2:69][CH2:68]4)=[O:51])=[CH:48][C:47]=2[O:55][CH3:56])=[N:34][CH:35]=3)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Reactant: COCCN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(C)(C)C(=O)N4C)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of HATU (126 mg, 0.33 mmol) in DMA (5 mL) was added to a mixture of 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-3-methoxy-benzoic acid (Example 242 132 mg, 0.3 mmol), DIPEA (261 uL, 1.5 mmol) and 4-amino N-(2-methoxyethyl)piperidine (60 mg, 0.375) in DMA (5 mL). The resulting mixture was stirred at room temperature for 2 hours, then partially purified by SCX. The compound was retrieved from the SCX column using 7N ammonia in methanol, then concentrated in vacuo, and further purified by column chromatography, eluting with 0-10% ammonia (7N in methanol) in DCM. The pure material was recovered as an orange oil, which foamed and solidified under high vacuum. Trituration under ether gave a pale yellow amorphous solid. (55 mg, 32%)
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][Cl:20]>C(#N)C>[Cl:20][CH2:19][CH2:18][N:8]1[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(CCCl)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1-(methylsulfonyl)piperazine (250 mg, 1.522 mmol), potassium carbonate (1262 mg, 9.13 mmol) and 1-bromo-2-chloroethane (1092 mg, 7.61 mmol) in acetonitrile (5 mL) was stirred for 6 hours at room temperature. LCMS indicated the formation of desired product. The reaction mixture was filtered to remove the white precipitate, then quenched with distilled water (10 mL), extracted with ethyl acetate (3×8 mL), the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the clean desired product as white solid (100 mg, 29%). LCMS: m/e 227.15 (M+H)+, 1.21 min (method 10).
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].B(Cl)([C@H]1[C@H](C)C2C(C)(C)C(CC2)C1)[C@H]1[C@H](C)C2C(C)(C)C(CC2)C1.CO.C(CN)O>C1COCC1>[I:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([OH:11])[CH3:10]
Reactant: CC(=O)c1cccc(C)c1I
Agent: C[C@@H]1C2CCC(C[C@H]1B(Cl)[C@@H]1CC3CCC([C@H]1C)C3(C)C)C2(C)C
Solvent: CO
Solvent: C1CCOC1
Solvent: NCCO
Product: Cc1cccc([C@H](C)O)c1I
Temperature: -20 °C
Reaction time: 6 h
Yield: 23.8 %

Procedure:
1-(2-Iodo-3-methylphenyl)ethanone (500 mg, 1.92 mmol) (prepared according to the procedure of Buchwald, et al., J. Am. Chem. Soc. 1987, 109, 7137-7141) was added slowly over a period of 5 minutes to a cooled (−25° C.) solution of (−) DIP-Chloride™ (691 mg, 2.15 mmol) in THF (2 mL). The reaction was stirred at −20° C. for 6 hours. MeOH (0.8 mL) was added, then the reaction was warmed to ambient temperature and concentrated in vacuo. The resultant residue was taken up in ethyl acetate (1 mL) and ethanolamine (0.4 mL, 4.2 mmol) was added. As the solution stirred vigorously, a precipitate formed. The precipitate was filtered off; the liquors were diluted with hexane (1 mL) and filtered again. The liquors were concentrated in vacuo and the resultant residue was purified by flash column chromatography on silica, eluting with 10% ethyl acetate/isohexane, followed by recrystallisation with isohexane to give the title compound as a white solid (120 mg). SFC (10% MeOH, chiralpak AD-H) e.e. 100%; 1H NMR (400 MHz, d6-DMSO): δ 7.33 (1H, dd, J=1.6, 7.3 Hz); 7.27 (1H, t, J=7.5 Hz); 7.21 (1H, dd, J=1.5, 7.2 Hz); 5.36 (1H, d, J=4.1 Hz); 4.92-4.88 (1H, m); 2.40 (3H, s); 1.26 (3H, d, J=6.3 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:14]#[N:15])[N:6]([CH3:13])[CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH3:2].[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOCC>[CH2:1]([O:3][C:4](=[O:16])[C:5]([N:6]([CH3:13])[CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)=[C:14]([NH2:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:2]
Reactant: Br[Mg]c1ccccc1
Reactant: CCOC(=O)C(C#N)N(C)Cc1cccs1
Solvent: CCOCC
Product: CCOC(=O)C(=C(N)c1ccccc1)N(C)Cc1cccs1

Procedure:
Ethyl-2-[methyl(thienylmethyl)amino]-cyanoacetate (0.014 mol, 3.4 g) was dissolved in 100 mL of ether and added to 9.5 mL of 3M PhMgBr, and the resulting mixture was refluxed for 18 h. The reaction was cooled, quenched with sat. NH4Cl solution and extracted with ether. The organics were dried, concentrated, and chromatographed using 1:1 hexanes:ethyl acetate to give 1.4 g of product. 1H NMR (300 MHz) CDCl3: 7.58 (d, 2H), 7.4 (m, 3H), 7.21 (d, 1H), 6.89 (m, 2H), 5.0 (s, 1H), 4.28 (t, 2H), 3.85 (s, 2H), 2.75 (t, 2H), 2.38 (s, 3H).