Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17](O)[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)[Br:49]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@@H:17]([Br:49])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: BrC(Br)Br
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](Br)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
A mixture of salvinorin B (8a) (0.15 g, 0.38 mmol), triphenylphosphine (0.21 g, 0.80 mmol), and bromoform (0.15 g, 0.45 mmol) in CH2Cl2 (30 mL) was stirred at room temperature overnight. TLC indicated that starting material was still present after 16 h, thus additional triphenylphosphine (0.11 g, 0.42 mmol) and bromoform (0.07 g, 0.21 mmol) were added and the mixture was stirred for an additional 3 h. The solvent was removed under reduced pressure affording a crude solid. The oil was purified by column chromatography (eluent: 30% EtOAc/n-hexanes) to afford 0.10 g (59%) of 36 as a white solid, mp 170-173° C. (EtOAc/n-hexanes); 1H NMR (CDCl3): δ 1.15 (3H, s); 1.48 (3H, s); 1.60 (3H, m); 1.81 (1H, dd, J=2.7, 9.9); 1.95 (1H, dd, J=13.2, 26.1); 2.1 (2H, m); 2.27 (1H, s); 2.47 (1H, dd, J=4.8, 13.2); 2.66 (1H, m); 2.80 (1H, dd, J=3.3, 13.2); 3.70 (3H, s); 3.89 (2H, d, J=2.4); 4.45 (1H, m); 5.55 (1H, dd, J=4.8, 11.7); 6.38 (1H, dd, J=0.9, 1.5); 7.4 (2H, m).
Reaction SMILES: C([O-])(=O)C.[Na+].O.Br[CH:8](Br)[C:9]([C:11]([F:14])([F:13])[F:12])=[O:10].[F:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:19][C:18]=1[NH:28][NH2:29]>C(OCC)C>[Cl:23][C:21]1[C:20]([O:24][CH:25]([CH3:26])[CH3:27])=[CH:19][C:18]([NH:28][N:29]=[CH:8][C:9](=[O:10])[C:11]([F:14])([F:13])[F:12])=[C:17]([F:16])[CH:22]=1
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: CC(C)Oc1cc(NN)c(F)cc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)Oc1cc(NN=CC(=O)C(F)(F)F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixed solution of 5.3 g (53.5 mmol) of sodium acetate and about 100 ml of water was added under ice cooling 6.6 g (24.3 mmol) of 1,1-dibromo-3,3,3-trifluoroacetone, and the reaction was allowed to proceed at 70° C. for 20 minutes. Then, the reaction mixture was cooled to room temperature, to which a solution of 5.8 g (21.5 mmol) of 2-fluoro-4-chloro-5-isopropoxyphenylhydrazine dissolved in about 20 ml of diethyl ether was added, and the reaction mixture was stirred at room temperature for 1 hour. The ether layer was separated, washed once with 10 ml of saturated sodium chloride solution, and dried with magnesium sulfate. The diethyl ether was distilled out, which afforded 6.5 g (20.0 mmol) of 3,3,3-trifluoro-2-oxo-propanal 1-(4-chloro-2-fluoro-5-isopropoxyphenylhydrazone).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[S-:11][C:12]#[N:13].[K+].BrBr>CC(O)=O>[NH2:13][C:12]1[S:11][C:3]2[CH:4]=[C:5]([CH2:8][C:9]#[N:10])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: N#CCc1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N#CCc1ccc2nc(N)sc2c1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of 2-(4-aminophenyl)acetonitrile (6.00 g, 45.4 mmol) in AcOH (70 mL) was added potassium thiocyanate (17.6 g, 181 mmol) at rt in one portion. The mixture was stirred at rt until it became a clear solution. To this solution was then added a solution of bromine (2.3 mL, 44.9 mmol) in AcOH (30 mL) at rt over 1 hr. The resulting mixture was stirred at rt for 4 hr. The precipitate that formed during the reaction was collected by suction filtration, and then suspended into water (100 mL). The pH value of the aqueous suspension was adjusted to 8 with concentrated ammonium hydroxide. The insoluble product (7.39 g, 86% yield) was collected as a pale yellow solid by suction filtration and dried over Drierite® under vacuum at 65° C.
Reaction SMILES: [Na].[C:2]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:3][C:4]([C:6](OCC)=[O:7])=O.Cl.[NH2:16][NH2:17]>C(O)C.O.Cl>[CH2:13]([O:12][C:2]([C:3]1[NH:16][N:17]=[C:6]([OH:7])[CH:4]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: NN
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(O)n[nH]1
Temperature: 80 °C

Procedure:
To a solution of 5 g Diethyl Oxalacetate sodium salt in 100 ml ethanol, 1.5 g hydrazine monohydrochloride were added and the reaction mixture was heated to 80° C. for 3 h. Then the solution was diluted with 100 ml of water containing 3 ml of halfconcentrated HCl and extracted with DCM (3×100 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was subjected to the next reaction step without further purification; Yield: 3.4 g
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCCCCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCON=C(C(=O)O)c1csc(N)n1
Yield: 86.9 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetate (syn isomer, 28.6 g.), 2 N aqueous solution of sodium hydroxide (100.2 ml.), methanol (100 ml.) and tetrahydrofuran (100 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetic acid (syn isomer, 22.4 g.), mp 176° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH:23]=[C:22]([C@:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH2:25][CH3:26])[N:21]=[N:20]4)=[CH:15][CH:16]=3)[N:11]=[C:10]([C:32](=[O:34])[CH3:33])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:35][Mg]Br.CCOCC>C1COCC1>[F:28][C:27]([F:29])([F:30])[C@:24]([C:22]1[N:21]=[N:20][N:19]([CH2:18][C:14]2[CH:13]=[C:12]3[C:17]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:9][C:10]([C:32]([OH:34])([CH3:35])[CH3:33])=[N:11]3)=[CH:16][CH:15]=2)[CH:23]=1)([OH:31])[CH2:25][CH3:26]
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(C(C)=O)nc3c2)nn1)C(F)(F)F
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(C(C)(C)O)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of (S)-1-[4-(4-fluorophenyl)-7-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)quinolin-2-yl]ethanone (100 mg, 0.21 mmol) in THF (5 mL) at −78° C. was added methylmagnesium bromide 3M in ether (210 μL, 0.63 mmole). The reaction was warmed up to rt over 2 h and quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with acetone/dichloromethane, 2:8) gave the title compound. MS (+ESI): 490 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][CH2:16][C:17](O)=[O:18])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:5][C:4]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:26][CH3:27])[CH2:3]1.[C:33]([O:37][C:38]([C@H:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].N1C(C)=CC=CC=1C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[O:32]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][CH2:16][C:17](=[O:18])[NH:47][C@@H:40]([C:38]([O:37][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:39])[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:5][C:4]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:26][CH3:27])[CH2:3]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCCC(=O)O)cc2S(=O)(=O)C1
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCCC(=O)N[C@@H](C(=O)OC(C)(C)C)c3ccccc3)cc2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.9 %

Procedure:
To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(2-carboxyethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 89; 70 mg, 0.134 mmol) and (R)-α-(t-butoxycarbonyl)benzylamine (J. Amer. Chem. Soc.; EN; 117; 44; 1995; 10879–10888; 35 mg, 0.169 mmol) in DCM (2.5 ml) was added 2,6-lutidine (29 mg, 0.268 mmol) and TBTU (56 mg, 0.174 mmol). The reaction mixture was stirred at room temperature for 2.5 hours, then diluted with DCM. The solution was washed with NaHCO3 (aq, sat), water, dried and the solvent was evaporated under reduced pressure. The residue was suspended in ether/petroleum ether and the crystals filtered to give the title compound 85 mg (89%). NMR (500 MHz) 0.79–0.86 (m, 6H), 1.04–1.28 (m, 4H), 1.35–1.56 (m, 11H), 1.60–1.77 (m, 2H), 2.82 (t, 2H), 3.13–3.25 (m, 2H), 3.72 (brs, 2H), 4.35–4.44 (m, 2H), 5.54 (d, 1H), 6.95 (d, 1H), 7.04 (t, 1H), 7.08 (d, 2H), 7.15 (s, 1H), 7.29–7.43 (m, 6H), 7.52 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[C:17]1([C:23]2[CH:29]=[C:27]([NH2:28])[C:26]([CH3:30])=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:30][C:26]1[CH:25]=[CH:24][C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:29][C:27]=1[NH:28][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: Cc1ccc(-c2ccccc2)cc1N
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: Cc1ccc(-c2ccccc2)cc1Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Yield: 15.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (100 mg, 0.43 mmol) and 5-phenyl-o-toluidine (119 mg, 0.65 mmol) to provide 245 (25 mg, 14% yield) as a brown solid. LC-MS (M+H (parent)=378, obsd.=378). 1H NMR (400 MHz, d6-DMSO): δ 11.63 (s, 1H), 8.45 (m, 2H), 8.37 (d, 1H), 8.13 (d, 1H), 7.63 (m, 3H), 7.58 (s, 1H), 7.44 (m, 4H), 7.34 (m, 1H), 7.26 (m, 1H), 7.14 (dd, 1H). 2.28 (s, 3H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@@H:8]([NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:20])[NH:6]1)=[N+]=[N-].S([O-])([O-])(=O)=O.[Mg+2].[C:27]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:30])[CH:28]=O>[Pd].C(O)C.C(Cl)Cl>[CH2:32]([O:31][C:27](=[O:30])[CH:28]=[N:1][CH2:4][C@H:5]1[C@@H:8]([NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:20])[NH:6]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: [N-]=[N+]=NC[C@@H]1NC(=O)[C@@H]1NC(=O)COc1ccccc1
Reactant: O=CC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCO
Product: O=C(COc1ccccc1)N[C@H]1C(=O)N[C@H]1CN=CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 0.499 g (1.81 mmole) of cis-2-azidomethyl-4-oxo-3-phenoxyacetylaminoazetidine and 0.189 g of 10% palladium on carbon in 25 ml of absolute ethanol was hydrogenated at atmospheric pressure and at 40° for 1 hour. The solution was filtered through celite and the solvent was removed in vacuo to afford a colorless gum which was dissolved in 15 ml of methylene dichloride. Anhydrous magnesium sulfate was added followed by addition of a solution of 0.314 g (1.91 mmole) of benzyl glyoxalate in 10 ml of methylene dichloride. The reaction mixture was stirred at room temperature under argon for 2.5 hours then was allowed to stand at 0° overnight. After filtering the reaction mixture, the solvents were removed in vacuo to give a semi-crystalline residue which was recrystallized from ethyl acetate-hexane to give N-(cis-4-oxo-3-phenoxyacetylamino-2-azetidinylmethyl)iminoacetic acid benzyl ester as a colorless solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](O)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[N:12]=[C:13]2[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:9][C:10]=1[F:15]
Reactant: O=C(O)c1cn(C2CC2)c2nc(O)c(F)cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Temperature: 25 °C

Procedure:
A suspension of 0.19 g (0.72 mmole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylic acid in 2 ml of phosphorus oxychloride was heated at reflux for one-half hour. The resulting solution was cooled to room temperature and the solvent was removed in vacuo. The residue was triturated with ice water and the resulting solid was removed by filtration, washed with water, then ether, and dried in vacuo to give 0.11 g of the title compound, mp 209-212° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([OH:3])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:51][C:52](=[O:65])[C@H:53]([OH:64])[C@H:54]([NH2:63])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[Cl:62])[CH3:50]>C(Cl)Cl>[Cl:62][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=1[CH2:55][C@@H:54]([NH:63][C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:3])[C@H:53]([C:52]([O:51][CH2:49][CH3:50])=[O:65])[OH:64]
Reactant: O=C(O)CCCc1ccccc1C(=O)O
Reactant: CCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1Cl)NC(=O)CCCc1ccccc1C(=O)O
Yield: 27.9 %

Procedure:
2-(3-Carboxy-propyl)benzoic acid (50 mg, 240 μmol 1.0 eq.) was combined with DIPEA (134 μL, 3.2 eq.) and HATU (91.3 mg, 240 μmol, 1.0 eq.) in DCM (5 mL). (2R,3R)-3-Amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid ethyl ester (69.9 mg, 240 μmol, 1.0 eq.) was added and the mixture was stirred. The reaction was quenched after 1 hour by adding saturated NH4Cl and the product was extracted with DCM, dried and evaporated. The product was purified using preparative HPLC to yield the title compound (30 mg, 100% purity). MS m/z [M+H]+ calc'd for C23H26ClNO6, 448.14. found 448.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[S:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17](Br)[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C@:12]2([CH3:14])[CH2:11][CH2:10][S:9][C:8]([NH:7][C:6](=[O:23])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:13]2)=[CH:16][C:17]=1[C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2ccc(F)c(Br)c2)CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2ccc(F)c(-c3cnccn3)c2)CCS1
Reaction time: 0.33 h
Yield: 14 %

Procedure:
A solution of (S)-[4-(3-bromo-4-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-yl]-carbamic acid tert-butyl ester (100 mg, 250 μmoles, 1 equiv), tetrakis(triphenylphosphine)palladium (14 mg, 12.40 μmoles, 0.05 equiv) and 2-tributylstannylpyrazine (96 mg, 250 μmoles, 1 equiv) in dioxane (3 mL) is irradiated in a laboratory-grade microwave to a temperature of 130° C. and held for 20 minutes. The solvent is removed under reduced pressure and the residue is purified by silica gel chromatography eluting with a linear gradient of hexane to hexane:ethyl acetate (1:4) ramp 20 min to give the title compound (14% yield, 90% purity as determined by LCMS): MS (m/z): 403 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H].C>[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reaction time: 0.17 h

Procedure:
10% w/w palladium on charcoal (250 mg) was added to a solution of the product from step (i) (5.37 g) in ethanol (100 ml) and the mixture hydrogenated at room temperature and pressure until the theoretical amount of hydrogen had been taken up. Charcoal was added, the mixture stirred for 10 minutes then filtered through diatomaceous earth and the filtrate evaporated to dryness. The solid residue, on recrystallisation from ethyl acetate/hexane gave 4-(N-tertiary-butyloxycarbonylaminomethyl)aniline, 4.20 g: m.p. 80°-81° C.; NMR (d6DMSO) δ 7.10(1H,bt), 6.88(2H,d), 6.49(2H,d), 4.92(2H,s), 3.92(2H,d), 1.38(9H,s); m/e 223(M+H)+ ; calculated for C12H18N2O2 : C, 64.8; H, 8.2; N, 12.6. found: C, 65.4; H, 8.3; N, 13.0%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[F:20][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][N:7]=2)=[CH:3][C:2]=1[N:1]=[C:29]=[O:31]
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C=Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
To a suspension of 4-(3-amino-4-fluoro-benzyl)-2H-phthalazin-1-one (1)(4.0 g, 14.8 mmol) in anhydrous DCM (1.6 L) and triethylamine (4.62 mL, 40.86 mmol), was added a dropwise preformed solution of triphosgene (2.75 g, 9.28 mmol) in anhydrous DCM (327 mL) and stirred for 70 minutes and room temperature. The reaction mixture was then concentrated to dryness in vacuo yielding a grey solid. Single peak in LC-MS analysis, (yield taken to be quantitative) no purification performed. m/z (LC-MS, ESP), RT=4.49 mins, (M+MeOH) 328.0.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@H:13]([C:15](=[O:17])[NH2:16])[CH2:12][CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])=O)(C)(C)C.Cl.[CH3:32][N:33]1[CH2:38][CH2:37][C:36]2[N:39]=[C:40](C([O-])=O)[S:41][C:35]=2[CH2:34]1.[Li+]>O1CCOCC1>[C:15]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]([NH:18][C:19]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=3)=[O:20])[C@@H:9]([NH:8][C:6]([C:40]2[S:41][C:35]3[CH2:34][N:33]([CH3:32])[CH2:38][CH2:37][C:36]=3[N:39]=2)=[O:5])[CH2:14]1)(=[O:17])[NH2:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](C(N)=O)CC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: CN1CCc2nc(C(=O)N[C@H]3C[C@H](C(N)=O)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1

Procedure:
(1R*,2S*,4R*)-N2-(tert-Butoxycarbonyl)-4-carbamoyl-N1-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with a 4N dioxane solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([N:32]5[CH2:33][CH2:34][CH:30]([NH:29][CH3:28])[CH2:31]5)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: CNC1CCNC1
Product: CNC1CCN(C(=O)c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)C1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to N-methylpyrrolidin-3-amine via General Procedure B. The product was purified via reverse phase HPLC to give 16.7 mg of 253. MS (Q1) 463.8 (M)+.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][C:17]([CH3:21])([OH:20])[CH2:16][CH2:15]1)[CH3:3].[NH2:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([C:30]#[N:31])=[C:25](Cl)[N:24]=1.CCN(CC)CC>CN(C=O)C>[NH2:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([C:30]#[N:31])=[C:25]([NH:1][CH:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]2[CH2:15][CH2:16][C:17]([OH:20])([CH3:21])[CH2:18][CH2:19]2)[CH3:3])[N:24]=1
Reactant: CC(N)c1nc2ccn(C)c2cc1N1CCC(C)(O)CC1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CCC(C)(O)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a 10 mL vial were added 1-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-4-methylpiperidin-4-ol (56 mg, 0.194 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (32.9 mg, 0.194 mmol) and Et3N (0.054 mL, 0.388 mmol) in DMF (3 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The reaction mixture was purified by preparative HPLC eluting with 5-30% ACN in water (with 0.05% ammonium carbonate). The fractions containing the desired product were combined and lyophilized to give the title compound (racemate) as a white solid (40 mg, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17-1.29 (m, 3 H), 1.32-1.43 (m, 3 H), 1.52-1.87 (m, 4 H), 2.57-2.72 (m, 2 H), 2.73-2.94 (m, 2 H), 3.16-3.29 (m, 1 H), 3.71-3.86 (m, 3 H), 4.24-4.32 (m, 1 H), 5.74-5.88 (m, 1 H), 6.34-6.44 (m, 2 H), 6.44-6.52 (m, 1 H), 6.53-6.65 (m, 3 H), 7.48-7.58 (m, 1 H), 7.77-7.84 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C21H27N9O, 422.2; found 422.5.
Reaction SMILES: Br.[Br:2][CH:3]1[CH:9]([CH3:10])[CH2:8][NH:7][CH2:6][CH2:5][C:4]1=O.[C:12]([NH2:15])(=[S:14])[CH3:13]>C(O)C>[BrH:2].[CH3:13][C:12]1[S:14][C:3]2[CH:9]([CH3:10])[CH2:8][NH:7][CH2:6][CH2:5][C:4]=2[N:15]=1
Reactant: CC1CNCCC(=O)C1Br
Reactant: CC(N)=S
Agent: Br
Solvent: CCO
Product: Cc1nc2c(s1)C(C)CNCC2
Yield: 92.5 %

Procedure:
18.5 g 5-bromo-6-methylazepan-4-one hydrobromic acid salt and 5.0 g thioacetamide were dissolved in 125 mL ethanol. The mixture was heated for 3 h under reflux. The solids were removed by filtration and the filtrate was concentrated in vacuo. 100 mL acetonitrile was added and the precipitate formed was isolated by filtration to yield 15.7 g of the desired product.