Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][N:12]=1>CS(C)=O>[CH3:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]([CH3:4])[N:12]=1
Reactant: COc1ncc([N+](=O)[O-])cc1C
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1nc(C)c([N+](=O)[O-])cc1C
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
Dimethyl sulfoxide (35 mL) was added to a dry round-bottomed flask containing NaH (1.82 g, 45.5 mmol, 60% in mineral oil). The resulting suspension was heated at 70° C. for 35 min during which time the suspension became a solution. The reaction mixture was cooled to room temperature, trimethylsulfoxonium iodide (10.0 g, 45.5 mmol) was added, and the mixture was stirred at room temperature for 30 min. 2-Methoxy-3-methyl-5-nitropyridine (4.50 g, 26.80 mmol) was added and the resulting dark red solution was stirred at room temperature for 30 min, at which time TLC showed complete consumption of starting material. The reaction mixture was transferred to a separatory funnel containing water (30 mL), and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by MPLC (silica gel, 20% ethyl acetate in hexanes) to afford 2-methoxy-3,6-dimethyl-5-nitropyridine (2.00 g, 41% yield) as a colorless solid identical to that prepared by the previous method: mp 85.5-86.2° C.; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 4.02 (s, 3H), 2.77 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: ClC1C=C(NC2N=C(C3C(C4C=C(NC(=O)C5C(F)=CC=CC=5F)C=CC=4)=NN4C=CC=CC=34)C=CN=2)C=CC=1OCCN(C)C.[CH3:47][O:48][CH2:49][CH2:50][OH:51].[H-].[Na+].[F:54][C:55]1[CH:56]=[C:57]([N+:62]([O-:64])=[O:63])[CH:58]=[CH:59][C:60]=1F>>[F:54][C:55]1[CH:56]=[C:57]([N+:62]([O-:64])=[O:63])[CH:58]=[CH:59][C:60]=1[O:51][CH2:50][CH2:49][O:48][CH3:47]
Reactant: COCCO
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: CN(C)CCOc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)cc1Cl
Agent: [H-]
Agent: [Na+]
Product: COCCOc1ccc([N+](=O)[O-])cc1F

Procedure:
In a procedure analogous to Example 125, 0.64 g of the title compound was prepared from 0.39 mL (4.94 mmol) of 2-methoxyethanol, 0.24 g (6.11 mmol) of a 60% mineral oil dispersion of sodium hydride, and 0.75 g (4.7 mmol) of 3,4-difluoronitrobenzene as a light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 3.44 (s, 3H), 3.80 (d, 2H, J=4.6 Hz), 4.28 (t, 2H, J=4.6 Hz), 7.05 (dd, 1H, J=8.4 and 8.4 Hz), 7.98 (dd, 1H, J=10.6 and 2.7 Hz), and 8.03 (d, 1H, J=9.0 Hz).
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH3:28])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[C@H:17]([OH:29])[C@@H:16]1[OH:30])([O:4][P:5]([O:8]P(O)(O)=O)([OH:7])=[O:6])(=[O:3])[OH:2].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[O-]P(OP([O-])([O-])=O)(=O)[O-].[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-]>C(O)C(N)(CO)CO.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>[P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH3:28])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[C@H:17]([OH:29])[C@@H:16]1[OH:30])([O:4][P:5]([OH:8])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: Cc1cn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Agent: NC(CO)(CO)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Product: Cc1cn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Reaction time: 66 h

Procedure:
5-Methyluridine 5'-triphosphate (0.0047 g, 0.009 mMol) was dissolved in 0.7 mL 1M Tris buffer (pH 8.5 containing 1M MgCl2) then 0.3 mL of a 0.25M glucose solution in 1M Tris buffer (pH 8.5 containing 1M MgCl2) added. A T0 timepoint was taken by reverse phase anion exchange HPLC. Hexokinase (EC 2.7.1.1, Boehringer Mannheim, from yeast overproducer), 75 units in 3.2M ammonium sulfate suspension, was added to the reaction which was incubated at 25° C. An HPLC was taken at 66 hours indicating complete conversion to diphosphate with no triphosphate remaining. Triphosphate retention: 17.5 minutes; diphosphate retention: 10.3 minutes.
Reaction SMILES: [CH2:1]([O:19][C:20]1[C:33]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[C:32]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH:31]=[CH:30][C:21]=1[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[BH4-].[Na+].Cl>C(Cl)(Cl)Cl.CO>[CH2:1]([O:19][C:20]1[C:33]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[C:32]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH:31]=[CH:30][C:21]=1[CH:22]([OH:23])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)c2ccccc2)c(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(O)c2ccccc2)c(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 45 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
2,3,4-Tris(octadecyloxy)benzophenone (3.00 g, 3.04 mmol) was dissolved in a mixed solvent of chloroform (30 mL) and methanol (10 mL), sodium borohydride (360 mg, 9.51 mmol) was added, and the mixture was stirred at 45° C. for 2 hr. After completion of the reaction, 0.1 mol/L aqueous hydrochloric acid was added dropwise to decompose unreacted sodium borohydride and the mixture was washed with 1.0 mol/L aqueous hydrochloric acid. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Methanol was added to the concentrated solution, and the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (2.98 g, 99.0%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[C:5](=O)[CH3:6].Cl.[NH2:19]O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:6])=[N:19][O:16][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)=[O:17]
Reactant: COC(=O)C(C(C)=O)C(=O)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1c(C)noc1-c1ccc(Br)cc1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-(4-bromo-benzoyl)-3-oxo-butyric acid methyl ester (11 g, 39 mmol) in acetic acid (50 mL) was added hydroxylamine hydrochloride (2.66 g, 39 mmol), and the reaction was stirred at 115° C. for 1 hours. After cooling, saturated aqueous NaHCO3 was added to the mixture to adjust to pH 8. The solution was extracted with EtOAc, and the combined organic layers were washed with brine, dried, filtered, and concentrated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14](O)=O)[CH2:12][N:11]2[CH2:17][CH2:18][CH2:19][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH2:28][C:29]1[CH:33]=[C:32]([Br:34])[S:31][C:30]=1[C:35]([NH2:37])=[O:36].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[Br:34][C:32]1[S:31][C:30]2[C:35](=[O:36])[NH:37][C:14]([CH:13]3[CH2:12][N:11]4[CH2:17][CH2:18][CH2:19][C@@H:10]4[CH2:9][N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:28][C:29]=2[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCCN2CC1C(=O)O
Reactant: NC(=O)c1sc(Br)cc1N
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H]2CCCN2CC1c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.3 %

Procedure:
To a mixture of (8aR)-2-(tert-butoxycarbonyl)octahydropyrrolo[1,2-a]pyrazine-3-carboxylic acid (270 mg), triethylamine (0.18 mL) and tetrahydrofuran (10 mL) was added 2-methylpropyl chlorocarbonate (0.13 mL) with stirring at room temperature. After 2 hr, 3-amino-5-bromothiophene-2-carboxamide (221 mg) produced in Example 1, step D, was added and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (10 mL), 2M aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate/tetrahydrofuran mixture, and the extract was dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate) to give the title compound (65 mg) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][N:28]([S:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:9])=[O:8])[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
To a stirred solution of commercially available 5-bromo-thiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) in THF (8 ml) was added at room temperature triethylamine (0.59 ml, 4.21 mmol), the mixture was cooled (ice-water) and a solution of commercially available 1-BOC-piperazine (2.14 g, 11.5 mmol) in THF (8 ml) was added drop wise. The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) and subsequent crystallization from dichloromethane/hexane to yield the title compound (1.35 g, 86%) as a white solid. MS (ISP) 413.2 [(M+H)+], mp 127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]([CH3:23])=[C:4]([CH:3]=1)[C:24]([NH:25][CH2:26][C:27]1[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=1[CH3:33])=[O:36]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(N(C)C3CCNCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
A stirred solution of tert-butyl 4-((5-chloro-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)(methyl)amino)piperidine-1-carboxylate (0.2 g, 0.632 mmol) in DCM (5 mL) was cooled to 0° C. and TFA (0.15 mL) was added to it. Reaction mass was stirred at room temperature for 1 h. On completion, reaction was concentrated to dryness. Residue was purified by solvent washings to afford the desired compound (0.14 g, 53%) as its TFA salt. LCMS: 417.25 (M+1)+; HPLC: 96.16% (@ 254 nm) (Rt; 4.677; 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 11.47 (s, 1H), 8.49 (bs, 1H), 8.20 (t, 1H), 8.18 (bs, 1H), 7.19 (s, 1H), 6.96 (s, 1H), 5.86 (s, 1H), 4.25 (d, 2H, J=4.4 Hz), 3.25 (d, 2H, J=12 Hz), 3.08 (m, 1H), 2.88 (bs, 2H), 2.56 (s, 3H), 2.18 (s, 3H), 2.17 (s, 3H), 2.10 (s, 3H), 1.76 (bs, 4H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[CH3:8][O:9][C:10]1[C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH3:8][O:9][C:10]1[C:16]([C:2]2[N:3]=[C:4]([CH3:7])[S:5][CH:6]=2)=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]
Reactant: COc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nc(Br)cs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1c(N)cccc1-c1csc(C)n1
Temperature: 100 °C
Yield: 75.5 %

Procedure:
A stirred mixture of 4-bromo-2-methylthiazole (128 mg, 0.719 mmol), 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (197 mg, 0.791 mmol) and 1,1′-bis(di-tert-Butylphosphino)ferrocene palladium dichloride (14.06 mg, 0.022 mmol) in dioxane (4 mL) was degassed by bubbling nitrogen through the mixture for 5 minutes. To this was added aqueous potassium phosphate (K3PO4, 2M, 1.078 mL, 2.157 mmol) and the reaction mixture was heated to 100° C. for one hour. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate (75 mL). This solution was then dried over sodium sulfate, filtered, concentrated and purified by flash chromatography, eluting with 0-100% EtOAc in hexanes. Afforded 2-methoxy-3-(2-methylthiazol-4-yl)aniline (122 mg, 0.543 mmol, 75% yield) as a yellow oil. LC retention time 0.60 [J]. m/z: 221 (MH+).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:20]1[C:21]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])=[N:22][CH:23]=[CH:24][N:25]=1>CN(C)C=O>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:20]4[C:21]([N:26]5[CH2:30][CH2:29][CH2:28][C:27]5=[O:31])=[N:22][CH:23]=[CH:24][N:25]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: O=C1CCCN1c1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1c1nccnc1Oc1ccc2c(c1)CCN(C1CCC1)CC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.3 %

Procedure:
3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (103 mg, 0.47 mmol) was dissolved in dry dimethylformamide (3 ml), cooled to 0° C. and treated with sodium hydride (60% in mineral oil, 20 mg, 0.49 mmol). The mixture was allowed to warm to room temperature over 40 minutes. A solution of 1-(3-chloro-2-pyrazinyl)-2-pyrrolidinone (D46) (103 mg, 0.52 mmol) in dry dimethylformamide (1 ml) was added and the mixture stirred at room temperature for 2 hours and heated at 80° C. for 2.5 hours. The mixture was allowed to cool to room temperature and applied to a SCX column and washed with methanol then a mixture of 0.880 ammonia/methanol (1:9). The basic fractions were combined and concentrated in vacuo and resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the title compound (86 mg); MS (ES+) m/e 379 [M+H]+.
Reaction SMILES: [CH2:1]([P:3]([CH2:9][O:10][S:11]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])(=[O:13])=[O:12])(=O)[O:4]C(C)C)[CH3:2].S(Cl)([Cl:24])=O>ClCCCl>[CH2:1]([P:3]([Cl:24])([CH2:9][O:10][S:11]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])(=[O:13])=[O:12])=[O:4])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCP(=O)(COS(=O)(=O)c1c(C)cccc1Cl)OC(C)C
Solvent: ClCCCl
Product: CCP(=O)(Cl)COS(=O)(=O)c1c(C)cccc1Cl
Temperature: 50 °C
Reaction time: 65 h

Procedure:
A mixture of 20.0 g of O-isopropyl P-ethyl[[2-chloro-6-methylphenyl)sulfonyloxy]methyl]phosphinate (Compound 119), 80 ml of 1,2-dichloroethane and 4.6 ml of thionyl chloride was heated to 50° C. for four hours. 31P NMR analysis of an aliquot of the reaction showed that one third of the starting material was still present so the reaction was heated to 50° C. for 1.5 hours, cooled and let stand at room temperature for 65 hours, heated again to 50° C. for 4 hours and let stand overnight. 31P NMR indicated that starting material was still present so 2 ml of thionyl chloride was added and the reaction was heated to 50° C. for 3.5 hours. The reaction mixture was concentrated under reduced pressure to yield 19.4 g of the desired phosphinoyl chloride which was shown to be 95% pure by 31P NMR.
Reaction SMILES: [O:1]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:16]Cl>C(O)(=O)C>[I:16][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:8][O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][CH:6]=1
Reactant: c1ccc(OCOc2ccccc2)cc1
Reactant: ClI
Solvent: CC(=O)O
Product: Ic1ccc(OCOc2ccccc2)cc1
Yield: 67 %

Procedure:
4-(Phenoxy)methoxybenzene (7.40 g, 36.9 mmol) was dissolved in acetic acid and treated with iodine monochloride (7.50 g, 46.2 mmol) at 50° C. for 4 hours. The mixture was then concentrated and the residue taken up in methylene chloride. The solution was washed with 10% sodium sulfite solution, dried with magnesium sulfate, filtered and concentrated to a yellow solid. This was triturated with hexane, collected and dried to give 8.06 g of the title compound as a pale pink solid. GS-MS (m/z, EI): 326 [M]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[Br:13][CH2:14][CH2:15][CH2:16]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:13][CH2:14][CH2:15][CH2:16][O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[N:3]([CH2:1][CH3:2])[CH2:11][CH3:12]
Reactant: BrCCCBr
Reactant: CCN(CC)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCN(CC)c1cccc(OCCCBr)c1
Reaction time: 24 h
Yield: 17.4 %

Procedure:
To a solution of 3-(diethylamino)phenol (0.0104 g, 0.631 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.640 mL, 6.30 mmol) followed by Cs2CO3 (0.313 g, 0.961 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0314 g, 17.4%). EI-MS m/z 286 (M+H) Rt (1.59 min).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=[N+:16]=[N-:17])[C:6]([C:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]=1Cl)=[O:7])[CH3:2].C(P(CCCC)CCCC)CCC>O1CCOCC1>[CH2:1]([O:3][C:4]([C:5]1[C:6](=[O:7])[C:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:17][N:16]=1)=[O:18])[CH3:2]
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)C1=C(Cl)CCCCC1
Agent: CCCCP(CCCC)CCCC
Solvent: C1COCCO1
Product: CCOC(=O)c1n[nH]c2c(c1=O)CCCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
To a solution of 3-(2-chlorocyclohept-1-enyl)-2-diazo-3-oxopropionic acid ethyl ester (1 g) in 1,4-dioxan (20 ml) was added a solution of tri-n-butylphosphine (1 ml) in 1,4-dioxan (10 ml). On completion of the addition the reaction mixture was stirred at room temperature for 30 minutes then heated to reflux for 2 h. The solvent was evaporated under reduced pressure and the residue purified by chromatography using a gradient elution: CH2Cl2 (250 ml), CH2Cl2/MeOH 99:1 (250 ml), CH2Cl2/MeOH 98:2 (250 ml), CH2Cl2/MeOH 97:3 (250 ml), CH2Cl2/MeOH 96:4 (250 ml). The appropriate fractions were combined and evaporated under reduced pressure to give a solid (360 mg, 41%). C12H16N2O3 requires C, 61.00; H, 6.83; N, 11.86. Found C, 60.80; H, 6.88; N, 11.84%. δH (250 MHz; CDCl3) 1.42 (3H, t, J=7 Hz, CH3), 1.62 (2H, m, CH2), 1.73 (2H, m, CH2), 1.87 (2H, m, CH2), 2.86 (2H, m, CH2), 3.09 (2H, m, CH2), 4.48 (2H, t, J=7 Hz, CH2), m/z (ESP+) 237 (MH+).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:38]=[C:37]([CH3:39])[C:29]3[NH:30][C:31]([C:33]([F:36])([F:35])[F:34])=[N:32][C:28]=3[CH:27]=2)[CH:20]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C>[CH3:39][C:37]1[C:29]2[NH:30][C:31]([C:33]([F:34])([F:36])[F:35])=[N:32][C:28]=2[CH:27]=[C:26]([O:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:20]=2)[CH:38]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2nc(C(F)(F)F)[nH]c12
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2nc(C(F)(F)F)[nH]c12

Procedure:
21 mg (0.08 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 22 mg (0.07 mmol) 5-(6-chloropyrimidin-4-yloxy)-7-methyl-2-(trifluoromethyl)-1H-benzo[d]-imidazole and 40 μL (0.24 mmol) DIPEA in 2.0 mL DMF were stirred at 50° C. over the weekend. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with a 1M aqueous NaOH solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[C:8]([CH:15]([CH3:17])[CH3:16])[O:9]2)=[CH:4][CH:3]=1.Cl>CO.[Pd]>[NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[C:8]([CH:15]([CH3:16])[CH3:17])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)c1oc2c([N+](=O)[O-])c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)c1oc2c(N)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7-Amino-3-(4-chlorophenyl)-2-isopropyl-8-nitro-chromen-4-one (450 mg, 0.94 mmol) is suspended in methanol (5 ml). Concentrated hydrochloric acid (5 ml) is added. The mixture is placed under an atmosphere of argon, and 10% palladium on activated carbon (50 mg) is added. The reaction mixture is placed under an atmosphere of hydrogen and stirred at room temperature for 24 h. The mixture is filtered through a Celite pad, and the Celite pad is washed with methanol (3×30 ml). The filtrate and the washings are combined and evaporated to give a yellow solid.
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([O:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[NH:26][C:27]2[C:28]3[C:35]([CH3:36])=[C:34]([C:37]([OH:39])=[O:38])[S:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O[N:41]1[C:45](=[O:46])[CH2:44][CH2:43][C:42]1=[O:47]>CN(C=O)C>[O:47]=[C:42]1[CH2:43][CH2:44][C:45](=[O:46])[N:41]1[O:38][C:37]([C:34]1[S:33][C:29]2[N:30]=[CH:31][N:32]=[C:27]([NH:26][C:20]3[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=3[O:18][C@H:14]3[CH2:15][CH2:16][CH2:17][N:12]([C:10]([O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:11])[CH2:13]3)[C:28]=2[C:35]=1[CH3:36])=[O:39]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c12
Reactant: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1c(C(=O)ON2C(=O)CCC2=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (290 mg) was added into a solution of 4-[2-((S)-1-tert-butoxycarbonyl-piperidin-3-yloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (640 mg) and N-hydroxysuccinimide (218 mg) in anhydrous DMF (10 ml). The reaction was stirred at room temperature overnight. A further aliqout of EDC (58 mg) and N-hydroxysuccinimide (44 mg) were added and the reaction stirred for further 2 h. The DMF was removed in vacuo and the residue co-evaporated from toluene. The solid was portioned between EtOAc and water. The organic layer was separated and washed with brine. The combined organics were passed through a phase separator and concentrated in vacuo.