Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:26]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(C(F)(F)F)c4)cc3CC[C@@H]12
Yield: 74.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3-trifluoromethylphenylboronic acid (148 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 180 mg (77%) of the title compound as an amorphous foam. mp 64°-87°. FDMS: m/e=373. α[D]589 =+64.42 (c=1.04, chloroform).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:28])[CH2:13][N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C:15]1=[O:27].Cl.C(OCC)(=O)C>C(OCC)(=O)C>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:28])[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C:15]1=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)CN2CCc3ccccc3C2)C(=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1CNCCN1CC(O)CN1CCc2ccccc2C1
Temperature: 20 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of tert-butyl 4-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxyl propyl)-3-oxopiperazine-1-carboxylate (200 mg, 0.69 mmol) in ethyl acetate (10 mL) was added HCl/ethyl acetate (4 mL). The reaction mixture was stirred at 20° C. overnight, concentrated and used in the next step without further purification. (100 mg, yield 50%) MS (ESI+) e/z: 290.2 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:39])([F:38])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:31]=[CH:30][C:29]([CH2:32]O)=[C:28]([C:34]([F:37])([F:36])[F:35])[CH:27]=2)=[CH:22][CH:21]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:32][C:29]3[CH:30]=[N:31][C:26]([C:23]4[CH:22]=[CH:21][C:20]([O:19][C:18]([F:38])([F:17])[F:39])=[CH:25][CH:24]=4)=[CH:27][C:28]=3[C:34]([F:37])([F:35])[F:36])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: OCc1cnc(-c2ccc(OC(F)(F)F)cc2)cc1C(F)(F)F
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3cnc(-c4ccc(OC(F)(F)F)cc4)cc3C(F)(F)F)cc21

Procedure:
In analogy to the procedure described in example 5 f], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 6 b]) was reacted with [6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-yl]-methanol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield the title compound as colorless foam.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][OH:8].N1C=CC=CC=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:8][CH2:7][C@H:2]2[CH2:3][O:4][CH2:5][CH2:6][O:1]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: OC[C@H]1COCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Temperature: 0 °C
Reaction time: 15.5 h
Yield: 73 %

Procedure:
To a cooled (0° C.) solution of (S)-(1,4-dioxan-2-yl)methanol (Kim, H. Y., et al., Bioorg. Med. Chem. Lett. (2005), 15:3207-11) (2.02 g, 17.1 mmol) and pyridine (14 mL, 173 mmol) in dichloromethane (11 mL) was added p-toluenesulfonyl chloride (3.85 g, 20.2 mmol). The reaction was stirred at 0° C. for 20 min and at ambient temperature for an additional 15.5 h. The solution was diluted with dichloromethane (100 mL) and was washed sequentially with hydrochloric acid (100 mL, 2 M), water (50 mL) and brine (50 mL). The organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with hexanes/ethyl acetate (2:1 to 3:2) to afford (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (3.40 g, 73%) as a colorless solid: mp 53-54° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ7.79 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 4.02 (dd, J=10.8, 5.4 Hz, 1H), 3.95 (dd, J=10.5, 4.5 Hz, 1H), 3.82-3.50 (m, 6H), 3.35 (dd, J=11.6, 9.8 Hz, 1H), 2.45 (s, 3H); MS (ES+) m/z 295.0 (M+23).
Reaction SMILES: [OH-].[K+:2].[OH:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[O:15][CH3:16]>CO>[OH:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O-:14])=[O:13])=[CH:6][C:5]=1[O:15][CH3:16].[K+:2]
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(/C=C/C(=O)[O-])ccc1O
Yield: 100.3 %

Procedure:
Potassium hydroxide (580 mg, 10.3 mmol) was dissolved in methanol (10 ml) and put in a three-necked flask. Stirring was set on. Subsequently, (E)-3-(4-Hydroxy-3-methoxyphenyl)-2-propenoic acid (2.00 g, 10.3 mmol) in methanol (20 mL) was added to this solution through a funnel. After the addition was ended, the solution was allowed to react at room temperature for 3 h. Methanol was then evaporated off and then yellow solid residue was washed with Et2O and dried under reduced pressure. The product was obtained as a yellowish solid (2.40 g, quantitative yield).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([N:45]1[CH:49]=[C:48](B(O)O)[CH:47]=[N:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C1(C)C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:18]=[C:13]3[C:12]([C:48]3[CH:47]=[N:46][N:45]([C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:49]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(N3CCOCC3)cnc21
Reactant: OB(O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)c2cc(N3CCOCC3)cnc21
Temperature: 105 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
A mixture of iodide 55 (0.083 g, 0.18 mmol), (1-trityl-1H-pyrazol-4-yl)boronic acid (0.094 g, 0.27 mmol), PdCl2(PPh3)2 (0.012 g, 0.017 mmol), LiCl (0.022 g, 0.52 mmol) and 1.0 M aqueous Na2CO3 solution (0.442 mL, 0.442 mol) in EtOH (2 mL)-toluene (2 mL) was stirred at 105° C. for 2 hours. The mixture was cooled and the organic layer was poured into water and extracted with AcOEt. The organic extract was washed with brine, dried (MgSO4), and concentrated to afford a syrup. The syrup was purified by means of preparative TLC with hexane:AcOEt as eluent to afford 56 (0.093 g, 81%) as a tan syrup. 1H NMR (400 MHz, CDCl3) δ 2.97-3.02 (m, 4H), 3.77-3.82 (m, 4H), 7.11-7.16 (m, 6H), 7.24-7.29 (m, 8H), 7.35-7.40 (m, 2H), 7.44-7.49 (m, 1H), 7.51 (d, J=0.08 Hz, 1H), 7.61 (s, 1H), 7.86 (d, J=0.08 Hz, 1H), 8.06-8.09 (m, 2H), 8.13 (d, J=0.26 Hz, 1H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@:9]([C:15]#[N:16])([CH2:10][O:11]C(=O)C)[O:8][C@@H:7]([N:17]2[C:26]3[N:25]=[C:24]([F:27])[N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[CH:18]2)[CH2:6]1)(=O)C.N>CO>[C:15]([C@:9]1([CH2:10][OH:11])[O:8][C@@H:7]([N:17]2[C:26]3[N:25]=[C:24]([F:27])[N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[CH:18]2)[CH2:6][C@@H:5]1[OH:4])#[N:16]
Reactant: CC(=O)OC[C@@]1(C#N)O[C@@H](n2cnc3c(N)nc(F)nc32)C[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: N#C[C@]1(CO)O[C@@H](n2cnc3c(N)nc(F)nc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 7 (53.7 mg, 0.142 mmol) was dissolved in methanol (1.90 ml), and 28% aqueous ammonia (1.30 ml) was added to the resultant solution, followed by stirring at room temperature for 30 minutes. The resultant reaction mixture was concentrated under reduced pressure, and then the resultant residue was purified by means of silica gel column chromatography (silica gel 10 ml, hexane/ethyl acetate (5:1), ethyl acetate, ethyl acetate/methanol (10:1)), to thereby yield compound 8 (30.2 mg, 0.10 mmol, 72.3%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20]O)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:24].O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][Br:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrP(Br)Br
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCO
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)CCOCCOCCOCCOCCBr
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a stirred solution of 9a (1.0 g, 3.11 mmol) in 1 mL of pyridine at 0° C. was slowly added phosphorus tribromide (0.116 mL, 1.22 mmol) via syringe (Bradshaw et al., J. Het. Chem., 27:347-349 (1990)). The solution was allowed to stir overnight, at which time TLC analysis indicated that the reaction was complete. Water (25 mL) was poured into the reaction vessel and the organics were extracted into methylene chloride (3×25 mL). The combined organic layers were washed with sodium bicarbonate (25 mL), followed by brine (25 mL), dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified on silica gel using neat ethyl acetate as the eluant to give 400 mg (35% yield) of pure product 10a (FIG. 7). 1H NMR: 1.37 (s, 9H), 2.43 (t, 2H, J=6.4 Hz), 3.40 (t, 2H, J=6.4 Hz), 3.53-3.61 (m, 12H), 3.64 (t, 2H, J=6.4 Hz), 3.74 (t, 2H, J=6.4 Hz). 13C NMR: 27.90, 30.13, 36.06, 66.68, 70.17, 70.31, 70.32, 70.39, 70.46, 70.99, 80.22, 170.65.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][C@@H:29]1[CH2:33][CH2:32][O:31][CH2:30]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][C@@H:29]2[CH2:33][CH2:32][O:31][CH2:30]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCC[C@@H]1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CC[C@@H]3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 223 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and (3S)-3-(2-bromoethyl)tetrahydrofuran but conducting the alkylation over 1 hour at 60° C.
Reaction SMILES: FC(F)(F)C([O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=O.[F:14][CH2:15][C:16]([NH:18]O)=[O:17]>>[F:14][CH2:15][C:16]([NH:18][O:5][C:6](=[O:11])[C:7]([F:8])([F:9])[F:10])=[O:17]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(CF)NO
Product: O=C(CF)NOC(=O)C(F)(F)F
Yield: 93 %

Procedure:
Trifluoroacetic anhydride, 71 ml (0.5 mol), was added dropwise to a 37.22 g (0.4 mol) sample of powdered 2-fluoroacetohydroxamic acid. The reaction mixture became liquid and warmed spontaneously to 60°. After cooling, the reaction mixture was evaporated to dryness under reduced pressure to give 70.3 g (93%) of N-(fluoroacetyl)-O-(trifluoroacetyl)hydroxylamine as a colorless, crystalline residue: mp 56°-59°; 1H NMR (CDCl3) δ 5.05 ppm (d, J=47 Hz, 2H) and 9.8 ppm (NH); 19F NMR (CDCl3) δ -233.8 ppm (t, J=47 Hz, 1F) and 73.8 ppm (s, 3F).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[O:19]1[C:24]2[CH:25]=[CH:26][C:27](B(O)O)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1>>[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([C:2]3[CH:3]=[C:4]([N:8]4[CH2:16][CH:15]5[CH2:17][N:11]6[CH2:12][CH:13]([CH2:18][CH:9]4[CH2:10]6)[CH2:14]5)[CH:5]=[N:6][CH:7]=3)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: c1cc2c(cc1-c1cncc(N3CC4CC5CC3CN(C5)C4)c1)OCCO2

Procedure:
The title compound was prepared from the product of Example 65A and (2,3-dihydro-1,4-benzodioxin-6-yl)boronic acid according to General Method B: LC-MS Method D (ESI+) m/z 364.0 (M+H)+, retention time 1.30 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:58])[CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:29]2[C:28]3[C:23](=[CH:24][C:25]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=3)[NH:22][C:21]=2[N:20]=[C:19]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41](=[N:46]OS(C3C=CC(C)=CC=3)(=O)=O)[C:42]([F:45])([F:44])[F:43])[CH:36]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:59]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:58])[CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:29]2[C:28]3[C:23](=[CH:24][C:25]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=3)[NH:22][C:21]=2[N:20]=[C:19]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]3([C:42]([F:43])([F:44])[F:45])[NH:59][NH:46]3)[CH:36]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NOS(=O)(=O)c4ccc(C)cc4)C(F)(F)F)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C4(C(F)(F)F)NN4)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Temperature: 20 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
A solution of methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (0.217 g, 0.263 mmol) in DCM (5.07 mL) was cooled to −78° C. and ammonia (1.7 mL, 79 mmol) was condensed into the sealed tube. The mixture was allowed to slowly warm to 20° C. and stirred for 3 hours. After cooling again to −78° C., the sealed tube was fitted with a septa with gas outlet and slowly warmed to 20° C. to evaporate ammonia. After 3 hours, the mixture was concentrated to dryness and then purified by flash chromatography to afford methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(3-(trifluoromethyl)diaziridin-3-yl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (139 mg, 79% yield) as a white foam: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (s, 9H) 1.52-1.62 (m, 2H) 1.72-1.89 (m, 2H) 2.08-2.25 (m, 3H) 2.30-2.44 (m, 4H) 2.94 (q, J=6.4 Hz, 2H) 3.64 (q, J=6.5 Hz, 2H) 3.88 (s, 3H) 3.93 (d, J=8.4 Hz, 1H) 4.04 (d, J=8.4 Hz, 1H) 4.08 (s, 2H) 6.78 (br. s., 1H) 7.31-7.41 (m, 2H) 7.44-7.50 (m, 1H) 7.54 (t, J=5.5 Hz, 1H) 7.59 (s, 1H) 7.83 (dd, J=8.4, 1.4 Hz, 1H) 7.99 (d, J=1.4 Hz, 1H) 8.27 (d, J=8.4 Hz, 1H) 12.07 (s, 1H); MS m/z 671.4 (M+H)+; HPLC 98.6% @ 220 nm and 96.4% @ 254 nm, RT=1.91 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[N:25]=[CH:24]4)([OH:20])[C:16]([F:19])([F:18])[F:17])=[CH:7][N:8]2[CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.[CH2:37]([N:39](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CN>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[N:25]=[CH:24]4)([OH:20])[C:16]([F:17])([F:19])[F:18])=[CH:7][N:8]2[CH2:11][C:12]([NH:39][CH3:37])=[O:13])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)Cn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ccc(Br)cc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: CNC(=O)Cn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ccc(Br)cc21
Reaction time: 0.08 h
Yield: 14.5 %

Procedure:
To a room temperature solution of 135 mg (0.24 mmol) of (6-bromo-3-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}indol-1-yl)acetic acid in 1 mL of DMF was added 121 mg (1.2 mmol) of triethylamine followed by 210 mg (0.40 mmol) of benzotriazole-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP). After 5 minutes, 162 mg (2.4 mmol) of methyl amine was added. The mixture stirred overnight and was filtered and purified by HPLC using CH3CN-water buffered with 0.1% TFA (5-90% gradient). The material from the column was concentrated to remove CH3CN. The resulting aqueous portion was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 20.0 mg (15%) of the title compound. LCMS [M+H]=576.35.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH3:19])[CH2:18][CH2:17][CH2:16][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6]2)[CH2:4]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23](F)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[C:25]([NH:1][CH2:2][C:3]2([CH3:19])[CH2:18][CH2:17][CH2:16][C:5]3([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([CH3:14])([CH3:15])[CH3:13])[CH2:6]3)[CH2:4]2)[CH:26]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CC(C)(C)CN1CC2(CCCC(C)(CN)C2)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)CN1CC2(CCCC(C)(CNc3cc(Cl)ccc3[N+](=O)[O-])C2)OC1=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 110.7 %

Procedure:
A solution containing 7-(aminomethyl)-7-methyl-3-neopentyl-1-oxa-3-azaspiro[4.5]decan-2-one (0.100 g, 0.373 mmol) in MeCN (5 mL) was treated with 4-chloro-2-fluoro-nitrobenzene (0.065 g, 0.373 mmol) and potassium carbonate (0.077 g, 0.559 mmol). The reaction mixture was heated to 50° C. and stirred for 18 h. Additional 4-chloro-2-fluoro-nitrobenzene (0.020 g, 0.114 mmol) was added, and the reaction was stirred at 50° C. for an additional 3 h. The reaction was cooled to rt and concentrated for purification on a 40 g silica gel column (0-100% EtOAc/hexanes, 25 min gradient; 40 mL/min elution; 254 nm detection) to afford the title compound (0.175 g, 100% yield). MS (m/z) 424.1 (M+H+).
Reaction SMILES: [OH:1]O.[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[N:9][CH:10]=1)[CH3:4].O>CC(O)=O>[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[N+:9]([O-:1])[CH:10]=1)[CH3:4]
Reactant: CCc1ccc(NC(=O)C(C)(C)C)nc1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: CCc1ccc(NC(=O)C(C)(C)C)[n+]([O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
H2O2 (30%, 34 mL, 0.33 mol) was added to a solution of N-(5-ethylpyridin-2-yl)pivalamide (22 g, 0.11 mol) in HOAc (200 mL). The mixture was stirred overnight at 80° C. The reaction mixture was poured into water and was extracted with EtOAc. The organics were washed with sat. Na2SO3 and NaHCO3 before being dried over MgSO4. The solvent was evaporated in vacuo to afford 5-ethyl-2-pivalamidopyridine 1-oxide (16 g, 67%), which was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH:22]=[CH:21][C:13]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[C:23]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])=[C:12]([NH:11][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(F)cc2F)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(F)cc2F)cc1NC(=O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
0.055 mL of triethylamine and 0.036 mL of 4-fluorobenzoyl chloride were added to 3.5 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-(2,4-difluorophenyl)benzoate at room temperature sequentially and stirred at the same temperature for 1 hour. 0.014 mL of triethylamine and 0.012 mL of 4-fluorobenzoyl chloride were added to the reaction mixture at room temperature sequentially and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane: ethyl acetate=4:1] to obtain tert-butyl 4-(2,4-difluorophenyl)-2-(4-fluorobenzamido)benzoate.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](O)=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[NH:3]1.B.C(OCC)(=O)C>O1CCCC1.O>[OH:14][CH2:13][C:11]1[CH:10]=[CH:9][C:8]2[C:2](=[O:1])[NH:3][C:4]3[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=3[S:6][C:7]=2[CH:12]=1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1NC2=O
Agent: B
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2Sc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolve 5.1 gm. of 10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepin-3-carboxylic acid in 100 cc. of tetrahydrofuran and add 35 cc. of 1 M borane in tetrahydrofuran at room temperature under a nitrogen atmosphere. Stir the mixture at room temperature for 3 hours. Slowly dilute the reaction mixture with water and then with ethyl acetate. Wash with aqueous sodium chloride, dry and evaporate to an oil.