Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O>[O:21]1[C:9]2([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:4]1
Reactant: O=C1CCCCCCCCCCC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: C1CCCCCC2(CCCCC1)CO2
Temperature: 25 °C

Procedure:
To a dry flask under nitrogen is added 3.1 g (64.6 mmol) of 50% sodium hydride in mineral oil. The sodium hydride is washed twice with hexanes, is suspended in 80 ml of dry dimethyl sulfoxide and then 14.3 g (65.0 mmol) of trimethylsulfoxonium iodide is added. The mixture is stirred at room temperature for several hours and then 11.8 g (64.7 mmol) of cyclododecanone is introduced. The mixture is allowed to stir overnight at room temperature and then is heated for 1 hour at 50° C. The mixture is cooled to room temperature, is dissolved in 500 ml of cold water and is extracted seven times with ethyl ether. The combined organic layers are washed once with water, dried over magnesium sulfate and subjected to evaporation in vacuo. The residue is chromatographed on silica gel using 20% ethyl acetate/hexanes as the mobile phase to give 10g (78%) of the title compound as a colorless oil: NMR (CDCl3) δ1.2-1.8 (m, 18H), 2.05 (s, 1H), 2.4 (t, 2H, J=5.0 Hz), 2.45 (d, 2H), 2.58 (s, 2H ).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:22])=[CH:17][C:16]=1[N+:32]([O-:34])=[O:33].C([O-])(=O)CC([O-])=O>CS(C)=O.O>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:22])[C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[CH:17][C:16]=1[N+:32]([O-:34])=[O:33])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc(Br)c([N+](=O)[O-])c1
Agent: O=C([O-])CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
NaH, 60% dispersion in mineral oil, (1.27 g, 31.7 mmol) was washed with petroleum ether then suspended in anhydrous DMSO (30 mL). Diethyl malonate (4.85 mL, 31.7 mmol) was dissolved in 8 mL of anhydrous DMSO and added dropwise to the NaH suspension. The mixture was allowed to stir for 15 min at 100° C., during which time the reaction mixture became homogeneous. (4-Bromo-3-nitro-phenyl)-(-4-nitro-phenyl)-methanone (5.15 g, 14.4 mmol) was dissolved in anhydrous DMSO (15 mL) and subsequently added via syringe to the malonate solution. The mixture was allowed to stir at 100° C. for 2 h after which the reaction was cooled to room temperature and poured into water (˜300 mL). The mixture was extracted with EtOAc (3×300 mL) and dried over anhydrous Na2SO4. The organic layers were then concentrated in vacuo affording a crude black oil. The crude oil was then flashed through a plug of silica with 30% EtOAc/Hexanes. The solution was then concentrated in vacuo yielding a pale yellow solid that contained the desired product contaminated with excess diethyl malonate. The impure solid was washed with Hexanes, filtered and dried affording diethyl [2-nitro-4-(4-nitrobenzoyl)phenyl]malonate in 75% yield (4.64 g, 10.8 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:25]5[C:26](Br)=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[O:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:25]5[C:26]([C:35]6[CH:36]=[CH:37][O:33][CH:34]=6)=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: OB(O)c1ccoc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5-c5ccoc5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-(2-bromo-pyridin-3-yl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and furan-3-boronic acid following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=1.04 min; Mass spectrum (ESI+): m/z=486 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6](=[O:22])[N:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:8]=1)(=O)[NH2:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([C:4]1[NH:5][C:6](=[O:22])[N:7]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:13][CH2:14]2)[CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(N)=O)[nH]c2=O)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C#N)[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
tert-Butyl 4-(4-carbamoyl-2-oxo-2,3-dihydroimidazol-1-yl)piperidine-1-carboxylate (175 mg, 0.564 mmol) was suspended in pyridine (3.0 mL). Phosphorus oxychloride (53 μL, 0.569 mmol) was added to the mixture drop-wise. Mixture stirred at ambient temperature for 30 minutes. Reaction was quenched with the drop-wise addition of water. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Material was washed successively with 1N hydrochloric acid brine and the aqueous phases were discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as white solid in 29% yield. MS (M−H)−=291.1.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([S:22][CH2:23][CH2:24][NH2:25])[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1.Cl[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C>>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([S:22][CH2:23][CH2:24][NH:25][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=2)[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1
Reactant: NCCSc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Reactant: N#Cc1ccc(Cl)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NCCSc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)nc1

Procedure:
6-[(2-{[7-(2,4-Dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl]thio}ethyl)amino]nicotinonitrile (Example 88) is prepared in analogy to Example 82 from Example 47A (200 mg, 0.4 mmol), 2-chloro-5-cyanopyridine (75 mg, 0.5 mmol) and N,N-diisopropylethylamine (0.8 ml, 4 mmol). 92 mg (47% of theory) of product are obtained as solid after purification by preparative RP-HPLC (gradient of eluent: water:acetonitrile 90:10 to 10:90).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:21][CH:22]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[NH:8][S:25]([CH3:24])(=[O:27])=[O:26]
Reactant: Nc1ccc(CCN2CCN(c3ccc(N)c(F)c3)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(CCN2CCN(c3ccc(NS(C)(=O)=O)c(F)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 334.1 %

Procedure:
1-(3-Fluoro-4-aminophenyl)-4-(4-aminophenethyl)piperazine (0.06 g) was dissolved in pyridine (4.5 ml) and methanesulphonyl chloride (0.13 g) was added. The mixture was stirred at room temperature overnight, the pyridine removed by evaporation, and the residue chromatographed over silica, developing and eluting with 10% methanol in dichloromethane. The fractions containing the product were evaporated to give a residue (0.30 g) which was crystallized from methanol, yielding the pure title compound, (0.016 g), m.p. 232°-4°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][OH:8])[S:5][CH:6]=1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:11]([O:8][CH2:7][C:4]1[S:5][CH:6]=[C:2]([Br:1])[CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: OCc1cc(Br)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: Brc1csc(COCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To (4-bromo-thiophen-2-yl)-methanol (18.8 g, 97.4 mmol, Intermediate (85)] in tetrahydrofuran (200 mL) was added sodium hydride (3.9 g, 97.4 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. Tetrabutylammonium iodide (3.6 g, 9.7 mmol) was added followed by benzyl bromide (11.6 mL, 97.4 mmol). The mixture was stirred at room temperature for 1 hour. Water was added. The resulting mixture was extracted with diethyl ether. The ether layer was dried over magnesium sulfate and concentrated. The residue was chromatographed through silica gel (n-heptane/ethyl acetate, 90/10 as eluant) to provide 2-benzyloxymethyl-4-bromo-thiophene [29.2 g, Intermediate (86)] (quantitative) as a yellow oil. LC/MS: 282.96 (M+H), RT=3.68 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:38]=[CH:37][S:36][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:33]=[CH:34][CH:35]=3)/[CH:21]=[CH:22]/[C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].Cl>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:38]=[CH:37][S:36][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:33]=[CH:34][CH:35]=3)/[CH:21]=[CH:22]/[C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(/C=C/c2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2nc(-c3cccc(/C=C/c4ccc(C(=O)O)cc4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a stirred solution of (E)-methyl 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)styryl)benzoate (90 mg, 0.17 mmol) in 3 mL of 1,4-dioxane and 3 mL of H2O was added NaOH (140 mg, 3.5 mmol) at room temperature. Then the reaction was stirred at room temperature overnight and then treated by conc. HCl until pH=3-4. The solvent was removed under reduce pressure the residue was purified by preparative HPLC to give (E)-4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)styryl)benzoic acid (33 mg, 38%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 12.95 (brs, 1H), 10.09 (s, 1H), 9.38 (s, 1H), 8.37-8.30 (m, 2H), 7.82-7.78 (m, 3H), 7.47-7.32 (m, 5H), 6.92-6.78 (m, 3H), 3.81 (s, 3H), 3.80 (s, 3H). LC-MS: 511 [M+H]+, 509 [M−H]−, tR=1.71 min. HPLC: 99.30% at 214 nm, 99.65 at 254 nm, tR=4.98 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13]([OH:15])=O)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:63][C@@H:64]1[C:67](=[O:68])[NH:66][C@@H:65]1[CH2:69][C:70]1[N:71]=[N:72][N:73]([CH2:75][CH2:76][NH:77][C:78](=[O:84])[O:79][C:80]([CH3:83])([CH3:82])[CH3:81])[CH:74]=1>C(Cl)Cl.CN(C=O)C>[C:80]([O:79][C:78]([NH:77][CH2:76][CH2:75][N:73]1[CH:74]=[C:70]([CH2:69][C@@H:65]2[C@H:64]([NH:63][C:13](=[O:15])/[C:12](=[N:11]\[O:10][C:7]([CH3:8])([CH3:9])[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:29])/[C:16]3[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=3)[C:67](=[O:68])[NH:66]2)[N:71]=[N:72]1)=[O:84])([CH3:83])([CH3:81])[CH3:82]
Reactant: CC(C)(C)OC(=O)NCCn1cc(C[C@H]2NC(=O)[C@H]2N)nn1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
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: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCn1cc(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)nn1

Procedure:
Prepared in analogous manner to example 82 step 7, using (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (18.55 mg, 0.043 mmol), HATU (17.7 mg, 0.047 mmol), DCM:DMF (1:3, 800 μl), DIPEA (18.86 μl, 0.108 mmol), tert-butyl (2-(4-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-1H-1,2,3-triazol-1-yl)ethyl)carbamate (11.17 mg, 0.036 mmol). 6.5 mg. LCMS: Rt=0.971 min, m/z=722.4 (M+1). Method 2m_acidic. 1H NMR (400 MHz, Methanol-d4) δ 7.82 (s, 1H), 7.32 (s, 1H), 5.34 (d, J=4.9 Hz, 1H), 4.43 (t, J=5.9 Hz, 3H), 4.19 (dt, J=9.3, 4.5 Hz, 1H), 4.09 (q, J=7.1 Hz, 1H), 3.54-3.45 (m, 3H), 3.13 (ddd, J=15.0, 11.8, 6.0 Hz, 2H), 2.93 (dd, J=15.2, 9.6 Hz, 1H), 2.01 (s, 2H), 1.53 (d, J=1.4 Hz, 14H), 1.49 (s, 7H), 1.46 (d, J=1.7 Hz, 15H), 1.38 (s, 14H), 1.23 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([N+:18]([O-:20])=[O:19])=[C:13](F)[C:12]=1[F:22]>>[F:22][C:12]1[C:11]([F:10])=[CH:16][C:15]([CH3:17])=[C:14]([N+:18]([O-:20])=[O:19])[C:13]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1]
Reactant: Nc1ccc(I)cc1F
Reactant: Cc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Product: Cc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]

Procedure:
2-Fluoro-4-iodoaniline and 1,2,3-trifluoro-5-methyl-4-nitrobenzene were reacted using the condition described in Example 1 (Step A) to form the title compound. M−H+: 407.9
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([CH2:13][OH:14])[CH:10]=[CH:11][CH:12]=2)=[N:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[CH:13]=[O:14])=[N:4][CH:3]=1
Reactant: Cc1cnc(-c2cccc(CO)c2)s1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1cnc(-c2cccc(C=O)c2)s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of (3-(5-methylthiazol-2-yl)phenyl)methanol (210 mg; 1.02 mmol) in anh. DCM (8 ml) was treated with MnO2 (1.334 g; 15.34 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 1.5 h. The resulting reaction mixture was then filtered over celite, and the separated solids were washed with DCM. The filtrate was concentrated to dryness under reduced pressure giving 3-(5-methylthiazol-2-yl)benzaldehyde as a colorless solid. LC-MS (conditions A): tR=0.72 min.; [M+H]+: 203.99 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[CH2:18]([CH2:20][NH2:21])[OH:19].C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)([OH:9])[CH2:10][NH:21][CH2:20][CH2:18][OH:19])=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CO2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: OCCNCC(O)(c1ccc(Cl)cc1)c1ccc(I)cc1
Yield: 99.9 %

Procedure:
A solution of 2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-oxirane (0.60 g, 1.68 mmol), ethanolamine (0.5 mL, 8.3 mmol) and triethylamine (0.5 mL, 3.6 mmol) in iso-propanol (5 mL) was maintained at 50° C. for 72 hours then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with saturated potassium carbonate solution/water (1:9). The aqueous phase was extracted a second time with ethyl acetate, then the combined extracts were washed with brine, dried (MgSO4), filtered and concentrated to give the title compound (701 mg, quantitative); LCMS (PS-A2) Rt 2.29 min [M+H]+ 418, [M−H2O+H]+ 400.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6](=[O:7])[CH2:5][CH2:4][CH:3]1[NH:8]C(=O)OCC1C=CC=CC=1>[Pd].CO>[NH2:8][CH:3]1[CH2:4][CH2:5][C:6](=[O:7])[C:2]1([CH3:19])[CH3:1]
Reactant: CC1(C)C(=O)CCC1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC1(C)C(=O)CCC1N
Reaction time: 2 h
Yield: 92.9 %

Procedure:
A mixture of benzyl 2,2-dimethyl-3-oxocyclopentylcarbamate (950 mg, 3.64 mmol, from Step 1) and 10% palladium on carbon (193 mg) in methanol (20 mL) was stirred under hydrogen (20 psi) for 2 h. After filtration to remove the catalyst, the filtrate was concentrated to give crude 3-amino-2,2-dimethylcyclopentanone (430 mg), which was used in the next reaction without purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]2[S:16][CH:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[C:4]=2[O:3]1.[Br:22]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Br:22][C:17]1[S:16][C:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:8][CH:2]([CH3:1])[O:3][C:4]=2[C:18]=1[CH:19]([CH3:21])[CH3:20]
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(C(C)C)c2O1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CC1CN(C(=O)OC(C)(C)C)Cc2sc(Br)c(C(C)C)c2O1
Yield: 83.3 %

Procedure:
A solution of tert-butyl 2-methyl-8-(1-methylethyl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (763 mg) obtained in Example 10, steps 1 and 2, N-bromosuccinimide (458 mg) and acetonitrile (6 mL) was stirred at room temperature for 2 hr, 10% aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 3→7% ethyl acetate/hexane) to give the title compound (797 mg, 83%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:10][O:11][C:12]([NH:14][C:15](=NC(OC)=O)SC)=[O:13]>CO.C(O)(=O)C>[CH3:10][O:11][C:12](=[O:13])[NH:14][C:15]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccc(O)cc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Nc1nc2cc(O)ccc2[nH]1
Yield: 109.7 %

Procedure:
6 g of 3,4-diaminophenol were combined with 9.8 g of 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea in 50 ml methanol and 30 ml acetic acid. The reaction mixture was refluxed for 4 hours. Solvents were then evaporated under reduce pressure yielding 10.8 g crude (5-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid methyl ester. The residue was subjected to flash chromatography eluting with a mixture of dichloromethane-methanol (9:1; v/v) to give 5.6 g of a beige solid. Mass spectrum: 208 [M+H]+, retention time=0.56 minute.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:32][CH2:31][C:30]([OH:34])([CH3:33])[CH2:29][CH2:28]4)=[O:26])=[CH:21][N:20]=3)[C:15](=[O:35])[N:14]([CH3:36])[N:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:37]1[N:46]=[CH:45][C:44]2[C:39](=[C:40]([F:51])[CH:41]=[C:42]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:43]=2)[C:38]1=[O:52])(=O)C.[Li+].[OH-]>O1CCOCC1>[C:47]([C:42]1[CH:43]=[C:44]2[C:39](=[C:40]([F:51])[CH:41]=1)[C:38](=[O:52])[N:37]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([N:27]5[CH2:28][CH2:29][C:30]([OH:34])([CH3:33])[CH2:31][CH2:32]5)=[O:26])=[CH:21][N:20]=4)[C:15](=[O:35])[N:14]([CH3:36])[N:13]=3)[C:6]=1[CH2:5][OH:4])[N:46]=[CH:45]2)([CH3:48])([CH3:49])[CH3:50]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCC(C)(O)CC4)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(=O)N3CCC(C)(O)CC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 13.7 %

Procedure:
In a 250 mL round-bottomed flask, 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(4-hydroxy-4-methylpiperidine-1-carbonyl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (62 mg, 87.4 μmol) was combined with dioxane (5 ml) and 1M LiOH (1 ml) to give a brown solution. The reaction mixture was stirred at 25° C. for 5 h. The crude reaction mixture was concentrated in vacuo and partitioned between DCM and water. The aqueous layer was back-extracted with DCM (2×25 mL). The organic layers were combined, washed with sat NaCl (1×10 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 8% MeOH in DCM), isolated as an off-white powder and dried under vacuum for 3 hrs at 25° C. The material was repurified by flash chromatography (silica gel, 24 g, 0% to 4% MeOH in DCM) to afford 0.008 g (14%) of the title compound as a white solid. (M+H)+=668 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.69 (s, 1H), 8.39-8.47 (m, 2H), 8.29 (d, J=2.3 Hz, 1H), 7.75 (dd, J=8.5, 2.1 Hz, 1H), 7.43-7.70 (m, 5H), 6.99 (d, J=8.7 Hz, 1H), 4.43 (br. s., 2H), 3.91 (s, 3H), 3.20-3.87 (m, 4H), 1.65 (br. s., 6H) 1.43 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[CH3:18])=[N:7][N:6]=[CH:5]2.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[CH3:18])=[N:7][N:6]=[CH:5]4)[CH:25]=2)[CH2:20][CH2:21]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: C[C@H]1CCCCN1c1nncc2cc(Cl)ccc12
Agent: [Pd]
Agent: Cc1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCCC[C@@H]3C)nncc2c1
Temperature: 80 °C

Procedure:
A mixture of (S)-6-chloro-1-(2-methylpiperidin-1-yl)phthalazine (0.200 g, 0.76 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.474 g, 1.6 mmol), potassium carbonate (0.340 g, 2.5 mmol), 2-(dicyclohexylphosphino)-2′-methylbiphenyl (0.054 g, 0.15 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.045 g, 0.049 mmol) in 5 mL 80% aqueous degassed dioxane was heated at 80° C. for 15 h. The reaction was cooled to RT and partitioned between ethyl acetate/brine. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic layers were concentrated onto silica gel and purified flash chromatography eluting with 2 M NH3 in MeOH:CH2Cl2 (0:1→1:24) to give a brown oil. The material was further purified by reverse-phase HPLC (Prodigy 5u ODS(3), 100A, 250×21.2) with 0.1% formic acid/H2O:0.1% formic acid/CH3CN (3:7→7:3) to give a white amorphous solid. Found MS m/z: 401.2 [M+1].
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[CH:18]=[C:17]([C:19]([OH:21])=O)[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH2:29]([NH2:31])[CH3:30]>>[CH2:29]([NH:31][C:19]([C:17]1[S:16][C:14]2[N:15]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)[N:11]=[C:12]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:13]=2[CH:18]=1)=[O:21])[CH3:30]
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Reactant: CCN
Agent: Cl
Product: CCNC(=O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid 14 was coupled to ethylamine HCl via General Procedure B. The product was purified via reverse phase HPLC to give 31.8 mg of 129. MS (Q1) 409.2 (M)+.