Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]5)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.C(Cl)CCl.[NH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][CH:29]([C:32]([N:42]6[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]6)=[O:33])[CH2:28][CH2:27]5)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: C1CNCCN1
Reactant: O=C(O)C1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(C1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.9 %

Procedure:
A mixture of crude 1-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}-piperidine-4-carboxylic acid (75 mg, 0.15 mmole), EDC (72 mg, 0.376 mmole), and DMAP (37 mg, 0.3 mmole) in dry DCM (1 mL) was stirred at RT for 0.5 hr. Piperazine (104 mg, 1.2 mmole) was added and, after 64 hr, the reaction was diluted with DCM, washed with water and dried (Na2SO4). Removal of solvent followed by radial chromatography (1 mm silica gel plate, gradient elution with DCM containing 1 to 5% MeOH) afforded the title compound as a solid (11 mg, 13%). 1H NMR (CDCl3) δ 1.67-1.80 (m, 4H), 1.96-2.09 (m, 2H), 2.15-2.18 (m, 1H), 2.58-2.65 (m, 1H), 2.82-2.86 (m, 4H), 3.17-3.20 (m, 2H), 3.43-3.48 (m, 2H), 3.57-3.62 (m, 2H), 3.77 (s, 2H), 5.57 (s, 2H), 6.48 (d, 1H, J=2.5 Hz), 6.83-6.88 (m, 1H), 6.90-6.97 (m, 2H), 7.21-7.29 (m, 1H), 7.36-7.39 (m, 1H), 7.44 (d, 1H, J=2.7 Hz), 7.55-7.58 (m, 1H), 7.89 (s, 1H), 8.08 (s, 1H), 8.18 (d, 1H, J=1.5 Hz), 11.87 (br, 1H). MS: 568.67 (M+H+); HPLC Ret Time: 1.03 min (Gradient Time=2 min, Flow Rate=5 ml/min, Xterra 3.0×50 mm S7 C18 column).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1([CH3:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[F:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19]([NH:21][NH2:22])=O.Cl.C(N(CC)CC)C>CC1C=CC(C)=CC=1>[Cl:1][C:2]1[C:7]([C:8]2([CH3:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:5]2[N:4]([C:19]([C:18]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:17]=3[F:16])=[N:21][N:22]=2)[N:3]=1
Reactant: NNC(=O)c1ccc(F)cc1F
Reactant: CC1(c2cc(Cl)nnc2Cl)CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccc(C)cc1
Product: CC1(c2cc3nnc(-c4ccc(F)cc4F)n3nc2Cl)CCCCC1
Yield: 38.7 %

Procedure:
A mixture of 3,6-dichloro-4-(1-methylcyclohexyl)pyridazine (1.29 g, 5.27 mmol), 2,4-difluorobenzoic hydrazide (1.72 g, 10 mmol) and triethylamine hydrochloride (1.09 g, 7.9 mmol) in p-xylene (5 ml) was stirred and heated at reflux for 24 hours. Upon cooling, the volatiles were removed in vacuo and the residue was partitioned between dichloromethane (100 ml) and water (100 ml) and NaHCO3 (100 ml). Undissolved solid was removed by filtration. The layers were separated and the aqueous was further extracted with dichloromethane (2×100 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica eluting with 0%→25% ethyl acetate in dichloromethane to give the required product (0.74 g): 1H NMR (250 MHz, CDCl3) δ 1.34-1.74 (6H, m), 1.50 (3H, s), 1.90-2.15 (4H, m), 7.01-7.14 (2H, m), 7.87-7.98 (1H, m), 8.18 (1H, s); MS (ES+) m/e 365 [MH], 363 [MH]+.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[CH:18][C:19]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O.CO>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccc(-c4cccnc4)nc3Nc3ccc(OC)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc(Nc2nc(-c3cccnc3)ccc2-c2nc(C)nc(N)n2)cn1
Yield: 10.2 %

Procedure:
A solution of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-N-(6-methoxypyridin-3-yl)-2,3′-bipyridin-6-amine (276 mg, 0.440 mmol) in TFA (10 mL) was heated to 75° C. for 15 h. about 80% of the TFA was removed in vacuo and the crude oily residue was pipetted into an ice cooled solution of NaHCO3. The resulting suspension was collected by filtration and was washed with water and MeOH. The solid was then dry-packed on silica gel and purified on the ISCO (12 g column, 1-25% MeOH in DCM) to give partially purified product. This was suspended in MeOH and filtered, and the filtercake was dry-packed with silica gel and purified on the ISCO (12 g column, 3-15% MeOH in DCM) to give 5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-N-(6-methoxypyridin-3-yl)-2,3′-bipyridin-6-amine (17.2 mg, 0.045 mmol, 10.11% yield) as a brown amorphous solid. m/z (ESI, +ve ion) 387.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.86 (1H, s); 9.26 (1H, d, J=2.0 Hz); 8.88 (1H, d, J=8.0 Hz); 8.66 (2H, d, J=2.9 Hz); 8.41 (1H, dt, J=8.1, 1.8 Hz); 8.21 (1H, dd, J=8.9, 2.6 Hz); 7.89 (1H, br. s.); 7.74 (1H, br. s.); 7.58 (1H, d, J=8.0 Hz); 7.52-7.56 (1H, m); 6.90 (1H, d, J=9.0 Hz); 3.87 (3H, s); 2.45 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[NH:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:33]([C:29]3[CH:28]=[C:27]4[C:32](=[CH:31][CH:30]=3)[NH:24][CH:25]=[CH:26]4)=[O:34])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccc2[nH]ccc2c1

Procedure:
According to the general method of Example 50, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and indole-5-carboxylic acid were combined to provide N5-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-5-indolecarboxamide as an off white solid. 1H NMR (300 MHz, DMSO-d6) δ11.31 (s, 1H), 8.34 (t, J=5.5 Hz, 1H), 8.06 (m, 2H), 7.63-7.58 (m, 2H), 7.42-7.38 (m, 3H), 7.22 (t, J=7.1 Hz, 1H), 6.67 (broad s, 2H), 6.50 (s, 1H), 4.58 (m, 2H), 3.81 (t, J=6.6 Hz, 2H), 3.34 (m, 2H), 3.25 (s, 3H), 3.21 (t, J=6.6 Hz, 2H), 1.89 (m, 2H), 1.72 (m,2H); MS (EI) m/e 456.2264 (456.2274 calcd for C26H28N6O2).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]#[C:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19].F[B-](F)(F)F.[N:29]1(OC(N(C)C)=[N+](C)C)[C:33]2[CH:34]=[CH:35][CH:36]=CC=2N=N1.NCC1CC1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH:34]1([CH2:33][NH:29][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][CH:23]=[C:15]([C:14]#[C:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])[CH:16]=2)[CH2:36][CH2:35]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1onc(-c2ccccc2)c1C#Cc1cccc(C(=O)O)c1
Agent: F[B-](F)(F)F
Agent: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1C#Cc1cccc(C(=O)NCC2CC2)c1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 86.9 %

Procedure:
To a solution of 3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid (250 mg; 0.82 mmol) in N,N-dimethylformamide (4.8 mL) was added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (318 mg, 0.99 mmol) at 0° C. After stirring for 15 min at this temperature, aminomethylcyclopropane (86 μl, 0.99 mmol) and N-ethyldiisopropylamine (0.85 mL, 4.94 mmol) were added and the reaction mixture was allowed to warm to ambient temperature. After 1.75 h stirring at ambient temperature, it was extracted with dichloromethane (300 mL) and aqueous sodium carbonate (2 M, 75 mL). The combined organic layers were washed with brine (75 mL), dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 0:100) afforded the title compound (254 mg, 87%) as a white solid. MS: m/e=357.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:15])[CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[C:16](O)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].CCN=C=NCCCN(C)C>CC#N.CCOC(C)=O>[OH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([NH:1][CH2:2][CH2:3][N:4]([CH3:15])[CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:24]
Reactant: O=C(O)c1ccccc1O
Reactant: CN(CCN)CCNC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(CCNC(=O)OC(C)(C)C)CCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
tert-Butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate (500 mg, 2.3 mmol) was taken up in 10 mL of CH3CN along with salicylic acid (310 mg, 2.3 mmol) and EDCI (485 mg, 2.53 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and then diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (95% CH2Cl2, 5% MeOH) to afford 380 mg of tert-butyl 2-((2-(2-hydroxybenzamido)ethyl)(methyl)amino)ethylcarbamate (49% yield). MS (EI) calcd for C17H27N3O4: 337.2. found: 338 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([NH2:18])=[O:17])[S:15][C:8]=23)=[CH:4][CH:3]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:24][N:23]=1>C(O)(C)(C)C>[C:32]1([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22]([NH:1][C:2]3[CH:20]=[CH:19][C:5]([O:6][C:7]4[CH:12]=[CH:11][N:10]=[C:9]5[CH:13]=[C:14]([C:16]([NH2:18])=[O:17])[S:15][C:8]=45)=[CH:4][CH:3]=3)=[N:23][N:24]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: NC(=O)c1cc2nccc(Oc3ccc(N)cc3)c2s1
Solvent: CC(C)(C)O
Product: NC(=O)c1cc2nccc(Oc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)c2s1

Procedure:
A 5 ml microwave tube was charged with 7-(4-aminophenoxy)thieno[3,2-b]pyridine-2-carboxamide (85 mg, 0.300 mmol) and 1-chloro-4-phenylphthalazine (60 mg, 0.250 mmol) in 2.0 ml of tert-butanol. The vessel was capped and irradiated at 140° C. for 15 minutes in the microwave. Analysis of an aliquot of the crude mixture by LCMS showed remaining starting material and approximately 20% conversion to desired product. Irradiated at 150° C. for an additional 20 minutes, at which time reaction was deemed complete by LCMS analysis. Cooled to ambient temperature and diluted reaction mixture with methanol. Filtered solids, washed with additional methanol and concentrated in vacuo to afford 7-(4-(4-phenylphthalazin-1-ylamino)phenoxy)thieno[3,2-b]pyridine-2-carboxamide. MS m/z=490 [M+H]+. Calc'd for C28H19N5O2S: 489.55.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O-:12])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14].[K+].CN(C=O)C.Br[CH2:22][CH2:23][CH2:24][CH2:25][O:26][N+:27]([O-:29])=[O:28]>C(Cl)Cl>[N+:27]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][O:11][C:10](=[O:12])/[CH:9]=[CH:8]/[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:13][CH3:14])[CH:4]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])OCCCCBr
Reactant: COc1cc(/C=C/C(=O)[O-])ccc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(/C=C/C(=O)OCCCCO[N+](=O)[O-])ccc1O
Temperature: 40 °C
Yield: 70 %

Procedure:
A mixture of potassium (E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoate (2.07 g; 9 mmol), obtained in the previous step, DMF (8.3 g), KI (0.5 g) and a 20% w/w solution (82.5 g) of 4-bromobutylnitrate (16.5 g; 16.7 mmol) in CH2Cl2 is heated under stirring to 40° C. and kept at this temperature under stirring for 136 h. After work up, (E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid 4-(nitrooxy)butyl ester was obtained in 70% yield.
Reaction SMILES: [CH3:1][C@@:2]1([N:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[N+:21]([O-])=O)[N:12]=[C:11]2[CH3:24])[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9]>C(OCC)(=O)C.CO.[Pd]>[NH2:21][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:19](=[O:20])[N:10]([C@:2]1([CH3:1])[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9])[C:11]([CH3:24])=[N:12]2
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1[C@]1(C)CCC(=O)NC1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc2cccc(N)c2c(=O)n1[C@]1(C)CCC(=O)NC1=O
Yield: 44 %

Procedure:
A mixture of (R)-3-methyl-3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (0.40 g, 1.2 mmol) and 10% Pd—C (0.2 g, 50% wet), in 200 mL of 3:1 ethyl acetate-methanol was shaken under 50 psi H2 for 3 hours. The mixture was filtered through Celite, and the solvent was evaporated. The residue was chromatographed on silica gel using a dichloromethane-acetonitrile gradient, providing (R)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-3-methylpiperidine-2,6-dione as an off-white solid (0.16 g 44% yield): HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 1.62 (98.71%); mp 295-297° C.; 1H NMR (DMSO-d6) δ 1.88 (s, 3H, CH3), 2.31-2.36 (m, 1H, CHH), 2.53-2.59 (m, 2H, 2CHH), 2.62 (s, 3H, CH3), 2.71-2.84 (m, 1H, CHH), 6.53-6.56 (m, 2H, Ar), 6.95 (br, 2H, NH2), 7.35 (t, J=8 Hz, 1H, Ar), 10.72 (s, 1H, NH); 13C NMR (DMSO-d6) δ 24.5, 26.3, 28.3, 29.0, 62.2, 104.2, 110.5, 110.8, 135.0, 147.4, 150.4, 152.9, 164.9, 171.5, 173.0; Anal. Calcd for C15H16N4O3: C, 59.99; H, 5.37; N, 18.66. Found: C, 59.73; H, 5.26; N, 18.69.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1.Br[CH2:11][C:12](=O)[CH:13]([CH3:15])[CH3:14].C(=O)([O-])O.[Na+]>C(O)C>[CH:13]([C:12]1[N:9]=[C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]2[CH:11]=1)([CH3:15])[CH3:14]
Reactant: COc1cccnc1N
Reactant: CC(C)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cccn2cc(C(C)C)nc12
Temperature: 110 °C
Reaction time: 13 h
Yield: 49 %

Procedure:
[step 1] Commercially available 3-methoxypyridin-2-amine (1.0 g, 8.06 mmol) was dissolved in ethanol (8.1 mL), 1-bromo-3-methylbutan-2-one (Organic Syntheses, 1976, vol. 55, p 24; 1.46 g, 8.86 mmol) was added, and the mixture was stirred at 110° C. for 13 hr. To the mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 v/v-30/70 v/v) to give 2-isopropyl-8-methoxyimidazo[1,2-a]pyridine (746 mg, 49%).
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:53])([CH3:52])[C:29]([F:51])([F:50])[C@:30]([C:33]3[CH:38]=[C:37]([C:39]4[S:40][C:41]5[CH:47]=[C:46]([Cl:48])[CH:45]=[CH:44][C:42]=5[N:43]=4)[CH:36]=[CH:35][C:34]=3[F:49])([CH3:32])[N:31]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.FC(F)(F)C(O)=O.Cl>C(OCC)C>[ClH:48].[Cl:48][C:46]1[CH:45]=[CH:44][C:42]2[N:43]=[C:39]([C:37]3[CH:36]=[CH:35][C:34]([F:49])=[C:33]([C@:30]4([CH3:32])[C:29]([F:50])([F:51])[C:28]([CH3:53])([CH3:52])[O:27][CH2:26][C:25]([NH2:24])=[N:31]4)[CH:38]=3)[S:40][C:41]=2[CH:47]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4nc5ccc(Cl)cc5s4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OCC(N)=N[C@](C)(c2cc(-c3nc4ccc(Cl)cc4s3)ccc2F)C1(F)F
Yield: 104.9 %

Procedure:
Deprotection of [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(6-chloro-benzothiazol-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (26 mg, 35 μmol) with trifluoroacetic acid (27 μl, 349 μmol), treatment with hydrochloric acid and followed by trituration with diethyl ether yielded the (R)-5-[5-(6-Chloro-benzothiazol-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine hydrochloride (9 mg, 53% yield) as a white solid. MS (ISP): m/z=454.1 [M+H]+ and 456.1 [M+2+H]+.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[O:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=3)=[N:3][CH:4]=[CH:5][N:6]=2)[CH2:9][CH2:10]1
Reactant: Fc1nccnc1C1CCOCC1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2nccnc2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottomed flask was added 2-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyrazine (1.1147 g, 6.12 mmol), 4-aminophenol (0.801 g, 7.34 mmol), and cesium carbonate (5.98 g, 18.35 mmol) in DMSO (20.39 mL) in DMSO at 110° C. to stir overnight. The reaction was allowed to cool to room temperature. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with 50% sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% MeOH in DCM, to provide 4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)aniline. [M+H]=272.1.
Reaction SMILES: N1[C:8]([Cl:9])=NC(Cl)=NC=1Cl.C(Cl)Cl.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([CH2:20]CO)=[CH:18][CH:17]=1)([O-:15])=[O:14]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[Cl:9][CH2:8][CH2:20][C:19]1[CH:23]=[CH:24][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCCl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of cyanuric chloride (1.83 g) in DMF (2 mL) was stirred at RT for 1 h. To the resulting white suspension was added DCM (25 mL) followed by 4-nitrophenethyl alcohol (1.59 g). The reaction mixture was stirred at RT for 4 h and diluted with 1M Na2CO3. The phases were separated, the org. layer was washed with 1M HCl and brine and evaporated in vacuo to afford 1.4 g of orange slurry. 1H-NMR (CDCl3): 8.22 (m, 2H); 7.43 (m, 2H); 3.79 (t, 2H, 7.0 Hz); 3.20 (t, 2H, 6.8 Hz).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]#[N:17])=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C(N(CC)CC)C>C(O)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16](=[N:20][OH:21])[NH2:17])=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#N)sc1C(=O)NCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(C(N)=NO)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of N-benzyl-2-cyano-4-methylthiazole-5-carboxamide (0.15 g, 0.58 mmol) and hydroxylamine hydrochloride (0.09 g, 1.28 mmol) in ethanol (7 mL) was added triethylamine (0.2 mL, 1.43 mmol). The reaction mixture was heated to reflux for 3 hour, cooled to ambient temperature and concentrated in vacuo. The solid was washed with water and dried to afford the title compound in 70% yield (0.12 g): 1H NMR (300 MHz, CDCl3) δ 7.43-7.18 (m, 5H), 6.42 (br s, 1H), 5.74 (br s, 2H), 4.54 (d, J=5.3 Hz, 2H), 2.63 (s, 3H); MS (ES+) m/z 291.1 (M+1).
Reaction SMILES: [O:1]=[C:2]([C:6]1[N:14]2[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3](Cl)=[O:4].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=3)[CH2:31][CH2:30]2)[CH:23]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:3](=[O:4])[C:2](=[O:1])[C:6]4[N:14]5[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]5)=[CH:8][C:7]=4[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:37][CH:36]=3)[CH2:31][CH2:30]2)[CH:23]=1
Reactant: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2n1CCCC2
Reactant: Cc1cc(C)nc(N2CCN(c3ccc(N)cc3)CC2)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(N2CCN(c3ccc(NC(=O)C(=O)c4c(-c5ccccc5)cc5n4CCCC5)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
Oxo-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetyl chloride (prepared as described in Reference Example 21, 40 g, 0.14 mol) was added portion-wise to a solution of 4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine (prepared as described in Reference Example 94, 18 g, 63.8 mmol) in pyridine (150 mL). The reaction mass was stirred for 1 hour then quenched slowly into cold water (3 L). The precipitated solid was filtered and washed with water (3×50 mL). The solid was dissolved in chloroform (200 mL) and washed successively with bicarbonate solution (3×200 mL) and brine (200 mL). The chloroform layer was separated, diluted with chloroform (800 mL), and to this was added neutral alumina (150 g) and charcoal (5 g). The mixture was stirred for 2 hours at room temperature then filtered through celite. The treatment was repeated with another 75 g of neutral alumina with over night stirring. Filtration and concentration gave a solid which was dissolved in toluene (500 mL) and extracted with 25% aqueous acetic acid solution (3×500 mL). The combined aqueous layers were basified with 25% ammonium hydroxide solution (2 L) to pH ˜7 and extracted with diethyl ether (2×300 mL). The combined ether extracts were washed with bicarbonate solution (2×200 mL), brine (200 mL), dried over sodium sulfate and concentrated in vacuo to give a solid. This was further purified by passing through a short silica pad (60-120 silica gel) eluting with 30% ethyl acetate in chloroform. After concentration, the solid was dissolved at reflux in ethanol (300 mL). The solution was cooled to 0° C., and stirred for 15 minutes, whereupon the precipitated solid was filtered and dried on the sinter. Further drying at 60° C. under high vacuum afforded the title compound N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetamide (10.4 g, 30.5%) as a yellow powder.