Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=O)[CH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][NH:18]2.[OH-].[K+]>C(O)COCCO>[NH:18]1[C:19]2[C:15](=[C:14]([CH2:13][CH2:12][CH2:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[OH:4])[CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: O=C(CCc1cccc2[nH]ccc12)c1ccccc1O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Oc1ccccc1CCCc1cccc2[nH]ccc12
Temperature: 140 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
22.6 ml of hydrazine hydrate and then 11.6 g of 1-(2-hydroxyphenyl)-3-(1H-indol-4-yl)-1-propanone were slowly added with stirring to 50 ml of diethyleneglycol and then 20 ml of 78% potassium hydroxide were added thereto. The mixture was heated at 140° C. under an inert atmosphere for 30 minutes and the water and excess hydrazine hydrate were distilled at 210° C. with stirring over two hours and the mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried, filtered and evaporated to dryness. The residue was chromatographed over silica and eluted with methylene chloride to obtain 8.613 g of 2-[3-(1H-indol-4-yl)-propyl]-phenol melting at ≅89° C.
Reaction SMILES: [NH2:1]N.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C1C=CC=C2C(NC(=O)C=12)=O>CO>[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:1]
Reactant: CN1CCNCC1CCCCCCc1cccc2c1C(=O)NC2=O
Reactant: NN
Solvent: CO
Product: CN1CCNCC1CCCCCCN

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 6-(N-methylpiperazinyl)hexylphthalimide (263 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1>CC(O)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:17]=2[CH:18]=1)=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3
Reactant: COc1ccc(Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc2[nH]c3ccc([N+](=O)[O-])cc3c2c1
Temperature: 100 °C
Yield: 63.9 %

Procedure:
To 4-methoxy-N-(4-nitrophenyl)aniline (785 mg, 3.2 mmol) in 5 mL of AcOH was added Pd(OAc)2 (1.43 g, 6.4 mmol). The mixture was heated at 100° C. for 15 h under air atmosphere and cooled to rt and concentrated under reduced pressure. The residue was taken up in EtOAc (100 mL) and washed with NaHCO3 (2×100 mL) and water (100 mL). After solvent removal, the crude was purified with chromatography (hexane/EtOAc) to afford 3-methoxy-6-nitro-9H-carbazole as a orange solid (495 mg, 64%). 1H NMR (400 MHz, acetone-d6) δ 10.90 (s, 1H), 9.09 (d, J=2.4 Hz, 1H), 8.27 (dd, J=9.2, 2.4 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.62 (d, J=9.2 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.14 (dd, J=8.8, 2.8 Hz, 1H), 3.92 (s, 3H); MS (ESI) m/z 243 (M+H+).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][CH2:6][C:5]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[N:15][CH:16]=2)([C:8]([OH:10])=O)[CH2:4][CH2:3]1.Cl.[CH3:20][NH:21][O:22][CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:18][C:2]1([F:1])[CH2:3][CH2:4][C:5]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[N:15][CH:16]=2)([C:8]([N:21]([O:22][CH3:23])[CH3:20])=[O:10])[CH2:6][CH2:7]1
Reactant: CNOC
Reactant: Cc1ncc(C2(C(=O)O)CCC(F)(F)CC2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1(c2cnc(C)nc2)CCC(F)(F)CC1
Yield: 27.1 %

Procedure:
A solution of 4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexanecarboxylic acid (1.2 g, 4.68 mmol), N,O-dimethylhydroxylamine hydrochloride (456 mg, 4.68 mmol), HOBt (759.33 mg, 5.62 mmol), EDCI.HCl (1.08 g, 5.62 mmol) and DIPEA (3.23 mL, 18.73 mmol) in DMF (20 mL) was stirred at room temperature. The reaction mixture was added water and extracted with EtOAc (3×50 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give 4,4-difluoro-N-methoxy-N-methyl-1-(2-methylpyrimidin-5-yl)cyclohexanecarboxamide (380 mg), which was used for the next step directly. About 0.9 g of 4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexanecarboxylic acid was recycled.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]([OH:20])[CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:21]([C:23]([OH:30])([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])#[CH:22]>>[F:16][C:15]([F:18])([F:17])[C:14]([NH:13][CH2:12][CH2:11][CH:10]([OH:20])[C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([C:22]#[C:21][C:23]([OH:30])([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH:3]=1)=[O:19]
Reactant: C#CC(O)(CCC)CCC
Reactant: COc1ccc(C(O)CCNC(=O)C(F)(F)F)cc1Br
Product: CCCC(O)(C#Cc1cc(C(O)CCNC(=O)C(F)(F)F)ccc1OC)CCC

Procedure:
N-(3-(3-bromo-4-methoxyphenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide was coupled with 4-ethynylheptan-4-ol to give 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)-4-methoxyphenyl)propyl)acetamide as a yellow oil. Yield (0.92 g, 55%): 1H NMR (400 MHz, DMSO-d6) δ 9.31 (t, J=5.0 Hz, 1H), 7.24-7.21 (m, 2H), 6.95 (d, J=9.2 Hz, 1H), 5.25 (d, J=4.8 Hz, 1H), 5.05 (s, 1H), 4.51-4.47 (m, 1H), 3.75 (s, 3H), 3.24-3.17 (m, 2H), 1.77-1.72 (m, 2H), 1.61-1.42 (m, 8H), 0.89 (t, J=7.0 Hz, 6H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[CH2:7]([N:14]([CH2:16][CH2:17]Cl)[CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+]>CCO>[CH2:7]([N:14]([CH2:16][CH2:17][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: CN(CCCl)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(CCn1ccnc1)Cc1ccccc1
Yield: 34.6 %

Procedure:
A solution of imidazole (2.32 g, 34.1 mmol), the title compound of Step 10 (5.0 g, 22.7 mmol) and NaHCO3 (6.58 g, 78.3 mmol) in anhydrous EtOH (40 mL) was refluxed overnight in a modification of the procedure of Bach et al, [J. Am. Chem. Soc., 79, 2221-2225 (1957)]. After filtration, the filtrate was concentrated to a yellow oil. The oil was dissolved into a 1.0M KOH solution (10 mL) and was extracted with EtOAc (3×5 mL). The organic layer was washed with a 5% NaHCO3, solution (5 mL), H2O (5 mL), and brine (5 mL) and then was dried over MgSO4. The filtrate was concentrated and purified by medium pressure column chromatography on silica gel [eluting with NH4OH-EtOH-CHCI3 (1:4: 94)] to give the title compound as an oil (1.69 g, 30% yield). The proton spectral data were consistent with the proposed structure.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13]CC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:16][S:17][C:18]1[N:19]=[CH:20][C:21]2[C:26](=O)[O:25]C(=O)[N:23]([CH:29]([CH3:31])[CH3:30])[C:22]=2[N:32]=1.Cl>O>[CH2:10]([O:9][C:7]([C:6]1[C:5](=[O:13])[N:23]([CH:29]([CH3:30])[CH3:31])[C:22]2[N:32]=[C:18]([S:17][CH3:16])[N:19]=[CH:20][C:21]=2[C:26]=1[OH:25])=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CSc1ncc2c(=O)oc(=O)n(C(C)C)c2n1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1c(O)c2cnc(SC)nc2n(C(C)C)c1=O

Procedure:
To a solution of sodium ethoxide (0.9 g. 0.039 g. atom of sodium in 75 ml. of ethanol) was added 6.24 g. (0.03 mole) of diethyl malonate. The ethanol was removed in a rotary evaporator. To the residue was added 100 ml. of dimethyl formamide followed by 3.3 g. (0.013 mole) of 7-methylthio-1-isopropyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione. The reaction mixture was heated under reflux for 1 hour, cooled in ice and poured into 400 ml. of water. The solution was acidified with conc. hydrochloric acid and the resulting product was collected by suction filtration. Recrystallization from ethanol gave 2 g. of product--m.p. 138°-140° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][NH:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.C[C:13]1[C:21]2[C:20](N)=[N:19][CH:18]=N[C:16]=2[O:15][CH:14]=1.Cl.[CH:24](O)(C)[CH3:25]>>[CH3:16][O:15][C:14]1[CH:13]=[CH:21][C:20]([N:19]([CH3:18])[C:2]2[C:3]3[CH:11]=[CH:10][NH:9][C:4]=3[N:5]=[C:6]([CH3:8])[N:7]=2)=[CH:25][CH:24]=1
Reactant: CC(C)O
Reactant: Cc1coc2ncnc(N)c12
Reactant: Cc1nc(Cl)c2cc[nH]c2n1
Agent: Cl
Product: COc1ccc(N(C)c2nc(C)nc3[nH]ccc23)cc1
Reaction time: 6 h
Yield: 80 %

Procedure:
Compound 4 (0.005 mol, 0.835 g) was added to a solution of 4-methoxy-N-methylaniline (5, 0.006 mol, 0.822 g) in i-propanol (10 ml) with drops of conc. HCl. The resulting solution was transferred to a microwave vial (20 ml) and irradiated at 110° C. After 6 h, the reaction was completed and AAG20 was obtained after the chromatographic purification as a white solid (1.01 g) with 80% yield. TLC Rf=0.85 (CH3OH:CHCl3=1:5). 1H NMR (DMSO-d6): δ 2.65 (s, 3H, 2-CH3), 3.62 (s, 3H, N—CH3), 3.84 (s, 3H, OCH3), 6.99 (bs, 4H, C6H4), 7.11-7.13 (d, 1H, 5-H), 7.39-7.41 (d, 1H, 6-H), 12.44 (s, 1H, 7-H, D2O exchanged). Anal. Calcd. (C15H16N4O. 0.3688 CHCl3.), C, 59.10; H, 5.28; N, 17.94; Found C, 58.98; H, 5.65; N, 18.16.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:49]1[CH2:54][CH2:53][S:52](=[O:56])(=[O:55])[CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:49]3[CH2:54][CH2:53][S:52](=[O:56])(=[O:55])[CH2:51][CH2:50]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S1(=O)CCNCC1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Yield: 58 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), thiomorpholine 1,1-dioxide (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product as a light yellow solid (58%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O1CCCC1.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH2:26]([O:25][C:23]([N:6]1[CH:7]=[CH:8][C:3](=[O:2])[CH2:4][CH:5]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccncc1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: O=C1C=CN(C(=O)OCc2ccccc2)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 40 ml of tetrahydrofuran was dissolved 5.46 g of 4-methoxypyridine, and added dropwise thereto was 55 ml of a 1M phenylmagnesiumbromide-tetrahydrofuran solution under nitrogen atmosphere at −60° C. of below. Subsequently, added dropwise thereto was a solution of 10.24 g of benzyl chloroformate in 50 ml of tetrahydrofuran, and the mixture was stirred for 3 hours. The temperature of the mixture was raised to room temperature, and 120 ml of a 5% aqueous citric acid solution was added thereto. The mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried and concentrated. To the residue was added diisopropyl ether and the precipitates were collected by filtration, to give 8.51 g of 1-benzyloxycarbonyl-4-oxo-2-phenyl-3,4-dihydro-2H-pyridine.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.O>C1C=CC=CC=1.N1C=CC=CC=1>[C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C1CCNC1
Reactant: CCCCCC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCC(=O)N1CCCC1
Yield: 79.9 %

Procedure:
Hexanoyl chloride (13.46 g, 0.1M) was added gradually to a cooled, stirred solution of pyrrolidine (7,25 g, 0.1M) in 200 ml of benzene and dry pyridine (7.91 g, 0.1M). Two hours after the addition water was added. The organic layer was washed successively with 5% aqueous hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Distillation of the residue gave 13.52 g (80%) of a colorless oil, b.p. 98-100/7 mm.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]1[S:35][CH:36]=[C:37]([C:39](O)=[O:40])[N:38]=1>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:39]([C:37]2[N:38]=[C:34]([C:28]3[C:27]([F:26])=[CH:32][CH:31]=[CH:30][C:29]=3[F:33])[S:35][CH:36]=2)=[O:40])[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Product: Cn1ncc(NC(=O)c2csc(-c3c(F)cccc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (see US2012/225061) gave 321. 1H NMR (400 MHz, DMSO-d6) δ 9.94-9.85 (m, 1H), 8.63 (d, J=1.2 Hz, 1H), 7.81 (d, J=1.1 Hz, 1H), 7.69-7.60 (m, 1H), 7.33 (t, J=8.7 Hz, 2H), 4.81 (dd, J=10.9, 3.5 Hz, 1H), 4.44-4.24 (m, 1H), 4.23-4.10 (m, 1H), 3.99 (ddd, J=37.2, 14.8, 3.5 Hz, 1H), 3.77 (s, 3H), 2.11-2.02 (m, 1H), 1.90-1.76 (m, 1H), 1.75-1.63 (m, 2H). LCMS (ES+) m/z 452 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][CH3:14])[C@H:9]1[C:15](=[O:17])[NH2:16])=O)(C)(C)C.CO.[ClH:20]>>[ClH:20].[CH3:14][O:13][C@H:10]1[CH2:11][CH2:12][NH:8][C@@H:9]1[C:15]([NH2:16])=[O:17]
Reactant: CO[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(N)=O
Agent: Cl
Solvent: CO
Product: CO[C@H]1CCN[C@@H]1C(N)=O
Yield: 38 %

Procedure:
(2S,3S)-2-Carbamoyl-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, 0.49 mmol) was stirred in hydrochloric acid (5 mL, 3M in methanol) and methanol for 4 h. The reaction mixture was concentrated in vacuo and the residue triturated in diethyl ether and methanol to give (2S,3S)-3-Methoxy-pyrrolidine-2-carboxylic acid amide hydrochloride salt as a white solid (69 mg, 38%). 1H NMR 400 MHz (DMSO-d6) δ: 8.28 (1H, br, s), 7.82 (1H, br, s), 4.23 (1H, m), 4.11-4.10 (1H, m), 3.37 (1H, m), 3.35 (3H, s), 3.19-3.16 (1H, m), 2.07 (1H, m), 1.84-1.83 (1H, m)
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[CH3:15][O:16][CH2:17][CH2:18]Br>CO>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:18][CH2:17][O:16][CH3:15])[CH2:5][CH2:4]1)=[O:2]
Reactant: COCCBr
Reactant: O=CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COCCN1CCN(C=O)CC1
Temperature: 25 °C
Yield: 102.2 %

Procedure:
To a solution of 37.1 g of N-formylpiperazine and 37.1 g of anhydrous sodium carbonate in 50 mL of methanol was added dropwise 53.15 g of methoxyethyl bromide, and the mixture was refluxed for 3.5 hours. After cooling to room temperature, insolubles were filtered out and the filtrate was concentrated. To the residue was added water and chloroform. After separating the organic layer, the aqueous layer was extracted with chloroform. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated to give 57.2 g of the title compound.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([CH3:18])=[N:9][C:10]([N:13]=CN(C)C)=[N:11][CH:12]=1)=O.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH2:31])=[NH:30])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]2[N:31]=[C:5]([C:7]3[C:8]([CH3:18])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=3)[CH:4]=[CH:3][N:30]=2)=[CH:26][CH:27]=1
Reactant: Cc1nc(N=CN(C)C)ncc1C(=O)/C=C/N(C)C
Reactant: N=C(N)Nc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N)ncc1-c1ccnc(Nc2ccc(F)cc2)n1
Yield: 80 %

Procedure:
A solution of N′-{5-[(2E)-3-(dimethylamino)prop-2-enoyl]-4-methylpyrimidin-2-yl}-N,N-dimethylimidoformamide (27) (50 mg, 0.191 mmol), 1-(4-fluorophenyl)guanidine hydrochloride (102 mg, 0.383 mmol), and K2CO3 (106 mg, 0.765 mmol) in DMF (1018 μl) was heated at 120° C. for 2 d. The crude product was filtered through a syringe filter, then the crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] to obtain ˜80% pure desired product. The product was taken up in 10% MeOH/DCM, then was purified by Biotage™ silica gel chromatography [10 g SNAP column, 2-10% MeOH/DCM] and further purified by trituration with acetone and acetonitrile to obtain the desired product as a pale yellow solid (10.23 mg, 18% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.47 (s, 3 H) 6.93 (s, 2 H) 7.02 (d, J=5.05 Hz, 1 H) 7.12 (t, J=8.84 Hz, 2 H) 7.77 (dd, J=9.35, 4.80 Hz, 2 H) 8.44 (s, 1 H) 8.46 (d, J=5.05 Hz, 1 H) 9.61 (s, 1 H). HRMS (ES+) for C15H13FN6.H+ [MH+]: calcd, 297.1264. found, 297.1274. UV-LC: 98.95/100% UV purity at 214/254 nm; tR=4.30 minutes over 7.75 minutes.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:31]([C:30]4[CH:34]=[CH:35][CH:36]=[C:28]([O:27][CH3:26])[CH:29]=4)=[O:32])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1cccc(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 3-methoxybenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA to yield the title compound.
Reaction SMILES: C([S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)(=O)C.[N:13]([CH2:16][C@@H:17]([O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:18]O)=[N+:14]=[N-:15]>>[N:13]([CH2:16][C@@H:17]([O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:18][S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)=[N+:14]=[N-:15]
Reactant: CC(=O)Sc1ncn2ccsc12
Reactant: CC[Si](CC)(CC)O[C@@H](CO)CN=[N+]=[N-]
Product: CC[Si](CC)(CC)O[C@H](CN=[N+]=[N-])CSc1ncn2ccsc12
Yield: 85.2 %

Procedure:
The procedure of Synthesis Example 11b) was repeated, except that 907 mg of 7-acetylthioimidazo[5,1-b]thiazole and 1.27 g of (2R)-3-azido-2-triethylsilyloxy-1-propanol was used as the starting compound. Thus, 1.44 g of 7-((2R)-3-azido-2-triethylsilyloxypropyl)thioimidazo[5,1-b]thiazole was prepared.
Reaction SMILES: I/[CH:2]=[CH:3]/[C@@H:4]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C([Li])(C)(C)C.C(N([CH2:29][C:30]1[C:31](=[O:43])[CH2:32][C@@H:33]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH:34]=1)CC)C.CCCCCC>CCOCC>[CH2:29]=[C:30]1[C@@H:34](/[CH:2]=[CH:3]/[C@@H:4]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[C@H:33]([O:35][Si:36]([C:39]([CH3:41])([CH3:40])[CH3:42])([CH3:37])[CH3:38])[CH2:32][C:31]1=[O:43]
Reactant: CC(C)(C)[Si](C)(C)O[C@H](/C=C/I)C1CCCCC1
Reactant: CCN(CC)CC1=C[C@H](O[Si](C)(C)C(C)(C)C)CC1=O
Agent: [Li]C(C)(C)C
Solvent: CCCCCC
Solvent: CCOCC
Product: C=C1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1/C=C/[C@@H](O[Si](C)(C)C(C)(C)C)C1CCCCC1
Temperature: 0 °C

Procedure:
(1E,3S)-1-Iodo-3-(tert-butyldimethylsiloxy)-3-cyclohexyl-1-propene (2.66 g) was dissolved in ether (28 ml), tert-butyl lithium (1.7 M, pentane solution, 8.24 ml) was added at −78° C. After stirring at the same temperature for an hour, lithium 2-thienylcyanocuprate (0.25 M, tetrahydrofuran solution, 39.2 ml) was added, followed by stirring at the same temperature for 20 minutes, and (4R)-2-(N,N-diethylamino)methyl-4-(tert-butyldimethylsiloxy)cyclopent-2-en-1-one (0.25 M, ether solution, 28 ml) was added. The temperature was raised to 0° C. with stirring over 1.5 hours. To the reaction solution were added hexane (70 ml) and a saturated aqueous ammonium chloride solution (105 ml) and, after extraction with hexane, the extract was washed with a saturated aqueous sodium chloride solution, dried, concentrated and purified by a silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=30:1) to give (3R, 4R)-2-methylene-3-[(1E,3S)-3-(tert-butyldimethylsiloxy)-3-cyclohexyl-1-propenyl]-4-(tert-butyldimethylsiloxy)cyclopentan-1-one (910 mg).
Reaction SMILES: Br[C:2]1S[C:5]([C:7]([NH:9][CH:10]([C:12]2[N:17]=[N:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:14][CH:13]=2)[CH3:11])=[O:8])=[CH:4][CH:3]=1.N[CH:28]([C:30]1N=NC(NC2C=CC(OC)=CC=2)=NC=1)[CH3:29].C1(CC(O)=O)CCCCC1>>[CH:4]1([CH2:5][C:7]([NH:9][CH:10]([C:12]2[N:17]=[N:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:14][CH:13]=2)[CH3:11])=[O:8])[CH2:30][CH2:28][CH2:29][CH2:2][CH2:3]1
Reactant: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccc(Br)s3)nn2)cc1
Agent: O=C(O)CC1CCCCC1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)CC3CCCCC3)nn2)cc1
Reaction time: 4 h

Procedure:
In a similar manner as described for Intermediate 48, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and cyclohexylacetic acid (64 mg, 0.45 mmol), except that the reaction was stirred for 4 h and the crude reaction mixture reduced under vacuum, partitioned between dichloromethane and saturated sodium bicarbonate solution and the layers separated. The aqueous was re-extracted with dichloromethane and the combined organic layers washed with brine, dried with magnesium sulfate, filtered and reduced to give 2-cyclohexyl-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]acetamide (100 mg) as a yellow solid. MS m/z 370 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:24])(=[N:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH:26]1([NH:25][C:4]2[C:3]([C:1]3[N:32]=[N:33][NH:34][N:2]=3)=[CH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:24])(=[N:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:17])=[CH:12][CH:11]=3)[N:5]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(C#N)c(NC3CCCCC3)n2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3nn[nH]n3)c(NC3CCCCC3)n2)cc1
Yield: 53 %

Procedure:
In accordance with procedure 10, 990 mg (2.24 mmol) (RS)—S-(4-{[5-cyano-4-(cyclohexylamino)pyrimidine-2-yl]amino}phenyl)-N-(ethoxycarbonyl)-S-methyl-sulfoximide, 291 mg (4.47 mmol) sodium azide and 263 mg (4.92 mmol) ammonium chloride in 19 ml DMF are stirred for 24 hours at 120° C. After cooling, the mixture is added dropwise to 200 ml. A gel-like precipitate is filtered off at the pump and then washed with water. After drying, the product is obtained in 53% yield (571 mg).