Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([N:28]3[CH2:27][CH2:26][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29]3)=[O:15])[C:9]2=[O:17])=[CH:19][CH:20]=1
Reactant: O=C(O)CN1CCC(c2ccc(Cl)cc2)(c2ccc(Cl)cc2)C1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CN2CCC(c3ccc(Cl)cc3)(c3ccc(Cl)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 25D (0.8 g, 2.2 mmol) in CH2Cl2 (30 mL) was added tert-butyl piperazine-1-carboxylate (0.41 g, 2.2 mmol) under nitrogen. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.84 g, 4.4 mmol) and 4-(dimethylamino)pyridine (0.027 g, 0.22 mmol) were added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then washed with water and brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography on silica gel (Analogix Intelliflash 280; (CH3OH/CH2Cl2, 2:98 eluant) to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[C:11]([F:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].[OH-:21].[K+].[CH2:23]([OH:25])C>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][C:23]([OH:25])=[O:21])=[C:11]([F:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCO
Reactant: Fc1cc(OCc2ccccc2)ccc1CBr
Agent: [C-]#N
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccc(OCc2ccccc2)cc1F
Temperature: 70 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
A solution of 4-benzyloxy-2-fluoro-benzyl bromide (Compound 10, 18 g, 58 mmol) in a mixture of ethanol (90 mL) and water (10 mL) was treated with sodium cyanide (4.25 g, 86,8 mmol) and the resulting reaction mixture was heated at 70° C. for 1 h. Potassium hydroxide (6.5 g, 115.7 mmol) was then added and heating was continued for another 5 h. The volatiles were evaporated in vacuo, the residue was diluted with water and neutralized with hydrochloric acid and the precipitated solid was filtered, washed with water and dried to afford the title product as a yellow solid (13 g, 81%).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[CH:11]=[C:10](Cl)[N:9]=[CH:8][N:7]=1)=[O:5].[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]2[NH:25][C:24](=[O:26])[N:23]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH2:22][CH2:21][C:20]=2[CH:33]=1.CCN(C(C)C)C(C)C>C1COCC1.O>[CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[CH:11]=[C:10]([N:30]2[CH2:29][CH2:28][CH:27]([N:23]3[CH2:22][CH2:21][C:20]4[CH:33]=[C:16]([O:15][CH3:14])[CH:17]=[CH:18][C:19]=4[NH:25][C:24]3=[O:26])[CH2:32][CH2:31]2)[N:9]=[CH:8][N:7]=1)=[O:5]
Reactant: CON(C)C(=O)c1cc(Cl)ncn1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N(C)OC)ncn3)CC1)C(=O)N2

Procedure:
0.20 g (0.99 mmol) 6-chloro-pyrimidine-4-carboxylic acidmethoxy-methyl-amide, 0.28 g 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 0.20 mL (1.16 mmol) DIPEA in 1.5 mL THF were heated to 120° C. in the microwave for 30 min. The mixture was diluted with water and extracted with DCM. The combined organic phases were dried on sodium sulphate, filtered and evaporated down i. vac. The residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:13][N:14]=[C:15]=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>O1CCOCC1.O>[CH3:12][O:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:13]([NH:14][CH3:15])=[N:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc(N)c1C(=O)O
Reactant: CN=C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CNc1nc2cccc(OC)c2c(=O)o1
Temperature: 80 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
A mixture of 2-amino-6-methoxybenzoic acid (2.00 g, 12.0 mmol) and methylisocyanate (1.00 g, 17.5 mmol) in dioxane (50 ml) was stirred at 80° C. for 2 h. After cooling to room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.88 g, 36.0 mmol) and triethylamine (5.00 ml, 36.0 mmol) were added. The mixture was stirred at room temperature for 16 h, diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with 20% ethyl acetate/n-hexane to afford 1.06 g (43%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]3)[C:6]=2[CH:28]=1.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:7]2[C:6]3[CH:28]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(F)cc32)CC1
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: NC1CCN(CCN2C(=O)COc3ccc(F)cc32)CC1

Procedure:
tert-Butyl {1-[2-(6-fluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 55) (640 mg, 1.56 mmol) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield).
Reaction SMILES: CC(C)(C(=O)[N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][N:9]([C:14]1[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=1)[CH2:10]2)C#N.C(N(CC)CC)C.[C:32]([CH2:34][CH2:35][N:36]([CH3:41])[S:37](Cl)(=[O:39])=[O:38])#[N:33]>C1COCC1>[C:32]([CH2:34][CH2:35][N:36]([CH3:41])[S:37]([N:6]1[CH2:7][CH2:8][N:9]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][C:11]21[CH2:12][CH2:13]2)(=[O:39])=[O:38])#[N:33]
Reactant: CC(C)(C#N)C(=O)N1C2CCC1CN(c1ncnc3[nH]ccc13)C2
Reactant: CN(CCC#N)S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CCC#N)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reaction time: 16 h

Procedure:
Intermediate 2 (0.05 mmol) was dissolved in THF (1.0 mL). Triethylamine (0.12 mmol) and 2-cyanoethyl(methyl)sulfamoyl chloride (0.06 mmol) was added. The reaction mixture was left at it for 16 hours. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:17]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:16][C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])=[N:14]2)[CH:8]=1)C.[Li+].[OH-]>CO>[C:28]([C:15]1[CH:16]=[C:17]([NH:18][C:19](=[O:27])[C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[N:13]([C:9]2[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:32])=[O:3])[CH:12]=[CH:11][CH:10]=2)[N:14]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)c2ccc(Cl)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)c2ccc(Cl)cc2)n(-c2cccc(CCC(=O)O)c2)n1
Yield: 90.4 %

Procedure:
A solution of Example 158 (45 mg, 0.1 mmol) arid 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was neutralized to pH=4, and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine, and dried (NaSO4) and filtered. The filtrate was concentrated to afford 3-{3-[3-t-butyl-5-(4-chloro-benzoylamino)-pyrazol-1-yl]-phenyl}-propionic acid, (38.5 mg, 87%). 1H NMR (DMSO-d6): 10.38 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.39 (s, 1H), 7.32 (d, J=4.8 Hz, 2H), 7.15 (t, J=4.8 Hz, 1H), 6.38 (s, 1H), 2.80 (t, J=7.6 Hz, 2H), 2.44 (t, J=7.2 Hz, 2H), 1.29 (s, 9H); MS (ESI) m/z: 426 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH2:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH:10][C:4](=[O:5])[CH2:3][O:2][CH3:1]
Reactant: COCC(=O)Cl
Reactant: Cc1cccc(C)c1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1c(C)cccc1C
Yield: 56.9 %

Procedure:
55 g (0.5 mol) of methoxyacetyl chloride were added dropwise to a solution of 61 g (0.5 mol) of 2,6-dimethylaniline and 50.5 g (0.5 mol) of triethylamine in 250 ml of toluene at 5° to 15° C., while stirring and cooling. The mixture was subsequently stirred at 20° C. for 2 hours, filtered and concentrated and the residue was taken up in water. The aqueous mixture was extracted with methylene chloride and the extract was dried over sodium sulphate and concentrated by distilling off the solvent. The residue was distilled under a high vacuum. 55 g (57% of theory) of 2,6-dimethyl-N-methoxyacetyl-aniline of boiling point 122°-132° C./0.1 mm Hg and of melting point 61°-63° C. were obtained. ##STR177##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC#N>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][PH:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[Br-:12]
Reactant: COC(=O)CCCCCCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COC(=O)CCCCCCCC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 91 %

Procedure:
A solution of 13 (1.02 g, 4.06 mmol, 10 equiv) in CH3CN (3.5 mL 1.16M) was treated with triphenylphosphine (1.17 g, 4.47 mmol, 1.1 equiv) and stirred at reflux for 10 h. Additional triphenylphosphine (0.532 g, 2.03 mmol, 0.5 equiv) was added to the reaction mixture and stirring was continued at reflux for 5 h. The reaction mixture was concentrated under reduced pressure and washed repeatedly with Et2O (5×10 mL washes). The remaining residue was then solubilized in the minimum volume of CH2Cl2 and concentrated under reduced pressure to afford 14 as a colorless foam (1.90 g, 2.08 g theoretical, 91.3%): 1H NMR (CDCl3, 250 MHz) δ7.82-7.51 (m, 15H, ArH), 3.70-3.46 (m, 5H, CH3OC(O)R and CH2PPh3), 2.13 (t, 2H, J=7.4 Hz, CH2C(O)OCH3), 1.62-1.02 (m, 12H, alkyl protons); FABHRMS (NBA) m/e 433.2312 (C28H34BrO2P--Br- requires 433.2296).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[N:6][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:18]3[CH:19]=[CH:20][C:21]([S:24][CH3:25])=[CH:22][CH:23]=3)[CH:10]=[C:11]([C:13]([F:15])([F:14])[F:16])[N:12]=2)=[N:6][CH:7]=1
Reactant: CSc1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(C)cn2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(C)cn2)cc1

Procedure:
A mixture of the dihydro-imidazole of step 3 (3. 95 g, 13.9 mmol) and p-toluenesulfonic acid monohydrate (785 mg, 4 mmol) in toluene (500 ml) was heated to reflux for 4–5 hours. The reaction mixture was cooled and 10 ml of triethylamine was added and the solvent removed-under reduced pressure. The crude mixture was purified by chromatography on silica gel using ethyl acetate to give the desired product which was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH2:5]([O:7][C:8]([C:10]1[C:15]([CH2:16][Br:17])=[N:14][CH:13]=[CH:12][N:11]=1)=[O:9])[CH3:6]>O1CCCC1>[BrH:17].[CH2:5]([O:7][C:8]([C:10]1[C:15]([CH2:16][S:3][C:2](=[NH:4])[NH2:1])=[N:14][CH:13]=[CH:12][N:11]=1)=[O:9])[CH3:6]
Reactant: NC(N)=S
Reactant: CCOC(=O)c1nccnc1CBr
Solvent: C1CCOC1
Product: Br
Product: CCOC(=O)c1nccnc1CSC(=N)N
Temperature: 120 °C
Yield: 84.1 %

Procedure:
A suspension of thiourea (620 mg) and 3-bromomethyl-pyrazine-2-carboxylic acid ethyl ester (2 g) in tetrahydrofuran was heated in the microwave at 120° C. for 5 minutes. The product formed an oil so the tetrahydrofuran was simply decanted to leave 3-carbamimidoylsulfanylmethyl-pyrazine-2-carboxylic acid ethyl ester hydrobromide (2.2 g) as an oil. MH+=241, RT=0.26 min (Method A).
Reaction SMILES: [Cl:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:23])[C:9]=1[N:10]2C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:23])[C:9]=1[NH:10]2
Reactant: CC(C)(C)OC(=O)n1c2c(c3c(Cl)c(F)ccc31)CCCC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCCc2c1[nH]c1ccc(F)c(Cl)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.5 %

Procedure:
To tert-butyl 5-chloro-6-fluoro-1-oxo-3,4-dihydro-1H-carbazole-9(2H)-carboxylate (0.4 g, 1.1 mmol) in DCM (10 mL), cooled to 0° C., was added TFA (1 mL). The reaction mixture was stirred at room temperature for 4 h, quenched with saturated NaHCO3 (pH-8) and then extracted with DCM (4×40 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude compound which was washed with hexane (2×5 mL) to provide the title compound (0.20 g, 71%). 1H NMR (200 MHz, DMSO-d6, δ in ppm) 12.04 (bs, 1H), 7.41-7.26 (m, 2H), 3.33 (t, J=6.0 Hz, 2H), 2.60 (t, J=5.8 Hz, 2H), 2.22-2.13 (m, 2H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=O)[CH2:2][C:3]#[CH:4].[CH3:13][C:14]1([CH3:37])[O:19][C:18]2[CH:20]=[CH:21][C:22]([C@@H:24]([OH:36])[CH2:25][NH:26][C@@H:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][OH:29])=[CH:23][C:17]=2[CH2:16][O:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:26]([C@@H:27]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:28][OH:29])[CH2:25][C@@H:24]([C:22]1[CH:21]=[CH:20][C:18]2[O:19][C:14]([CH3:13])([CH3:37])[O:15][CH2:16][C:17]=2[CH:23]=1)[OH:36])[CH2:2][C:3]#[CH:4]
Reactant: CC1(C)OCc2cc([C@@H](O)CN[C@H](CO)c3ccccc3)ccc2O1
Reactant: C#CCCOCCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: C#CCCOCCCCCCN(C[C@H](O)c1ccc2c(c1)COC(C)(C)O2)[C@H](CO)c1ccccc1
Reaction time: 48 h
Yield: 79 %

Procedure:
A mixture of 6-(but-3-ynyloxy)hexanal (434 mg) and (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}ethanol (710 mg) (WO/0196278) in chloroform (10 ml) was treated at 20° C. with sodium triacetoxyborohydride (866 mg) and stirred under nitrogen for 2 days. The mixture was diluted with ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was separated and washed with sodium bicarbonate solution, brine, dried and purified on a silica Bond Elut cartridge (10 g) eluting with dichloromethane, diethyl ether and finally ethyl acetate to give the title compound (810 mg): LCMS RT=2.69 min, ES+ve m/z 496 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:31][CH2:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Reactant: COc1ccc(CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CNc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a suspension of 8A (300 mg, 0.920 mmol) in NMP (2 mL) was added (4-methoxyphenyl)methanamine (0.120 mL, 0.920 mmol) and DIEA (0.161 mL, 0.920 mmol). The reaction mixture was stirred at 80° C. for 1 h, and then cooled to room temperature. Water was added. The light yellow solid was collected by filtration, rinsed with water and dried under vacuum to give 19A (348 mg, 89%). [M+H]=426. HPLC Peak Rt=3.000 minutes. (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 254 nm.)
Reaction SMILES: [OH-].[K+].[C:3]([O:7][OH:8])([CH3:6])([CH3:5])[CH3:4].[CH2:9](Cl)/[CH:10]=[C:11](/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])\[CH3:12]>S1(CCCC1)(=O)=O>[C:3]([O:7][O:8][CH2:9]/[CH:10]=[C:11](/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])\[CH3:12])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OO
Reactant: CC(C)=CCC/C(C)=C/CCl
Agent: [K+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Product: CC(C)=CCC/C(C)=C/COOC(C)(C)C
Temperature: 10 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
Sulpholane (40 cc) and potassium hydroxide pellets (6.5 g) are introduced into a 250-cc three-necked round-bottomed flask. After cooling to 10° C., a 70% strength aqueous solution of tert-butyl hydroperoxide (12.9 g) is added dropwise. The temperature is maintained at 20° C. for two hours and geranyl chloride (17.2 g, 0.1 mole) is then added dropwise at a temperature of between 10° and 20° C. The solution is kept at 20° C. for 16 hours. After extraction with pentane and purification of the product obtained by flash chromatography, geranyl tert-butyl peroxide (12 g) is obtained, and its structure is confirmed by the infrared spectrum, the mass spectrum and the proton nuclear magnetic resonance spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C([O-])([O-])=O.[Cs+].[Cs+].C(O)(C)C>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[C:18]([O:19][CH3:20])[CH:17]=2)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(-c2cc(Cl)nc(SC)n2)cc1OC
Temperature: 100 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
Argon is bubbled through a mixture of 4,6-dichloro-2-(methylthio)pyrimidine [4.98 g, 25.55 mmol, Intermediate (29)], 3,4-dimethoxyphenylboronic acid [3.874 g, 21.29 mmol, Intermediate (32)], and Cs2CO3 (17.34 g, 53.23 mmol) in ethylene glycol dimethyl ether (56 mL) and water (14 mL), for a period of 15 minutes. To this mixture is added tetrakis(triphenylphosphine)palladium (0) (1.22 g, 1.06 mmol) the reaction vessel is heated to 100° C. After stirring overnight the mixture is diluted with water (250 mL) and extracted three times with EtOAc (100 mL). The organic extracts are combined, washed with brine (100 mL), and dried over magnesium sulfate. The mixture is filtered and concentrated to provide a solid that is dissolved in boiling isopropyl alcohol (40 mL) and allowed to cool to ambient temperature. After standing for 24 hours the solid is collected by filtration, washed with cold isopropyl alcohol and dried under high vacuum to afford 4-chloro-6-(3,4-dimethoxy-phenyl)-2-methylsulfanyl-pyrimidine [5.28 g, 83.5%, Intermediate (48)].
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[C:25](Cl)(Cl)=[S:26].[NH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][C:34]([N:43]([CH3:45])[CH3:44])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:17])[CH:5]([NH:6][C:25]([NH:29][CH2:30][CH:31]1[CH2:32][CH2:33][C:34]([N:43]([CH3:45])[CH3:44])([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:35][CH2:36]1)=[S:26])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Reactant: S=C(Cl)Cl
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C(Cc1c[nH]c2ccccc12)NC(=S)NCC1CCC(c2ccccc2)(N(C)C)CC1
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Tryptophan methyl ester hydrochloride (382 mg, 1.5 mmole) was dissolved in dry chloroform (15 ml) and combined with triethylamine (633 μl, 4.5 mmole). The mixture was cooled to −5° C. Thiophosgene (115 μl, 1.5 mmole) dissolved in chloroform (10 ml) was then added dropwise, resulting in the formation of a precipitate. After 18 h stirring at RT, the reaction mixture was clear. (4-Aminomethyl-1-phenyl-cyclohexyl)-dimethylamine (348.55 mg, 1.5 mmole), dissolved in chloroform (10 ml), was added at RT. After a reaction time of 48 h, the batch was washed with saturated NaHCO3 solution (3×5 ml) and water (5 ml). The organic phase was dried with Na2SO4 and evaporated. The product was a mixture of two diastereoisomers. These were purified and separated by column chromatography [silica gel 60 (100 g); eluent: MeOH/EE 1:4 (1500 ml) and MeOH/EE 1:1 (500 ml)]. The more nonpolar diastereoisomer of 2-[3-(4-dimethylamino-4-phenylcyclohexylmethyl)thioureido]-3-(1H-indol-3-yl)propionic acid methyl ester (193 mg, m.p. 178-183° C., 26%) and also the more polar diastereoisomer of 2-[3-(4-dimethylamino-4-phenylcyclohexyl-methyl)thioureido]-3-(1H-indol-3-yl)propionic acid methyl ester (157 mg, m.p. 228-234° C., 21%) were light yellow solids.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[CH3:16][C:17]1[N:22]=[C:21]([OH:23])[CH:20]=[CH:19][CH:18]=1.C[O:25][C:26](=[O:35])[CH:27](Br)[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([CH2:28][CH:27]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:23][C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:16])[N:22]=3)[CH:6]=[N:5]2)[C:26]([OH:25])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Cc1cccc(O)n1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: Cc1cccc(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)n1

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 6-methyl-pyridin-2-ol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(6-methyl-pyridin-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (9.7 g, 66% for the final step); LC-MS: tR=3.28 min, 344 [M+H]+. HPLC: tR=9.16 min, 95.62% at 214 nm, 96.87% at 254 nm. 1H NMR (300 MHz, DMSO-d6): δ13.04 (broad, 1H), 8.07 (d, 1H, J=2.4 Hz), 7.89 (t, 1H, J=7.5 Hz), 7.21 (d, 1H, J=7.2 Hz), 7.06 (d, 1H, J=8.4 Hz), 6.52 (d, 1H, J=2.4 Hz), 5.36 (dd, 1H, J=10.5 Hz, J=4.2 Hz), 2.43 (s, 3H), 2.23-2.17 (m, 1H), 2.02-2.00 (m, 1H), 1.70-1.44 (m, 7H), 1.13-1.05 (m, 2H).