Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=4)[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[CH:66][C:65]=1[O:74][CH3:75]>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)=[O:31])=[C:65]([O:74][CH3:75])[CH:66]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2ccc(F)c(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2ccc(F)c(Cl)c2)c(OC)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-4-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 82 (0.4 g, 0.69 mmol) was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with methyl 4-amino-3-methoxybenzoate (Ark Pharm) (0.19 g, 1.07 mmol) to give rac-4-{[(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-4-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-benzoic acid methyl ester as a white solid (Yield, 0.22 g, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([OH:16])=O)=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[O:16])=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:5]=2[CH:4]=1
Reactant: COC(=O)CCCCN
Reactant: COc1ccc2sc(C(=O)O)c(OC(C)C)c2c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCNC(=O)c1sc2ccc(OC)cc2c1OC(C)C
Temperature: 0 °C
Yield: 69.8 %

Procedure:
A solution of 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid (500 mg, 2.00 mmoles) and 1,1'-carbonyldiimidazole (421 mg, 2.60 mmoles) in 20 mL of tetrahydrofuran is heated at reflux for 1 hour. After cooling to 0° C., the HCl salt of methyl 5-aminovalerate (787 mg, 4.7 mmoles) is added followed by triethylamine (836 μL, 6.0 mmoles). The mixture is heated at reflux overnight. The mixture is partitioned between ethyl acetate and 1N HCl. The organic layer is washed with 1N HCl, saturated NaHCO3, then brine. The organic layer is next dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography, eluting with 1:9 ethyl acetate:hexane to provide 530 mg (70%) of product; mp 82°-84° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:12]2)C1C=CC=CC=1>CCO.C1COCC1.[Pd]>[CH3:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[CH:12]=[C:13]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cn1c(C=Cc2ccccc2)cc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1c(CCc2ccccc2)cc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.8 %

Procedure:
To a solution of 5-(benzyloxy)-1-methyl-2-(2-phenylethenyl)-1H-indole (204 mg, 0.601 mmol) in EtOH (5 ml) and THF (5 ml) was added 10% palladium on carbon (50 mg). The resulting mixture was stirred under hydrogen (2 atm) for 15 h at room temperature. The mixture was filtered through Celite and washed with EtOH. The filtrate was concentrated in vacuo and then the residue was purified by silica gel (4.5 g) chromatography eluted with chloroform to give 1-methyl-2-(2-phenylethyl)-1H-indol-5-ol (110 mg, 72.8%).
Reaction SMILES: [CH2:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)[CH2:2][CH3:3].[Li]CCCC.[CH3:14][Sn:15](Cl)([CH3:17])[CH3:16]>C1COCC1>[CH2:1]([C:4]1[S:5][C:6]([Sn:15]([CH3:17])([CH3:16])[CH3:14])=[CH:7][CH:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1cccs1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1ccc([Sn](C)(C)C)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
2-propylthiophene (5.0 g, 39.6 mmol) was dissolved in 160 ml THF and n-BuLi (27 ml, 1.6 M in hexanes, 43.6 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 1 h and then cooled down to −78° C. A solution of trimethyltin chloride (8.679 g, 43.6 mmol) in 50 ml THF was added dropwise. The mixture was allowed to warm slowly to room temperature and stirred for 2 h. After quenching with ice water and aqueous work-up, the product was obtained as a light brown liquid (10.1348 g, 88.6% yield).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1[C:40]1[C:45]2[CH2:46][CH2:47][O:48][C:44]=2[C:43]([Cl:49])=[C:42]([CH2:50][O:51][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:49][C:43]1[C:44]2[O:48][CH2:47][CH2:46][C:45]=2[C:40]([C@H:10]2[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:11]2)=[CH:41][C:42]=1[CH2:50][OH:51]
Reactant: CC(C)(C)[Si](OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c(c1Cl)OCC2)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c(c1Cl)OCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of compound 65 (1.80 g, 1.9 mmol) in THF (9.5 mL) was added dropwise tetra-n-butylammonium fluoride (1.0 M in THF, 4.75 mL, 4.75 mmol) at 0° C. After being stirred for 2 hours at room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 66 (1.28 g, 94%) as colorless oil.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:16]([N:18]([CH3:22])[N:19]([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:21][N:19]([CH3:20])[N:18]([CH3:22])[C:16](=[O:17])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)N(C)N(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccccc1)C(=O)N(C)N(C)C
Reaction time: 0.5 h
Yield: 148 %

Procedure:
To a solution of N-methyl-N-[(1R)-2-phenyl-1-(N,N',N'-trimethylhydrazinocarbonyl)ethyl]carbamic acid tert-butyl ester (0.3 g, 0.89 mmol) in methylene chloride (1 ml) was added trifluoroacetic acid (1 ml) and the mixture was stirred for 30 min. The mixture was concentrated in vacuo, stripped three times with methylene chloride and suspended in methylene chloride:(methanol/ammonia) (1:1) (2 ml) and trifluoroammonium acetate precipitated. Then diethyl ether (10 ml) was added and the mixture was filtered and the filtrate was concentrated in vacuo to give 0.31 g of (2R)-2-methylamino-3-phenylpropionic acid trimethylhydrazide as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][NH:9][C:10](=[O:20])[O:11][CH2:12][CH2:13][CH2:14][C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10](=[O:20])[O:11][CH2:12][CH2:13][CH2:14][C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)=[CH:21][CH:22]=1
Reactant: O=C(NCc1ccc([N+](=O)[O-])cc1)OCCCc1c[nH]cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CNC(=O)OCCCc2c[nH]cn2)cc1

Procedure:
2 mmol of the compound obtained in Example 67 are hydrogenated in 10 ml of methanol with 40 mg of palladium-on-charcoal (10%) with hydrogen. After absorption of the calculated amount of hydrogen, the solution is filtered, concentrated and purified by chromatography. The title compound obtained is crystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:20](=[O:21])[N:19]([CH3:22])[C:10]3[N:11]=[C:12](S(C)(=O)=O)[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CO>CN1CCCC1=O>[CH2:25]([NH:32][C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=3)[C:20](=[O:21])[N:19]([CH3:22])[C:10]=2[N:11]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2)cc2cnc(S(C)(=O)=O)nc21
Reactant: NCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cn1c(=O)c(Oc2ccc(F)cc2)cc2cnc(NCc3ccccc3)nc21
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 6-(4-fluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (see Example 8 made by replacing methyl 2-fluorophenoxyacetate with methyl 4-fluorophenoxyacetate-Steps A and B, 0.35 g, 1.0 mmol) and benzylamine (0.33 mL, 3 mmol) in 0.5 mL of 1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and then cooled to room temperature. Methanol (2 mL) was added and the suspension was stirred for 30 minutes. Filtration and washing of the precipitate thoroughly with methanol followed by drying provided the free amine. This was dissolved in ethyl acetate (1-2 mL) and hydrochloric acid in ether (1M, 1.5 eq) was added. Isolation of the solid via filtration and drying provided 0.317 g of the hydrochloride salt (Mass spec. M+1=377, MP=203.2-204° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([C:12]#[N:13])=[C:5]([O:9][CH2:10][CH3:11])OCC.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[NH:24][NH2:25]>C(O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([O:9][CH2:10][CH3:11])=[N:25][N:24]([C:17]2[C:18]([Cl:23])=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[Cl:15])[C:12]=1[NH2:13])=[O:14]
Reactant: CCOC(OCC)=C(C#N)C(=O)OC
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Solvent: CCO
Product: CCOc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(=O)OC
Yield: 26 %

Procedure:
The crude product obtained in Step A (4.76 g, containing approximately 1.9 g, 9.6 mmol of 2-cyano-3,3-diethoxy-acrylic acid methyl ester) was combined with 2,4,6-trichlorophenylhydrazine (2.02 g, 9.6 mmol) in ethanol (15 ml). The resulting mixture was refluxed for 18 hours. The solvent was removed in vacuo, and the residue was extracted with methylene chloride/water (100 ml of each) with the pH adjusted to 10 with sodium carbonate. The separated aqueous extract was washed with two 50 ml portions of methylene chloride. The three combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to an oil (5.98 g). The purity of this crude title compound was significantly improved by flash chromatography (silica gel, 40 micron mesh; elution with ethyl acetate/hexane=15:85 in volume), yielding 910 mg of the title compound as an orange oil. TLC Rf (silica gel plates, u.v. detection; ethyl acetate hexane=15.85 in volume): 0.26. The product was used in the next step without further purification.
Reaction SMILES: C(=O)([O-])O.[Na+].[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[C:9]([NH2:24])=[N:8]1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O1CCCC1.O>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:14]=2)[C:9]([NH:24][C:26](=[O:27])[O:28][CH2:29][CH3:30])=[N:8]1
Reactant: Cn1nc(N)c2ccc(OCc3ccccc3)cc21
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Nc1nn(C)c2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
9.8 g of sodium hydrogen carbonate (0.117 mol) are added to a solution of 19.7 g (0.078 mol) of 1-methyl-6-(phenylmethoxy)-1H-indazol-3-amine in 200 ml of a 9:1 mixture of tetrahydrofuran/water, and then 8.9 ml (0.093 mol) of ethyl chloroformate are added dropwise while maintaining the temperature at 25° C. A milky suspension is obtained which is left with stirring for 30 minutes, and then the solvent is evaporated off under reduced pressure. The residue is treated with dichloromethane and water. The organic phase is decanted off, dried over sodium sulphate and concentrated under reduced pressure. The product is crystallized from diisopropyl ether. 20.1 g of product are obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=4)[CH2:26][CH2:25]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: Oc1ccc(C2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
DIPEA (48.2 mL, 276.86 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (24.65 g, 110.74 mmol) and 4-(piperidin-4-yl)phenol (20.61 g, 116.28 mmol) in DMF (200 mL). The resulting solution was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, then evaporated to dryness and re-dissolved in DCM (1 L) and washed with water (2×1 L). The organic layer was washed with saturated brine (500 mL), then dried over MgSO4, filtered and evaporated to afford crude product. The crude product was triturated with ether to afford 4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (36.6 g, 91%) is as a solid.
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[C:4]([N+:10]#[C-:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[O:14]([C@H:21]1[CH2:26][CH2:25][C@H](N)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)CCC>[O:14]([C@H:21]1[CH2:26][CH2:25][C@H:12]([N:2]2[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:10]=[CH:11]2)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@H]1CC[C@H](Oc2ccccc2)CC1
Reactant: [C-]#[N+]C(=CN(C)C)C(=O)OCC
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn([C@H]2CC[C@H](Oc3ccccc3)CC2)cn1
Temperature: 150 °C
Reaction time: 3.25 h

Procedure:
Ethyl 3-(dimethylamino)-2-isocyanoacrylate (0.70 g) and the compound (1.14 g) obtained in Step 2 of this Reference Example were dissolved in n-butanol (7.0 mL). Then, to the solution, triethylamine (0.70 mL) was added at room temperature, and the mixture was stirred at 150° C. for 3.25 hours. The reaction solution was concentrated and then purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=50/50-ethyl acetate) to obtain the title compound (0.28 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:16])[C@@H:4]([C:6]1[CH:7]=[CH:8][C:9]2[CH2:14][O:13][CH2:12][O:11][C:10]=2[CH:15]=1)[OH:5].CCN(C(C)C)C(C)C.C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1>C1COCC1>[O:11]1[C:10]2[CH:15]=[C:6]([C@H:4]3[O:5][C:31](=[O:32])[NH:2][C@H:3]3[CH3:16])[CH:7]=[CH:8][C:9]=2[CH2:14][O:13][CH2:12]1
Reactant: C[C@H](N)[C@H](O)c1ccc2c(c1)OCOC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1NC(=O)O[C@@H]1c1ccc2c(c1)OCOC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (1R,2S)-2-amino-1-(4H-benzo[d][1,3]dioxin-7-yl)propan-1-ol hydrochloride (I3b) (120 mg, 0.49 mmol), DIEA (0.100 mL, 0.59 mmol) and CDI (90 mg, 0.56 mmol) in THF (2 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated by evaporation, the residual material was partitioned between EtOAc and water, the organic phase was washed with 10% NaHSO4, dried over MgSO4, filtered and evaporated. The crude product was analysed by LC/MS and was considered pure enough for further analysis by NMR. Yield 66 mg (57%)
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)(=[O:3])[CH3:2].[C:13]([CH:15]1[CH2:17][NH:16]1)#[N:14].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([N:16]1[CH2:17][CH:15]1[C:13]#[N:14])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCCCC(=O)O
Reactant: N#CC1CN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)NCCCCCC(=O)N1CC1C#N

Procedure:
3.46 g. 6-Acetylaminohexanoic acid, 1.36 g. 2-cyanoaziridine and 4.3 g. dicyclohexylcarbodiimide are reacted in the usual manner in 35 ml. tetrahydrofuran and the reaction mixture then worked up to give 1.1 g. 1-(6-acetylaminohexanoyl)-2-cyanoaziridine which, after recrystallization from ethyl acetate-ligroin, melts at 74°-77° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]([CH3:29])([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[NH2:23]>>[CH3:21][C:22]([NH:23][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH3:29]
Reactant: CC(C)(N)c1nccs1
Reactant: O=C(O)c1ccc(C2CCOCC2)c(OCC2CC2)n1
Product: CC(C)(NC(=O)c1ccc(C2CCOCC2)c(OCC2CC2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (Example 9 f) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (LC/MS): 402.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([OH:11])=[N:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].[Br:12]N1C(=O)CCC1=O>>[Br:12][C:7]1[C:8]([CH3:9])=[C:3]([C:1]#[N:2])[C:4]([OH:11])=[N:5][C:6]=1[CH3:10]
Reactant: Cc1cc(C)c(C#N)c(O)n1
Reactant: O=C1CCC(=O)N1Br
Product: Cc1nc(O)c(C#N)c(C)c1Br

Procedure:
In a method to prepare 5,6,7-tri-substituted-5-deazapteridine, for example, 3-cyano-2-hydroxy-4,6-dimethylpyridine (commercially available) may be brominated with N-bromosuccinimide, affording the corresponding 5-bromo-3-cyano-2-hydroxy-4,6-dimethylpyridine: The bromo compound was in turn may be treated with phosphorus oxychloride in the presence of N,N -dimethylformamide, yielding 2-chloro-5-bromo-3-cyano-4,6-dimethylpyridine. The so-prepared pyridine was cyclized with quanidine carbonate in N,N-dimethylacetamide, yielding the targeted 5,6,7-tri-substituted-5-deazapteridine, for example, 2,4-diamino-6-bromo-5,7-dimethylformamide. Example 19 provides a detailed description of how this reaction is conducted.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH2:7]([O:9][CH2:10][C:11]([OH:13])=[O:12])[CH3:8].Cl[CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O>[CH2:7]([O:9][CH2:10][C:11]([O:13][CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:12])[CH3:8]
Reactant: CCOCC(=O)O
Reactant: ClCSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCC(=O)OCSc1ccccc1
Temperature: 70 °C
Yield: 68.7 %

Procedure:
To a mixture of Cs2CO3 (29.5 g, 91 mmol) in DMF (150 mL) at 0° C. was added 2-ethoxyacetic acid (18.0 mL, 191 mmol), and the resulting mixture was heated at 70° C. for 30 min. The reaction was cooled to 0° C., chloromethyl phenylsulfide (10.56 mL, 79 mmol) was added, and the reaction was heated at 70° C. for 90 min. The mixture was cooled to room temperature, and then 0° C., before diluting with H2O (200 mL; an exotherm was observed). The reaction mixture was divided into two equal portions and one portion was further diluted with water (400 mL) and extracted with Et2O (200 mL×2, 100 mL×1). The combined organic extracts were diluted with hexane (100 mL) and washed successively with 1.0 M aqueous NaOH (100 mL) and brine (2×200 mL), dried over anhydrous MgSO4, filtered, and concentrated. The second portion of the reaction mixture from above was processed in an identical fashion and the two lots were combined and concentrated in vacuo to afford the title compound as a yellow oil (12.28 g, 97%): 1H NMR (400 MHz, CDCl3) δ 7.48-7.41 (m, 2H), 7.31 (ddd, J=12.6, 7.9, 6.3 Hz, 3H), 5.51 (s, 2H), 4.11 (s, 2H), 3.59 (q, J=7.0 Hz, 2H), 1.24 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.00, 134.35, 130.53, 129.16, 127.55, 68.46, 68.10, 67.32, 14.99; ESIMS: m/z 226 ([M]+).
Reaction SMILES: CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:16]([O:23][C:24]1[CH:41]=[CH:40][C:39]2[C@@H:38]3[C@H:29]([C@H:30]4[C@@:34]([CH2:36][CH2:37]3)([CH3:35])[C@@H:33]([OH:42])[CH2:32][CH2:31]4)[C@H:28]([CH:43]=[CH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53](O)=[O:54])[CH2:27][C:26]=2[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:56][NH:57][CH2:58][CH:59]([CH3:61])[CH3:60].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:58]([N:57]([CH3:56])[C:53](=[O:54])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH:44]=[CH:43][C@@H:28]1[CH2:27][C:26]2[CH:25]=[C:24]([O:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:41]=[CH:40][C:39]=2[C@@H:38]2[C@@H:29]1[C@H:30]1[C@@:34]([CH2:36][CH2:37]2)([CH3:35])[C@@H:33]([OH:42])[CH2:32][CH2:31]1)[CH:59]([CH3:61])[CH3:60]
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](C=CCCCCCCCCC(=O)O)[C@H]3[C@@H]1CC[C@@H]2O
Reactant: CNCC(C)C
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)CN(C)C(=O)CCCCCCCCC=C[C@@H]1Cc2cc(OCc3ccccc3)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
N-Methylmorpholine (0.028 ml.) and isobutyl chloroformate (0.038 ml.) were successively added to a stirred solution of 11-(3-benzyloxy-17β-hydroxyoestra-1,3,5(10)-trien-7α-yl)undec-10-enoic acid (0.109 g.) in tetrahydrofuran (3 ml.) which was cooled to -10° C. The mixture was stirred at -10° C. for 30 minutes, N-methylisobutylamine (0.05 ml.) was added and the mixture was stirred at laboratory temperature for 2 hours. Saturated aqueous sodium bicarbonate solution (5 ml.) was added and the mixture was extracted 3 times with methylene chloride (10 ml. each time). The combined extracts were washed with water (2 ml.), dried and evaporated to dryness, and there was thus obtained as oily residue N-isobutyl-N-methyl-11-(3-benzyloxy-17β-hydroxyoestra-1,3,5(10)-trien-7αyl)undec-10-enamide.