Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:35]
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A151) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:11]([O:13][C:14](=[O:34])[CH:15]=[C:16](C1C=CC(OC)=C2C=1C=CN2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:34])[CH:15]=[C:16]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12]
Reactant: Brc1cccc2[nH]ncc12
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Product: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]ncc12

Procedure:
3-(1H-Indazol-4-yl)-3-phenyl-acrylic acid ethyl ester CXCI was prepared from using 4-bromo-1H-indazole using the procedure described for preparation of 3-(7-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LIII (Example 13).
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:11]([O-])=O)[CH:3]=1.CCO.CC(O)=O>[Fe].O>[NH2:11][C:4]1[CH:3]=[C:2]([Br:1])[C:9]([F:10])=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(Br)c(F)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To a mixture of 4-bromo-5-fluoro-2-nitrobenzaldehyde (2.219 g, 8.947 mmol) and iron powder (2.535 g, 45.39 mmol), EtOH (30.0 mL) was added, followed by AcOH (10.0 mL) and water (5.0 mL). The reaction mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure. EtOAc (150 mL) was added to the resulting residue. The mixture formed was filtered through a pad of diatomaceous earth. The diatomaceous earth pad was washed with 10 wt % aq. K3PO4 (150 mL) and EtOAc (100 mL). The organic layer was separated and then was washed with brine (150 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-30% EtOAc in hexanes) to give the sub-title compound as a yellow solid (1.518 g, 78%). LCMS calc. for C7H6BrFNO (M+H)+: m/z=218.0. found 217.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[C:22]3[CH:23]=[CH:24][C:25]([C:27]4[C:28]5[C@H:35]([CH3:36])[CH2:34][C@@H:33]([OH:37])[C:29]=5[N:30]=[CH:31][N:32]=4)=[CH:26][C:21]=3[S:20][N:19]=2)[CH2:9][NH:10]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[ClH:38]>C(Cl)Cl.O1CCOCC1>[ClH:1].[ClH:38].[ClH:1].[NH2:10][CH2:9][CH:8]([C:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27]3[C:28]4[C@H:35]([CH3:36])[CH2:34][C@@H:33]([OH:37])[C:29]=4[N:30]=[CH:31][N:32]=3)=[CH:26][C:21]=2[S:20][N:19]=1)[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc4c(C(CNC(=O)OC(C)(C)C)c5ccc(Cl)cc5)nsc4c3)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc4c(C(CN)c5ccc(Cl)cc5)nsc4c3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A solution of tert-butyl 2-(4-chlorophenyl)-2-(6-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzo[d]isothiazol-3-yl)ethylcarbamate (41 mg, 0.076 mmol) in DCM was treated with 4N HCl in dioxane (0.5 mL). The reaction was stirred at room temperature overnight. The reaction was concentrated and triturated with ether (twice) to yield (5R,7R)-4-(3-(2-amino-1-(4-chlorophenyl)ethyl)benzo[d]isothiazol-6-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol trihydrochloride (32 mg, 77%). LCMS (APCI+) m/z 437, 439 [M+H]+; Rt=2.48 min.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:22]=[N:23][C:24]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:25][CH:26]=2)=[CH:15][C:14]=3[O:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[N:8][CH2:7]1)C.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH3:31][S:28]([CH2:27][C:24]1[N:23]=[CH:22][C:21]([O:20][C:16]2[CH:17]=[C:18]3[C:13](=[C:14]([O:32][CH:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:15]=2)[NH:12][C:11]([C:9]2[S:10][CH:6]([CH2:5][C:4]([OH:39])=[O:3])[CH2:7][N:8]=2)=[CH:19]3)=[CH:26][CH:25]=1)(=[O:29])=[O:30]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(CS(C)(=O)=O)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)Cc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.9 %

Procedure:
To a solution of ethyl{2-[5-({6-[(methylsulfonyl)methyl]pyridin-3-yl}oxy)-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (1.0 g) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added 1N hydrochloric acid (5 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.95 g, yield 100%) as a yellow amorphous solid.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].CC[N:26]([CH2:29][CH3:30])CC>CCO>[N+:21]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[NH:26][CH2:29][CH:30]1[CH2:3][CH2:4][CH2:5][CH2:6][O:7]1)[C:6]([N:8]([CH2:14][C:15]([F:18])([F:16])[F:17])[CH2:9][C:10]([F:13])([F:11])[F:12])=[O:7])([O-:23])=[O:22]
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Reactant: CCN(CC)CC
Solvent: CCO
Product: O=C(c1ccc(NCC2CCCCO2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (83 mg, 0.238 mmol) and R/S-2-aminomethyl-tetrahydropyran hydrochloride (40 mg, 0.262 mmol) in 3 mL of EtOH containing Et3N (0.070 mL, 0.476 mmol). The product was purified by flash chromatography on silica gel using 2:1/hexanes:EtOAc as eluent. Yield: 100 mg (95%); 1H NMR (CDCl3) 1.48 (m, 1H), 1.58 (m, 3H), 1.68 (m, 1H), 1.95 (m, 1H), 3.35 (m, 1H), 3.41 (m, 1H), 3.52 (m, 1H), 3.64 (m, 1H), 4.07 (m, 1H), 4.26 (m, 4H), 6.96 (d, J=8.98 Hz, 1H), 7.54 (d, J=8.98 Hz, 1H), 8.31 (s, 1H), 8.55 (brs, 1H); MS (ESI) 530.21 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][NH:3][NH:2]1.[C:7](N)([CH3:10])([CH3:9])[CH3:8].C=O>>[C:7]([C:6]1[CH:5]=[CH:4][N:3]=[N:2][N:1]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)N
Reactant: C1CNNNC1
Agent: C=O
Product: CC(C)(C)c1ccnnn1
Yield: 90 %

Procedure:
In carrying out the reaction to prepare the preferred hexahydro-triazine, the tert-butylamine is added slowly to a concentrated aqueous solution of the formaldehyde (formalin) and the stoichiometry is maintained to so that there is an exact equivalent to a slight excess of the amine at the end of the reaction. Typically, a molar ratio of at least 1.00 to 1.05 of the amine to the formaldehyde is preferred for the overall process to form the tert-butyltriazine quantitatively (in excess of 90% yield). For the reaction to go to completion satisfactorily and to yield the tert-butyltriazine, careful control of the reaction conditions must be observed in order to avoid side-reactions. During the slow addition of the amine it is desirable to maintain a reaction temperature below 46° C.
Reaction SMILES: [C-]#N.[K+].C([O:7][CH2:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([S:16](=[O:23])(=[O:22])[N:17]=[CH:18][N:19]([CH3:21])[CH3:20])=[CH:11][C:10]=1[Cl:24])(=O)C>CO>[Cl:24][C:10]1[CH:11]=[C:12]([S:16]([N:17]=[CH:18][N:19]([CH3:21])[CH3:20])(=[O:22])=[O:23])[CH:13]=[C:14]([F:15])[C:9]=1[CH2:8][OH:7]
Reactant: CC(=O)OCc1c(F)cc(S(=O)(=O)N=CN(C)C)cc1Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: CN(C)C=NS(=O)(=O)c1cc(F)c(CO)c(Cl)c1
Yield: 80.8 %

Procedure:
To a solution of KCN (82 mg, 1.26 mmol) in MeOH (80 mL) was added 2-chloro-4-(N-((dimethylamino)methylene)sulfamoyl)-6-fluorobenzyl acetate (850 mg, 2.52 mmol) at 0° C. The mixture was allowed to attain room temperature and then refluxed 1 h. After cooling, the reaction mixture was quenched with H2O, concentrated, and extracted with EtOAc. The combined extracts were washed with brine, dried over anhyd MgSO4, filtered and concentrated under reduced pressure to give N′-(3-chloro-5-fluoro-4-(hydroxymethyl)phenylsulfonyl)-N,N-dimethylformimidamide (600 mg, 80%) as ivory solid. 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.74 (s, 1H), 7.55 (d, 1H), 4.86 (d, 2H), 3.17 (s, 3H), 3.05 (s, 3H), 2.07 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][CH:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C@H:9]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][O:19][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[O:14][CH:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1C[C@@H](OCc2ccccc2)[C@H](O)[C@@H](CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: COC1C[C@@H](OCc2ccccc2)[C@H](O)[C@@H](COS(=O)(=O)c2ccc(C)cc2)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.3 %

Procedure:
The compound (12.2 g, 45.3 mmol) synthesized in Example 6 (6b) was dissolved in pyridine (100 mL) and p-toluenesulfonyl chloride (13 g, 68.0 mmol) and 4-dimethylaminopyridine (553 mg, 4.53 mmol) were added thereto, followed by stirring of the mixture at room temperature for 12 hours. The reaction mixture was poured to 10% aqueous hydrochloric acid solution (80 mL) under ice cooling, and ethyl acetate (200 mL) and the organic layer was washed with 10% aqueous hydrochloric acid solution (80 mL), saturated aqueous sodium hydrogencarbonate solution (80 mL) and saturated brine (50 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 5:1-3:1, V/V) to obtain the desired title compound (16.9 g, yield: 88%) as pale yellow amorphous matter.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>CCOC(C)=O>[OH:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: OCCCc1cccc(B(O)O)c1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(CCCO)c3)nc12

Procedure:
1-{2-[3-(3-Hydroxy-propyl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 3-(3-hydroxypropyl)benzeneboronic acid following general procedures as described in these Examples. Silica gel chromatography using 20-100% EtOAc in hexanes as eluant provided 80 mg (48%) of a yellow solid. MP 170-171° C., M+H=338.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([C:14]([OH:16])=[O:15])[CH:13]=2)O1.Br[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=1>>[N+:25]([C:21]1[CH:20]=[C:19]([C:9]2[CH:10]=[N:11][N:12]([C:14]([OH:16])=[O:15])[CH:13]=2)[CH:24]=[CH:23][CH:22]=1)([O-:27])=[O:26]
Reactant: CC1(C)OB(c2cnn(C(=O)O)c2)OC1(C)C
Reactant: O=[N+]([O-])c1cccc(Br)c1
Product: O=C(O)n1cc(-c2cccc([N+](=O)[O-])c2)cn1

Procedure:
Using the same method as in Example 5-(i), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid.tert-butyl was reacted with 1-bromo-3-nitrobenzene to give 4-(3-nitrophenyl)-1H-pyrazole-1-carboxylic acid.tert-butyl (yield: 64%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][N:22](CC4C=CC=CC=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+].C([O-])(O)=O.[Na+]>CO.C(Cl)Cl.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][NH:22][CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Agent: [Pd+2]
Agent: O=C([O-])O
Agent: O=C[O-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ncnc3c2CNCC3)C1
Yield: 66.2 %

Procedure:
To a solution of (S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 22) (30.1 g, 73.5 mmol) in MeOH (100 mL) was added 20% palladium hydroxide on carbon (3.3 g) then ammonium formate (4.63 g, 73.5 mmol) and the mixture heated at reflux for 1 h. Added ammonium formate (0.38 g, 6.02 mmol) and continued heating at reflux for 30 min. The reaction mixture was allowed to cool and filtered through a celite pad, washing with MeOH (50 mL) then CH2Cl2 (50 mL). The filtrate was evaporated in vacuo to give a brown oil. Dissolved in CH2Cl2 (100 mL), added solid NaHCO3 (10 g) and filtered through a celite pad. The filtrate was evaporated in vacuo to give a brown oil. Dissolved in EtOAc (50 mL) and a solid precipitated which was filtered to give (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester as a beige solid (15.55 g, 66% yield). 1H-NMR (400 MHz, DMSO-d6, 298 K): δ ppm 1.40 (s, 9H) 1.81-1.98 (m, 1H) 2.05-2.17 (m, 1H) 2.92 (t, 2H) 3.10-3.46 (m, 5H) 3.49-3.63 (m, 3H) 4.47-4.63 (m, 1H) 6.46 (d, 1H, N—H) 8.25 (s, 1H). LCMS: [M+H]+=320.0, Rt(6)=1.29 min.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:20][CH:21](OC)[O:22]C)[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.O>C1COCC1>[CH2:13]([O:12][CH2:11][CH:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:20][CH:21]=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(CC(COCc1ccccc1)COCc1ccccc1)OC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=CCC(COCc1ccccc1)COCc1ccccc1

Procedure:
A mixture of benzyl 2-benzyloxymethyl-4,4-dimethoxybutyl ether (51.62 g, 0.15 mol), acetic acid (70 ml), water (30 ml), and THF (100 ml) was refluxed for 2 h and then evaporated in vacuum. The residue was dissolved in ether and the solution washed with aqueous potassium carbonate solution and water, dried (MgSO4), and evaporated in vacuum. The residue of crude 4-benzyloxy-3-benzyloxymethylbutanal (quantitative yield) was dissolved in 100 ml of THF and added during 30 min. to a suspension of lithium aluminum hydride (7.6 g, 0.20 mol) in 100 ml of THF. Then 8 ml of water, 8 ml of 15% aqueous NaOH and 24 ml of water were added and the mixture was stirred until a white, sandy suspension was obtained. The inorganic salts were filtered off and washed with several portions of THF. The combined extracts were evaporated in vacuum to yield 41.93 g (93%) of the title compound.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([C@:7]23[CH2:15][NH:14][CH2:13][C@H:12]2[CH2:11][S:10][C:9]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:8]3)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:35]1[N:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=1>O1CCOCC1.C(OCC)(=O)C>[F:41][C:38]1[CH:37]=[N:36][C:35]([N:14]2[CH2:13][C@@H:12]3[C@@:7]([C:5]4[S:6][C:2]([F:1])=[CH:3][CH:4]=4)([N:8]=[C:9]([NH:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:10][CH2:11]3)[CH2:15]2)=[N:40][CH:39]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)s3)CNC[C@H]2CS1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(NC1=N[C@@]2(c3ccc(F)s3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Yield: 82.7 %

Procedure:
To a stirred mixture of the N-[(4aR,7aR)-7a-(5-fluorothiophen-2-yl)-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (415 mg, 1.15 mmol) in 1,4-dioxane (23 mL) is added diisopropylethylamine (601 μL, 3.44 mmol) and 2-chloro-5-fluoropyrimidine (1.10 mL, 11.5 mmol). The solution is heated to reflux for 3 hours. The pale yellow solution is allowed to cool, diluted with ethyl acetate, (120 mL) and washed with dilute aqueous sodium bicarbonate (100 mL, prepared from 50 mL saturated sodium bicarbonate and 50 mL water), water (50 mL), and brine (50 mL). The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with hexanes/ethyl acetate, gradient from 60:40 to 30:70, to give the title compound (435 mg, 83%) as a white foam. ES/MS (m/e): 458.0 (M+H).
Reaction SMILES: [P:1](=[S:5])([OH:4])([OH:3])[SH:2].[OH-].[Sr+2:7].[OH-].OO.C(OCCOCCOCCOC(=O)CCCCCCCC)(=O)CCCCCCCC>>[P:1]([O-:4])([O-:3])([S-:5])=[S:2].[Sr+2:7].[P:1]([O-:4])([O-:3])([S-:5])=[S:2].[Sr+2:7].[Sr+2:7]
Reactant: OP(O)(=S)S
Agent: CCCCCCCCC(=O)OCCOCCOCCOC(=O)CCCCCCCC
Agent: OO
Agent: [OH-]
Product: [O-]P([O-])(=S)[S-]
Temperature: 75 °C

Procedure:
A three neck round bottom flask was charged with 89.0 grams of the dithiophosphoric acid that was obtained from Example 9. To this was added 15.1 grams of strontium hydroxide. The reaction was heated to 75° C. for approximately 30 minutes. The reaction was attached to an aspirator to remove any water that had formed. The reaction was then allowed to cool back to 35° C., and 4.2 g of 17.5% hydrogen peroxide was added. After mixing for 2.5 hours, 11.1 grams of triethylene glycol dinonanoate was added. The reaction was then heated under vacuum and any remaining water was removed by distillation. After the temperature reached 105° C., the final product was filtered with diatomaceous earth.
Reaction SMILES: [K].[C:2]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.[CH2:13]([C:17]1[C:21]([CH2:22]Cl)=[C:20]([CH3:24])[O:19][N:18]=1)[CH2:14][CH2:15][CH3:16]>CN(C=O)C.O>[CH2:13]([C:17]1[C:21]([CH2:22][N:6]2[C:2](=[O:12])[C:3]3[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:5]2=[O:7])=[C:20]([CH3:24])[O:19][N:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1noc(C)c1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1noc(C)c1CN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Yield: 78 %

Procedure:
Phthalimide potassium was suspended in DMF (35 mL) and the reaction mixture heated to 90° C. A solution of 3-butyl-4-chloromethyl-5-methyl-isoxazole (970 mg, 5.2 mmol) in DMF (25 mL) was added. After 45 min the reaction mixture was cooled, evaporated and the residue obtained was diluted with water then extracted with ether. The combined organic extracts were dried, filtered and concentrated then purified by chromatography (silica, 0 to 50% ethyl acetate in heptane) to give the title compound (1.21 g, 78%) as an off white solid that was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH:15]=O.C([O-])(=O)C.[NH4+].[N+:22]([CH2:25][CH3:26])([O-:24])=[O:23]>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH:15]=[C:25]([N+:22]([O-:24])=[O:23])[CH3:26]
Reactant: COc1cc(C=O)c(OC)c2ccccc12
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1cc(C=C(C)[N+](=O)[O-])c(OC)c2ccccc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step A (0.8 g, 2.93 mmol) in nitroethane (10 mL) was added ammonium acetate (0.45 g, 5.84 mmol). The mixture was stirred at 60° C. overnight. The excess nitroethane was removed and the residue purified by flash chromatography (silica gel, ethyl acetate/hexane: 0.5/9.5) to give 0.5 g of a yellow solid: 1H NMR (DMSO-d6) δ 2.45 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 6.95 (s, 1H, Ar—H), 7.65 (m, 2H, Ar—H), 8.10 (m, 2H, Ar—H), 8.29 (s, 1H, CH═).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[CH3:21][CH:22]([C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24])[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=1)=[O:27]
Reactant: Cc1cccc(CNC(=O)C(C)C(=O)O)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: Cc1cccc(CNC(=O)C(C)C(=O)NC2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1

Procedure:
The title compound, MS: m/e=468.2 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(3-methyl-benzyl)-malonamic acid.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH:6]([OH:12])[C:7]([CH3:11])=[CH:8][CH2:9][CH3:10])[CH3:3].[CH3:13][O:14][C:15]([CH3:17])=[CH2:16]>Cl.CCCCCC>[CH3:13][O:14][C:15]([CH3:17])([O:12][CH:6]([C:7]([CH3:11])=[CH:8][CH2:9][CH3:10])[CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:16]
Reactant: C=C(C)OC
Reactant: CCC=C(C)C(O)CCC(C)C
Agent: Cl
Solvent: CCCCCC
Product: CCC=C(C)C(CCC(C)C)OC(C)(C)OC

Procedure:
10 g of 2,6-dimethyl-6-nonen-5-ol and 12 7 g of isopropenyl methyl ether are mixed and treated with 3 drops of concentrated hydrochloric acid. The mixture is subsequently held at reflux temperature for 15 hours, cooled, taken up in hexane and washed neutral with sodium hydrogen carbonate solution and water. After distillation of the solvent, there are obtained 14.1 g of crude 5-[1'-methoxy-1'-methyl-ethoxy]-2,6-dimethyl-6-nonene which are rectified in a water-jet pump vacuum (boiling point 109° C./12 Torr, nD20 =1.4379). The mixed acetal decomposes when subjected to gas chromatography and must therefore be tested for purity by thin-layer chromatography (elution agent: hexane/pentane/chloroform/ethyl acetate in the ratio 25:25:50:5); Rf =0.60.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>CCO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1cccc2ccccc12
Solvent: CCO
Product: COc1cc2ncnc(Nc3cccc4ccccc34)c2cc1OC
Reaction time: 0.17 h

Procedure:
To a 25 mL flask with 10 ml of abs. EtOH is added 0.137 g of 4-chloro-6,7-dimethoxyquinazoline and 0.087 g of 1-aminonaphthalene. The solution is heated to reflux whereupon the insoluble materials dissolve. After 5 minutes at reflux a precipatate forms. The solution is allowed to stir an additional 10 min before cooling and isolation of the product as the hydrochloride salt by simple filtration. High-vacuum drying of the solid provided analytically pure (6,7-dimethoxy-quinazolin-4-yl)-alpha-naphthalenylamine (0.142 g, white powder, m.p. 271°-273° C.