Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([S:19][CH3:18])=[CH:21][CH:22]=2)[CH2:7]1
Reactant: CSc1ccc(CC(=O)O)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: CSc1ccc(CC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1
Yield: 32.3 %

Procedure:
Example 5 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and 4-(methylthio)phenylacetic acid (0.036 g) to give the title compound (0.028 g).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][N:5]([CH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][C:17]([N:19]1[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21][C@H:20]1[CH3:34])=[O:18])[CH3:6].O1CCCC1.O.[OH-].[Li+]>O>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][C:17]([N:19]2[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:21][C@H:20]2[CH3:34])=[O:18])=[C:8]([CH:13]=1)[CH2:7][N:5]([CH2:4][C:3]([OH:35])=[O:2])[CH3:6]
Reactant: COC(=O)CN(C)Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CN(C)CC(=O)O

Procedure:
To a solution of [(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzyl)-methyl-amino]-acetic acid methyl ester (0.051 g, 0.10 mmol) in 1:1 tetrahydrofuran:water (1 ml) and lithium hydroxide hydrate (0.016 g, 0.38 mmol) was added. After 1.5 hours the reaction was concentrated and the title compound isolated by chromatography on silica gel (0.045 g, LRMS: 492.4).
Reaction SMILES: O.[CH2:2]([O:9][C:10]([N:12]([CH2:19][CH:20](OCC)[O:21]CC)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[CH2:2]([O:9][C:10]([N:12]([CH2:19][CH:20]=[O:21])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CN(CC(OCC)OCC)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)CN(CC=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
After adding water (60 ml) to a solution of the compound obtained in Step 1 (14.1 g) in chloroform (120 ml), trifluoroacetic acid (153 ml) was added dropwise over 2 hours under cooling with ice. The mixture was stirred under cooling with ice for 1 hour and at room temperature for 1.5 hours. After adding water to the reaction mixture and extracting with methylene chloride, the organic layer was washed with aqueous solution of 10% potassium carbonate, water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain the title compound (10.3 g).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[C:49]1([C:62](O)=[O:63])[C:61]2[CH2:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]=2[CH:52]=[CH:51][CH:50]=1>C(Cl)Cl>[C:49]1([C:62]([N:16]2[CH2:17][CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:14]([CH2:13][N:10]3[CH2:9][CH2:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:12][CH2:11]3)[CH2:15]2)=[O:63])[C:61]2[CH2:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]=2[CH:52]=[CH:51][CH:50]=1
Reactant: O=C(O)c1cccc2c1Cc1ccccc1-2
Reactant: c1ccc(C2CCN(CC3CNCC3c3ccccc3)CC2)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc2c1Cc1ccccc1-2)N1CC(CN2CCC(c3ccccc3)CC2)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A solution of 10 mg (0.03 mnmol) of 3-(RS)-((4-phenyl)piperidin-1-yl)methyl-4-(SR)-phenylpyrrolidine (from Example 30, Step A), 10 mg (0.07 mmol) of DIEA and 10 mg (0.04 mmol) of bis (2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) in 2 mL of CH2Cl2 (2 mL) at 0° C. was treated with 7 mg (0.16 mmol) of 1-fluorene carboxylic acid. The cooling bath was removed; the reaction was stirred at rt for 2 h and then was concentrated in vacuo . Preparative thin layer chromatography (silica gel GF, 20×20 cm, 1000 microns) using 95:5 v/v MeOH/CH2Cl2 as the eluant afforded 14 mg (88%) of the title compound as a foam. 1H NMR (500 MHz, CDCl3): δ7.12-7.87 (17H), 1.28-4.13 (19H). Mass Spectrum (NH3 -CI): 513 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)=[O:4].[CH3:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.[OH-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:7]3[O:6][C:5]([C:3]([OH:2])=[O:4])=[CH:9][CH:8]=3)=[CH:13][CH:14]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(COc2ccc(I)cc2)o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2ccc(OCc3ccc(C(=O)O)o3)cc2)cc1
Temperature: 50 °C
Yield: 92.7 %

Procedure:
A mixture of 5-(4-iodo-phenoxymethyl)-furan-2-carboxylic acid methyl ester (Intermediate 6; 100 mg, 0.28 mmol), 4-methyl-phenyl-boronic acid (42 mg, 0.31 mmol), sodium hydroxide (45 mg, 1.13 mmol), palladium(II) acetate (2 mg, 0.01 mmol) and water (10 mL) was heated at ˜50° C. overnight. The mixture was filtered and the residue was washed with water, ethyl acetate, methylene chloride, and methanol. The aqueous layer was acidified and extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried (magnesium sulfate), filtered, and evaporated to give 5-(4′-methyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (80 mg, 84%) as a white solid.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[C:6](=[O:14])[O:7][C:8](C)(C)[O:9][C:10]=1[CH3:11].Cl>CO>[CH3:8][O:7][C:6](=[O:14])[CH:5]([Cl:4])[C:10]([CH3:11])=[O:9]
Reactant: CC1=C(Cl)C(=O)OC(C)(C)O1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Cl)C(C)=O
Reaction time: 0.17 h
Yield: 65 %

Procedure:
A solution of 25% sodium methoxide in methanol (5 ml, 21.6 mmol) was added to a solution of 5-chloro-2,2,6-trimethyl-4H-1,3-dioxin-4-one (3.24 g, 18.4 mmol) in 10 ml of methanol at 20° C. The resulting yellow solution was stirred for 10 minutes, acidified with 10% HCl, and extracted with ether. Evaporation of the ether provided 2.35 g (94% yield, NMR assay ~90%) of a pale yellow oil, which was distilled to provide 1.8 g (66%) of pure title compound as a colorless liquid.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:19])[O:17][CH3:18])=[CH:11][C:10]=2[N+:20]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[NH2:20][C:10]1[CH:11]=[C:12]([NH:15][C:16](=[O:19])[O:17][CH3:18])[CH:13]=[CH:14][C:9]=1[NH:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)Nc1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccc(NCC2CCCCC2)c(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl {4-[(cyclohexylmethyl)amino]-3-nitrophenyl}carbamate (1.05 g, 3.42 mmol) was dissolved in 30 mL of EtOAc containing a catalytic amount of 10% Pd/C. The solution was shaken in a Parr hydrogenation apparatus under H2 atmosphere (40 psi) at rt overnight. The solution was filtered through Celite and the solvent evaporated. The product was directly used for the next step without further purification. Yield: 950 mg (99%). MS (ESI) (M−1-H)+ 277.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[C:6]([O:8][CH3:9])=[O:7].[N+:18]([O-])([OH:20])=[O:19]>CC(O)=O>[CH3:1][O:2][C:3]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:11][C:10]([N+:18]([O-:20])=[O:19])=[C:5]([CH:4]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COCCOc1ccc(C(=O)OC)cc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COCCOc1cc([N+](=O)[O-])c(C(=O)OC)cc1OC
Yield: 79.9 %

Procedure:
Using the procedure described in Example 6A Step 2, methyl 3-methoxy-4-(2-methoxyethoxy)benzoate (8.39 g, 34.9 mmol) was reacted with fuming nitric acid (90%, 3.15 g) in AcOH (60 mL) at 50° C. for 8 hours, to afford methyl 5-methoxy-4-(2-methoxyethoxy)-2-nitrobenzoate as a yellow solid (7.956 g, 80%). 1H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H), 7.07 (s, 1H), 4.25 (t, 2H), 3.96 (s, 3H), 3.91 (s, 3H), 3.82 (t, 2H), 3.46 (s, 3H); LC-MS (ESI) m/z 286 (M+H)+.
Reaction SMILES: C1(/C(=N/NS(C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)(=O)=O)/C)CC1.[Si](OC[C@@H](N(CC(N(OC)C)=O)C(=O)OC(C)(C)C)C=C)(C(C)(C)C)(C)C.[Si:53]([O:60][CH2:61][C@@H:62]([N:65]([CH2:73][C:74](=[O:80])[C:75](=[CH2:79])[CH:76]([CH3:78])[CH3:77])[C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69])[CH:63]=[CH2:64])([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54]>>[Si:53]([O:60][CH2:61][C@@H:62]([N:65]([CH2:73][C:74](=[O:80])[C:75]([CH:76]1[CH2:77][CH2:78]1)=[CH2:79])[C:66](=[O:72])[O:67][C:68]([CH3:69])([CH3:70])[CH3:71])[CH:63]=[CH2:64])([C:56]([CH3:59])([CH3:57])[CH3:58])([CH3:55])[CH3:54]
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)C(=C)C(C)C)C(=O)OC(C)(C)C
Agent: C/C(=N\NS(=O)(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C)C1CC1
Agent: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Product: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)C(=C)C1CC1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from (E)-N′-(1-cyclopropylethylidene)-2,4,6-triisopropylbenzenesulfonohydrazide (Intermediate 261, 17.58 g, 48.22 mmol) and (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)but-3-en-2-yl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (Intermediate 5, 9.71 g, 24.11 mmol) following the procedure described for Intermediate 34. The desired product was obtained as a light yellow oil (4.86 g, 49%).
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[C:14]([N:21]1[CH2:29][C@H:27]([OH:28])[CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>CC(C)=O>[C:17]([O:16][C:14]([N:21]1[CH2:29][C:27](=[O:28])[CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Jones' reagent (3.9 mL, 31.3 mmol) is added dropwise over a period of 5 mins to a solution of Boc-L-hydroxyproline (1 g, 4.3 mmol) in acetone (55 mL). The stirring is continued for an additional 30 minutes. The reaction is quenched with methanol (1 mL) and stirred at room temperature for 10 minutes. The reaction mixture is filtered through Celite® and the filtrate is concentrated under reduced pressure. It was diluted with water and extracted with dichloromethane 3 times. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound. ESI m/z 130 [M+H+−100].
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH3:14][N:15]=[C:16]=[O:17].O>C(Cl)Cl>[CH3:14][NH:15][C:16]([NH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: O
Product: CNC(=O)N[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 3.5 h

Procedure:
tert-Butyl (3R)-3-aminopyrrolidine-1-carboxylate 6-2 (1.813 g, 9.73 mmol) was dissolved in 10 mL CH2Cl2. A solution of methylisocyanate (0.555 g, 9.73 mmol) in 10 mL CH2Cl2 was added. The solution was stirred for 3.5 hours. 50 mL H2O was added and the precipitate was extracted with CH2Cl2 (2×). The combined organic layers were dried (Na2SO4), filtered, and concentrated to afford tert-butyl (3R)-3-{[(methylamino)carbonyl]amino}pyrrolidine-1-carboxylate 6-3 as a white semi-solid. Free base: 1H NMR (DMSO-d6) δ 6.15 (bs, 1H), 5.63 (bd, 1H, J=4.22 Hz), 4.02 (m, 1H), 3.42-3.34 (m, 1H), 3.28-3.19 (m, 2H), 2.93-2.98 (m, 1H), 2.53 (d, 3H, J=4.58 Hz), 1.99-1.93 (m, 1H), 1.68-1.63 (m, 1H), 1.39 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][C:3]=1[C:4]([NH:6][C:7](=[NH:19])[CH2:8][O:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][O:9][CH2:8][C:7]2[NH:6][C:4](=[O:5])[C:3]3[CH:20]=[C:21]([CH2:24][CH3:25])[CH:22]=[N:23][C:2]=3[N:19]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCc1cnc(Cl)c(C(=O)NC(=N)COCCc2cccc(Cl)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cnc2nc(COCCc3cccc(Cl)c3)[nH]c(=O)c2c1

Procedure:
In analogy to the procedure described in example 78.4, 2-chloro-N-{2-[2-(3-chloro-phenyl)-ethoxy]-1-imino-ethyl}-5-ethyl-nicotinamide was treated with potassium carbonate in DMF for 5 h at 100° C. to obtain 2-[2-(3-chloro-phenyl)-ethoxymethyl]-6-ethyl-3H-pyrido[2,3-d]pyrimidin-4-one as off-white crystals. MS: m/e=344.3 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH3:24])=[C:6]([C:8]2[NH:9][C:10](=[O:21])[C:11]3[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)[CH:7]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.C(=O)([O-])[O-].[K+].[K+].II>CN(C)C=O.[Cu].O>[CH2:23]([O:22][C:5]1[CH:4]=[CH:3][C:2]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:7][C:6]=1[C:8]1[NH:9][C:10](=[O:21])[C:11]2[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=2[N:13]=1)[CH3:24]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc12
Reactant: c1c[nH]cn1
Agent: [Cu]
Agent: II
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(-n4ccnc4)ccc3OCC)nc12
Yield: 7.7 %

Procedure:
A solution of 5-(5-bromo-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.20 g, 0.0051 mol), imidazole (0.172 g, 0.0025 mol), anhydrous potassium carbonate (0.077 g, 0.00056 mol), copper bronze (0.036 g, 0.00057 mol) and iodine (0.015 g, 0.00012 mol) in dimethylformamide (10 ml) was heated under reflux under nitrogen for 4.5 hours, cooled and poured into water (50 ml). This mixture was extracted with a 9:1 mixture of dichloromethane and methanol (6×50 ml) and the extracts combined, dried (MgSO4) and evaporated under vacuum to give a pale brown oil. The oil was chromatographed on silica gel (20 g), eluting with a mixture of dichloromethane, methanol and triethylamine (97.8:20:0.2), to give a yellow solid, crystallisation of which from ethyl acetate-hexane gave the title compound as a cream solid (0.073 g, 38%), m.p. 193°-194° C. Found: C,63.61; H,5.97; N,22.03. C20H22N6O2 requires C,63.48; H,5.86; N,22.21%.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:31])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Cl>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:31])[CH:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1ccc(Oc2ccccc2)cc1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(Oc2ccccc2)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
To a solution of zinc chloride (5.39 g, 39.6 mmol) in diethyl ether (100 ml) was added sodium borohydride (3.00 g, 79.1 mmol) and the mixture was stirred at room temperature for 30 min. The insoluble material was filtered off. To the filtrate was added a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-((4-(phenyloxy)phenyl)methyl)propionate (7.76 g, 19.8 mmol) in diethyl ether (50 ml) and the mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid was added to the reaction solution under ice-cooling for quenching, water (200 ml) was added, and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) to give ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(phenyloxy)phenyl)methyl)propionate (6.66 g, 85%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[S:12][CH:13]=[C:14]([CH3:17])[C:15]=3[CH3:16])=[C:6]2[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl>[C:25]([O:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[S:12][CH:13]=[C:14]([CH3:17])[C:15]=3[CH3:16])=[C:6]2[N:5]=[CH:4][N:3]=1)(=[O:27])[CH3:26]
Reactant: Cc1csc(-c2cnn3c(O)ncnc23)c1C
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ncnc2c(-c3scc(C)c3C)cnn12
Reaction time: 0.17 h

Procedure:
To a mixture of 4-hydroxy-8-(3-methyl-4-methylthiophenyl)pyrazolo[1,5-a]-1,3,5-triazine (0.100 g), triethylamine (0.1 ml) and methylene chloride (10 ml) is added dropwise acetyl chloride (0.1 ml) at room temperature. After reacting for 10 minutes, to the reaction mixture is added methylene chloride (90 ml). The mixture is washed with water (20 ml×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.110 g).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=O.C([O:18][C:19]([NH:21][NH2:22])=[S:20])C>C(#N)C>[NH:11]1[C:12]2[C:7](=[CH:6][C:5]([C:3]3[CH2:2][S:20][C:19](=[O:18])[NH:21][N:22]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:9][C:10]1=[O:15]
Reactant: O=C1CCc2cc(C(=O)CCl)ccc2N1
Reactant: CCOC(=S)NN
Solvent: CC#N
Product: O=C1CCc2cc(C3=NNC(=O)SC3)ccc2N1
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of acetonitrile (100 ml) were added 6-chloroacetyl-3,4-dihydrocarbostyril (6.7 g) and ethoxythiocarbonylhydrazine (5.4 g) and the mixture was stirred for 2 hours, cooled and then filtered off. The filtrate was recrystallized from dimethylformamide (30 ml) and water (10 ml) to obtain pale yellowish 5-(3,4-dihydrocarbostyril-6-yl)-3,6-dihydro-1,3,4-thiadiazin-2-one (5.2 g), m.p. 271°-272° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:16])[C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[Br:17][CH2:18]/[CH:19]=[CH:20]/[CH2:21]Br.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:17][CH2:18]/[CH:19]=[CH:20]/[CH2:21][O:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([N:8]([C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH3:16])[CH2:14][CH2:13]1
Reactant: CN(c1ncc(Br)cn1)[C@H]1CC[C@H](O)CC1
Reactant: BrC/C=C/CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(c1ncc(Br)cn1)[C@H]1CC[C@H](OC/C=C/CBr)CC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A solution of 2.47 g (8.62 mmol) of trans-4-[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-cyclohexanol, 5.53 g (25.86 mmol) of trans-1,4-dibromo-2-butene and 0.87 g (2.57 mmol, 0.3 eq) tetrabutylammoniumhydrogensulfate in 55 ml CH2Cl2 were treated with 55 ml of 50% aqueous NaOH. The mixture was stirred at RT for 40 h, 2.76 g (12.93 mmol) of trans-1,4-dibromo-2-butene were added and stirred for further 60 h. Then CH2Cl2 was added and the layers were separated. The inorganic layer was extracted with CH2Cl2 (3×), the combined organic layers washed with brine and dried over Na2SO4. The residue was purified by column chromatography on silica gel with hexane:EtOAc (9:1 to 2:1) as eluent yielding 0.8 g (22%) trans-(2E)-[4-(4-Bromo-but-2-enyloxy)-cyclohexyl]-(5-bromo-pyrimidin-2-yl)-methyl-amine as light yellow solid, MS: 418 (MH+, 2Br).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]([CH3:17])=[C:12]([C:14]([OH:16])=[O:15])[N:13]=2)=[CH:4][C:3]=1[O:18][CH3:19].[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:18][CH3:19])[CH:4]=1)[C:9]1[S:10][C:11]([CH3:17])=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1)=[O:24]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COc1cc(Nc2nc(C(=O)O)c(C)s2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc(C(=O)O)c(C)s2)ccc1Cl
Temperature: 50 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
A mixture of 4.3 g (14 mmol) 2-(4-chloro-3-methoxy-phenylamino)-5-methyl-thiazole-4-carboxylic acid, 7.5 g (35 mmol) 2,4-dichloro-benzoyl chloride and 2.01 g (14.5 mmol) potassium carbonate in 200 mL THF was stirred at 50° C. for 18 h. After evaporation of the volatiles the residue was partitioned between water and ethyl acetate. Organic phases were pooled, dried with MgSO4 and the solvent was removed in vacuo. Crystallisation from n-heptane/ethyl acetate yielded 6.6 g (97%) of the title compound.
Reaction SMILES: C1([Si:7]([CH3:16])([CH3:15])[CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)C=CC=CC=1.[C:17]([NH:19][C:20]([NH2:22])=[NH:21])#[N:18]>>[NH2:21][C:20]1[N:19]=[C:17]([NH2:18])[C:9]2[CH:8]([SiH:7]([CH3:15])[CH3:16])[CH:13]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:12][CH2:11][C:10]=2[N:22]=1
Reactant: N#CNC(=N)N
Reactant: C[Si](C)(c1ccccc1)C1CCC(=O)CC1
Product: C[SiH](C)C1c2c(N)nc(N)nc2CCC1c1ccccc1

Procedure:
When the bridging group n is --Si(CH3)2 --, the Grignard reagent of 8-bromo-1,4-dioxaspiro[4.5]decane is reacted with, for example, chlorodimethylphenylsilane, affording 8-phenyldimethylsilyl-1,4-dioxaspiro[4.5]decane. The 1,4-dioxaspiro functional group is then cleaved from the so-prepared molecule with acetic acid and water, yielding the corresponding 4-(phenyldimethylsilyl)cyclohexanone. The cyclohexanone is then reacted with cyanoguanidine, affording the target 2,4-diamino-6-phenyldimethylsilyl-5,6,7,8-tetrahydroquinazoline. Example 14 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=[O:22])=[CH:13]1>>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH:21]=[O:22])=[CH:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: O=Cc1cn(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12
Yield: 61.6 %

Procedure:
The same procedures used in Example 7 were repeated except for using 5.96 g of 4-nitrobenzyl bromide and 2.00 g of indole-3-carbaldehyde as a starting material to give 2.38 g of 1-(4-nitrobenzyl) indole-3-carbaldehyde as pale brown crystals. The yield thereof was found to be 62%.