Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:32])[N:8]2[C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]([F:27])[C:20]=3[F:28])[C:14]([O:29][CH3:30])=[CH:13][C:12]=2[Cl:31])=[C:4]([O:33][CH3:34])[N:3]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([NH:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:32])[N:8]2[C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]([F:27])[C:20]=3[F:28])[C:14]([O:29][CH3:30])=[CH:13][C:12]=2[Cl:31])=[C:4]([O:33][CH3:34])[N:3]=1)(=[O:37])[CH3:36]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(N)nc32)cc1OCc1c(OC)ccc(F)c1F
Reactant: CC(=O)OC(C)=O
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(NC(C)=O)nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 110 °C

Procedure:
A mixture of 2-amino-9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (29 mg) and acetic anhydride (3 mL) was stirred at 110° C. in a reaction vessel equipped with a reflux condenser for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (2 mL). To the solution were added sodium methoxide (28% methanol solution, 2 mL) and water (1 mL), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. To the residue was added a mixed solvent (n-hexane/ethyl acetate=1/1), and the precipitated crystals were collected by filtration. The collected crystals were washed with diethyl ether, and dried under reduced pressure to give the title compound (20 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15]N(C)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.BrC1C=CC(CC=[O:27])=C(NC2CCN(C)CC2)C=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][O:27][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CN1CCC(Nc2cc(Br)ccc2CC=O)CC1
Reactant: CN1CCC(n2ccc3ccc(Br)cc32)CC1
Product: Brc1ccc2ccn(C3CCOCC3)c2c1

Procedure:
6-Bromo-1-(N-methyl-piperidin4-yl)-indole; from 4-Bromo-2-[(N-methyl-piperidin-4-yl)amino]-phenylacetaldehyde, dimethyl acetal (108 mg, 0.30 mmol). Yield 69.4 mg (79%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[CH3:9][O:10][C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[CH3:9][O:10][C:11]1[C:12]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=2)=[CH:13][CH:14]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:16]=1
Reactant: Cc1cc(Br)ccn1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(-c2ccnc(C)c2)c(OC)n1
Temperature: 80 °C

Procedure:
Degassed 1,2-dimethoxyethane (60 mL) and water (0.5 mL) were added to a flask charged with 4-bromo-2-methylpyridine (1.20 g, 6.98 mmol), methyl 6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (C31) (3.07 g, 10.5 mmol), potassium phosphate (4.44 g, 20.9 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.81 g, 0.70 mmol). The mixture was heated to 80° C. for 18 hours, then cooled to room temperature and concentrated in vacuo. Silica gel chromatography (Eluant: ethyl acetate) provided a solid, which was triturated twice with a 1:5 mixture of ethyl acetate and heptane to provide the title compound as a white solid. Yield: 1.68 g, 6.50 mmol, 93%. LCMS m/z 259.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.63 (s, 3H), 4.00 (s, 3H), 4.09 (s, 3H), 7.32 (br d, J=5.5 Hz, 1H), 7.36 (br s, 1H), 7.79 (AB quartet, JAB=7.3 Hz, ΔνAB=24.1 Hz, 2H), 8.57 (d, J=5.0 Hz, 1H).
Reaction SMILES: C1(COC([N:11]2[CH2:16][CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]4=[O:33])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=O)C=CC=CC=1>CO.[Pd]>[O:33]=[C:24]1[N:23]([C:20]2[CH:21]=[CH:22][C:17]([CH:14]3[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)=[CH:18][CH:19]=2)[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)OCc4ccccc4)CC3)cc2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)cc2)C(=O)O1
Reaction time: 16 h

Procedure:
A mixture of (S)-(-)-[4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylic acid phenylmethyl ester (EXAMPLE 17, Step 5, 625 mg) and 10% palladium-on-carbon (300 mg) in methanol (100 mL) is shaken on a Parr apparatus under a hydrogen atmosphere at 40 psi for one hour and at 20 psi for 16 hours, the catalyst is removed by filtration through Celite and the filtrate is concentrated under reduced pressure to give the title compound, mp 169-171° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CCN2Cc1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1)CCN2Cc1ccccc1
Yield: 79 %

Procedure:
A solution of compound 55e (80.2 mg, 0.3 mmol), and LiOH.H2O (50.4 mg, 1.2 mmol) in THF/H2O (1.2/1.2 mL) was stirred at room temperature overnight. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH ˜4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give 55f (60 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 254.1.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][CH2:17][CH:18]1[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20][CH2:19]1>CN(C=O)C>[CH3:24][C:21]1([CH3:25])[O:22][CH2:23][CH:18]([CH2:17][CH2:16][N:1]2[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]2=[O:3])[CH2:19][O:20]1
Reactant: CC1(C)OCC(CCBr)CO1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCn2ccc(=O)[nH]c2=O)CO1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
To a solution of uracil (88.5 g, 0.79 mol) in dry DMF (250 mL) was added cesium carbonate (171 g, 0.527 mol) at RT and stirred at the same temperature for 30 min. To the above reaction mixture was added a solution of compound 33 (117 g, 0.527 mol) in dry DMF (250 mL) over a period of 30 min and heated at 50° C. for 24 h. The reaction mixture was filtered, filtrate concentrated under vacuum and crude purified by column chromatography over silica gel (3% methanol in chloroform) to give the title compound (60 g, 45%). TLC: Chloroform/Methanol, 4:1, Rf=0.3
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[CH:33]=4)[CH:27]=3)[CH2:23][C:22](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)CC(C)C)c(Cl)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (4-chloro-5-(isobutyl-methyl-amino)-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M89) (0.35 g, 0.63 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (114 mg, 41%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH:6]=1)[CH3:2].[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][CH:14]([N:19]3[CH2:22][CH:21]([NH:23][C:24](=[O:25])[CH2:26][NH:27][C:28](=[O:39])[C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=4)[CH2:20]3)[CH2:13][CH2:12]2)[CH:6]=1)[CH3:2]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CCOC(=O)c1cccc(C2CCC(=O)CC2)c1
Product: CCOC(=O)c1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compound was prepared as a white solid by the reductive amination of 3-(4-oxo-cyclohexyl)-benzoic acid ethyl ester (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].P(OCC)(OCC)(O[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.ClC1C=CC(CC2C=C(C=O)SC=2)=CC=1>>[CH2:14]([C:6]1[O:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOP(=O)(OCC)OCc1ccccc1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Product: O=Cc1ccc(Cc2ccccc2)o1
Yield: 34.9 %

Procedure:
The title compound was synthesized from 5-formylfuran-2-ylboronic acid (0.80 g, 5.7 mmol) and benzyl diethyl phosphate (1.5 g, 6.3 mmol) using the same conditions used to synthesize 4-(4-chlorobenzyl)thiophene-2-carbaldehyde. Purification by flash chromatography yielded 5-benzyl-furan-2-carbaldehyde as a brown solid (0.37 g, 65%). 1H NMR (400 MHz, CDCl3) δ ppm 9.56 (s, 1H) 7.29-7.38 (m, 3H) 7.24-7.28 (m, 2H) 7.17 (d, J=3.5 Hz, 1H) 6.19 (d, J=3.6 Hz, 1H) 4.07 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-])=O)=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])(C)C.[C:21](OCC)(=O)[CH3:22].C([O-])=O.[NH4+]>CO.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:6]([O:5][CH2:1][CH2:4][CH2:21][CH3:22])=[O:7])[CH:9]=[N:10][C:11]=2[C:16]=1[CH3:17]
Reactant: CCOC(C)=O
Reactant: Cc1c([N+](=O)[O-])ccc2c1ncn2C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCCOC(=O)n1cnc2c(C)c(N)ccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-methyl-5-nitrobenzimidazole (8 g) in methanol (40 mL)/ethyl acetate (400 mL) is added palladium-on-carbon (Pd/C) (10%, 0.5 g) and ammonium formate (7.27g). The mixture is stirred at 50° C. for 2 hours, then filtered on Celite, with methanol wash of the solids. The filtrate is rotary evaporated and the residue partitioned between water and ethyl acetate. The organic layer is washed with saturated ammonium chloride, dried over magnesium sulfate, filtered and rotary evaporated to afford pure 5-amino-1-1-butoxycarbonyl-4-methylbenzimidazole as an off-white solid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:46]=[C:45]2[C:40]([CH2:41][CH2:42][C:43](=[O:52])[N:44]2[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=1>CCOC(C)=O.CCCCCCC>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41][CH2:42][C:43](=[O:52])[N:44]3[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCN1C(=O)CCc2ccc(CCl)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.477 g of tertbutyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.268 g of 7-chloromethyl-1-(3-methoxypropyl)-3,4-dihydro-1H-quinolin-2-one are reacted. The We compound is obtained as a slightly yellowish oil. Rf=0.11 (1:1 EtOAc-heptane); Rt=5.89.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]([C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[CH2:10][CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O.[CH2:32]([N:34](CC)[CH2:35][CH3:36])[CH3:33].N1CCCC1>C1(C)C=CC=CC=1>[CH3:8][N:9]([C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)[CH2:10][CH2:11][N:34]1[CH2:35][CH2:36][CH2:33][CH2:32]1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CN(CCN1CCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-[methyl-(4-nitro-phenyl)-amino]-ethyl ester TFA salt (74 mg, 0.21 mmol) in toluene (1 mL) is added triethylamine (50 μL) and pyrrolidine (53 μL, 0.63 mmol). The mixture is shaken in 70° C. block shaker overnight. The reaction mixture is concentrated and purified by reverse phase high performance liquid chromatography to give methyl-(4-nitro-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amine as a di-TFA salt (85 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[N:19]([C:31]4[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=4)[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[N:22]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][CH2:39][C@H:40]([NH2:44])[C:41]([OH:43])=[O:42]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[N:19]([C:31]4[CH:36]=[CH:35][C:34]([NH:44][C@@H:40]([CH2:39][CH3:38])[C:41]([OH:43])=[O:42])=[CH:33][CH:32]=4)[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[N:22]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(I)cc3)cc2)cc1
Reactant: CC[C@H](N)C(=O)O
Product: CC[C@H](Nc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1)C(=O)O

Procedure:
2-(4′-tert-Butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1-(4-iodo-phenyl)-1H-imidazole (191 mg, 0.3 mmol) was treated as described in general procedure R using L-2-aminobutyric acid (310 mg, 3 mmol) to give (S)-2-{-4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-butyric acid, which was then treated as described in general procedure F to give (4S)-5-{-4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-4-ethyl-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[CH3:17][O:18][C:19](=[O:22])[CH2:20]Br>CN(C=O)C>[CH3:17][O:18][C:19](=[O:22])[CH2:20][O:16][C:13]1[CH:14]=[N:15][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[F:3])=[CH:11][CH:12]=1
Reactant: Oc1ccc(-c2ccccc2F)nc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(-c2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, 157.3 mg (3.6 mmol) of sodium hydride (55% suspension in mineral oil) were added to 620 mg (3.27 mmol) of 6-(2-fluorophenyl)pyridin-3-ol in 25 ml of DMF. After stirring at room temperature for 60 min, 551.4 mg (3.6 mmol) of bromoacetic acid methyl ester were added, and the reaction mixture was stirred at room temperature for 2 h. After concentrating, water was added, and the mixture was extracted with ethyl acetate. The organic phase was separated and concentrated. Yield: 687 mg (80%).
Reaction SMILES: [CH2:1]=[C:2]1[O:5][C:4](=[O:6])[CH2:3]1.[C:7]1([CH2:13][NH2:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[CH2:13]([NH:14][C:4](=[O:6])[CH2:3][C:2](=[O:5])[CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: C=C1CC(=O)O1
Solvent: ClCCl
Product: CC(=O)CC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 4-methyleneoxetan-2-one (60.00 g, 713.69 mmol) in DCM (600 mL) was added phenylmethanamine (91.76 g, 856.43 mmol) dropwise at 0° C. After addition, the reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was beaten with a mixture of PE and EtOAc (10/1 (v/v), 200 mL) for 1 h and filtered. The filter cake was washed with a mixture of PE and EtOAc (10/1 (v/v), 100 mL) to give the title compound as a yellow solid (136.38 g, 100%).
Reaction SMILES: [Na].[Br-].[Li+].C([O:6][C:7](=O)[CH:8]([F:22])[CH2:9][CH2:10][N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([NH2:21])=[N:15][C:16]=2[Cl:20])C.Cl.C(=O)([O-])O.[Na+]>>[NH2:21][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[CH2:10][CH2:9][CH:8]([F:22])[CH2:7][OH:6])=[C:16]([Cl:20])[N:15]=1
Reactant: CCOC(=O)C(F)CCn1cnc2c(Cl)nc(N)nc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Br-]
Product: Nc1nc(Cl)c2ncn(CCC(F)CO)c2n1
Temperature: 100 °C
Yield: 60.4 %

Procedure:
Sodium borohyride (15 mg) was dissolved in dry diethyleneglycoldiethylether (0.9 ml) and stirred. Finely powdered and dry lithiumbromide (34 mg) was added, followed after 1/2 hour by 4-(2-amino-6-chloropurin-9-yl)-2-fluorobutyric acid ethyl ester (100 mg). The reaction mixture was heated at 100° C. for 3 hours, then poured onto crushed ice (10 g) with added concentrated hydrochloric acid (0.5 ml) and stirred. The pH was adjusted to 6.5 by sodium hydrogen carbonate, the solution was evaporated in vacuo and the residue was redissolved in methanol-chloroform (40-60, 10 ml) and filtered. The solution was purified by chromatography on a silica gel column eluted with a methanol-chloroform gradient, to give the desired product (52 mg, 60%) TLC (silica gel, methanol-chloroform 40-60): Rf =0.66. UV (ethanol)λmax : 310 and 247 nm.
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37].O1C2C=CC(C3(C(NC4C=CC(C(N(C)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([N:38]([CH2:39][CH3:40])[CH2:36][CH3:37])[C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])=[CH:16][N:17]=4)=[O:23])[CH2:26][CH2:25]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: CCNCC
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Product: CCN(CC)C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)c1ccccc1OC

Procedure:
1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((diethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and diethylamine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:17])=[CH:11]2.CN([CH:21]=[O:22])C>>[CH:21]([C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([O:7][CH3:6])[CH:9]=2)[NH:13][C:12]=1[CH3:17])=[O:22]
Reactant: CN(C)C=O
Reactant: COc1ccc2[nH]c(C)cc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c(C)c(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 60 mL of DMF at 0° C. was added 10.1 mL of phosphorous oxychloride dropwise. The resulting solution was stirred 10 min at 0° C., then was treated dropwise with a solution of 5-methoxy-2-methylindole (16.2 g, 100 mmol) in 25 mL of DMF. The orange solution was wanned to 40° C. for 45 min, then cooled and quenched with ice. The mixture was then poured into 300 mL of ice water and treated with 100 mL of 10N NaOH. The resulting slurry was heated to reflux for 4 h, then cooled and filtered. The solid was rinsed with water and air-dried to give 18.7 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C>ClCCl.O.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:24][C:23]1[CH:25]=[CH:26][C:20]([Cl:19])=[CH:21][CH:22]=1)=[O:9]
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1ccc(Br)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Br)cc1C(=O)Nc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
5-Bromo-2-methoxybenzoic acid (20 g) obtained in step B and 0.34 mL of N,N-dimethylformamide were dissolved in 380 mL of dichloromrethane, and the solution was cooled to 0° C. This solution was stirred for 30 minutes at 0° C., with oxalyl chloride (11.3 mL) being added little by little thereto, and then the mixture was stirred for 3 hours at room temperature. The reaction mixture was distilled under reduced pressure and dried to obtain a light yellow solid. This solid was added, with the use of 120 mL of dichloromethane, to a solution of 11.1 g of 4-chloroaniline and 45 mL of N,N-diisopropylethylamine dissolved in 380 mL of dichloromethane. The mixture was stirred for 2 hours and a half at room temperature, and then 300 mL of water was added. The organic layer was separated, and the aqueous layer was extracted twice with 100 mL of dichloromethane. After the respective organic layers were combined, the combined organic layer was washed with 200 mL of a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and then washed with dichloromethane. The filtrate and the washings were combined, dichloromethane was distilled off under reduced pressure, and the resulting residue was washed with methanol. The resulting solid was dried under reduced -pressure to obtain 23.6 g (80%) of 5-bromo-N-(4-chlorophenyl)-2-methoxybenzamide.
Reaction SMILES: [CH3:1][P:2]([O-:8])[O:3][CH2:4][CH:5]([CH3:7])[CH3:6].[C:9](#[N:13])/[CH:10]=[CH:11]/[CH3:12].[H-].[Na+].C(O)(=O)C>C(O)C>[C:9]([CH2:10][CH:11]([P:2]([CH3:1])(=[O:8])[O:3][CH2:4][CH:5]([CH3:7])[CH3:6])[CH3:12])#[N:13]
Reactant: C/C=C/C#N
Reactant: CC(C)COP(C)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)COP(C)(=O)C(C)CC#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 50.0 g of isobutyl P-methylphosphonite and 22.8 g of crotononitrile in 50 ml of dry ethanol is added to a stirred mixture of 0.8 g of sodium hydride (50% dispersion in oil) in 25 ml of ethanol at 0° C. , under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture is concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 25 ml of water, and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled to give isobutyl P-(3-cyanoprop-2-yl)-P-(methyl)phosphinate, b.p. 110°/0.125 mbar, 31P-NMR spectrum: δ=+55.9 and +55.5 ppm (CDCl3).