Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(N(C(C)C)CC)(C)C.[N:40]12[CH2:50][CH2:49][CH2:48][N:47]=[C:46]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2>C1COCC1>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][CH:9]([C:4]2[CH:3]=[C:2]([N:1]=[C:46]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][N:40]3[CH2:50][CH2:49][CH2:48][NH:47][C:25]3[N:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:7]=[C:6]([CH3:8])[CH:5]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:21][CH:20]=1)#[N:23]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(C)cc(N)c1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Clc1ncccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(C)cc(N=C2CCCCCN2CCCNc2ncccn2)c1
Yield: 23.2 %

Procedure:
A solution of the ethyl (RS)-(3-amino-5-methyl-phenyl)-(4-cyano-phenylamino)-acetate (475 mg, 1.54 mmol) obtained in Example 216.3, 2-chloropyrimidine (400 mg, 3.38 mmol), diisopropylethylamine (317 μl, 1.85 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (276 μl, 1.85 mmol) in THF (4 ml) was heated under reflux for 2 h. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, hexane/EtOAc 1:1→EtOAc). There were obtained 193 mg (23%) of ethyl (RS)-(4-cyano-phenylamino)-(3-methyl-5-{1-[3-(pyrimidin-2-ylamino)-propyl]-azepan-2-ylideneamino}-phenyl)-acetate as a yellowish foam; MS: 540 ([M+H]+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=O)C.O.[NH2:17][NH2:18]>C(O)C>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[C:4]([NH:17][NH2:18])=[O:3]
Reactant: NN
Reactant: CCOC(=O)c1ccc2ccccc2c1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc2ccccc2c1
Yield: 48.4 %

Procedure:
To a solution of 2-naphthyl carboxylic acid ethyl ester (2.0 g, 9.99 mmol) in absolute ethanol (30 ml) was added hydrazine hydrate (4.85 ml, 99.9 mmol) and the reaction mixture was heated at reflux temperature for 72 h. The reaction mixture was cooled and the precipitate was filtered off, washed with 96% ethanol (2×10 ml) and diethyl ether (3×10 ml), dried in vacuo at 50° C. which afforded 0.9 g (48%) of naphthalene-2-carboxylic acid hydrazide as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[CH3:26][N:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=2)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNc1ccccc1C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (50 mg, 0.12 mmol), methyl-o-tolyl-amine (44 mg, 0.36 mmol), BOP (69 mg, 0.36 mmol), DIEA (130 μL, 0.72 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methyl-o-tolyl-amide: MS m/z: (M+H) 518.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.[C:14]([CH2:16]C(O)=O)#[N:15].C(O)(=O)CCCCCC.C(N)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[CH2:16][C:14]#[N:15])=[CH:5][CH:4]=1
Reactant: N#CCC(=O)O
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: CCCCCCC(=O)O
Solvent: Cc1ccccc1
Solvent: NCc1ccccc1
Product: COc1ccc2c(c1)C(CC#N)=CCC2
Yield: 90 %

Procedure:
There are introduced into a 670 liter reactor 85.0 kg of 7-methoxy-1-tetralone, 60.3 kg of cyanoacetic acid and 15.6 kg of heptanoic acid in toluene in the presence of 12.7 kg of benzylamine. The mixture is heated at reflux. When all the starting substrate has disappeared, the solution is cooled and filtered. The precipitate obtained is washed with toluene and then the filtrate obtained is washed with a 2N sodium hydroxide solution and subsequently with water until neutral. After removal of the solvent by evaporation, the resulting solid is recrystallised from an ethanol/water (80/20) mixture to give the title product in a yield of 90% and with a chemical purity exceeding 99%.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24](=[O:27])[CH2:25][CH3:26])=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1.FC(F)(F)S(O[Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[C:41]([Si:38]([CH3:40])([CH3:39])[O:27][C:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[CH:15]=[CH:14][C:12]2[NH:13][C:9]([CH2:8][O:7][C:6]3[CH:28]=[CH:29][C:3]([C:2]([F:1])([F:30])[F:31])=[CH:4][CH:5]=3)=[N:10][C:11]=2[CH:17]=1)=[CH:25][CH3:26])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCC(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC=C(O[Si](C)(C)C(C)(C)C)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a solution of 1-{2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-phenyl}-propan-1-one (0.073 g, 0.172 mmol) in CH2Cl2 (4 mL)) at 0° C. was added tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) (0.109 g, 0.413 mmol) and triethylamine (0.07 mL, 0.516 mmol). After stirring for 2 hours, the reaction mixture was concentrated, and the residue was purified by chromatography (silica, hexanes: EtOAc, 4:1) to afford the title compound as a yellow oil (0.065 g, 86%).
Reaction SMILES: O[C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.S(Cl)([Cl:21])=O>>[Cl:21][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])cnc1O
Solvent: CN(C)C=O
Product: O=C(O)c1cc([N+](=O)[O-])cnc1Cl
Temperature: 80 °C
Yield: 68 %

Procedure:
2-Hydroxy-5-nitro-nicotinic acid (2.7 mmol) in a mixture of N,N-dimethylformamide (2.7 mmol) and thionyl chloride (5 ml) was heated at 80° C. for 1 h. The mixture was allowed to cool and concentrated in vacuo. To the resulting residue was added ice-water (20 ml) and with vigorous stirring a precipitate formed. The precipitate was filtered off and dried in a vacuum oven to give a white solid (68%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[CH2:3]1.[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:10][C:11]1[C:12]([C:9]#[C:8][CH2:7][N:4]2[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCN1CC[C@@H](O)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN3CC[C@@H](O)C3)c21

Procedure:
Using Method C above, (R)-3-Hydroxy-1-prop-2-ynyl-pyrrolidine (60 mg, 0.48 mmol) (Example 92A) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.16 mmol) (Starting Material 6) using (Ph3P)4Pd (18 mg, 0.02 mmol) and a catalylic amount of CuI in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 6 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-1,3-Dihydro-5-fluoro-4-[3-(3-hydroxy-pyrrolidin-1-yl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-20% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 45 mg, 76%).
Reaction SMILES: [C:1](=[O:19])([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:7]=1)[O:2][CH2:3][CH3:4].[H-].[Na+].Cl.Cl[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CN(C=O)C.C(Cl)Cl>[C:1](=[O:19])([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([N:14]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[S:15]([CH3:18])(=[O:16])=[O:17])[CH:7]=1)[O:2][CH2:3][CH3:4]
Reactant: CCOC(=O)Oc1ccc(OC)c(NS(C)(=O)=O)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(OC)c(N(CCN2CCOCC2)S(C)(=O)=O)c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 21.1 %

Procedure:
A solution of ethyl 4-methoxy-3-(methylsulfonamido)phenyl carbonate (0.850 g, 2.94 mmol) in dry DMF (15 ml) was cooled to 0° C. under nitrogen atmosphere, and sodium hydride (60% w/w, 0.300 g, 7.50 mmol) was added portion-wise. After 10 minutes, the cold bath was removed, 4-(2-chloroethyl)morpholine hydrochloride (0.680 mg, 3.65 mmol) was added, and the mixture was heated to 90° C. for 2 hours. After cooling to RT, the reaction mixture was diluted with DCM and washed with water. The organic layer was washed with brine and dried over Na2SO4; the solvent was evaporated and the crude was purified by flash chromatography on silica gel column (DCM:MeOH=10:0.1) affording ethyl 4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)-phenyl carbonate (0.250 g, 0.621 mmol, 21.14% yield, UPLC-MS purity: 97%, MS/ESI+ 403.1 [MH]+).
Reaction SMILES: [C:1]([S:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1.CO.Cl>C1COCC1.CCOC(C)=O>[C:1]([S:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][NH2:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Sc1ccccc1C#N
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)Sc1ccccc1CN
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.2 %

Procedure:
To a solution of 2-(tert-butylthio)benzonitrile (Guiu, E. et al., J. Organomet. Chem., 689:1911-1918 (2004)) (1.00 g, 5.23 mmol) in THF (10.5 mL) was added BH3.THF (10.5 mL, 10.5 mmol, 1.0M solution in THF) via syringe. The resulting clear, colorless solution was stirred at room temperature for 1.5 h and then at 50° C. for 2 h. The reaction mixture was cooled to room temperature, and MeOH (2.5 mL) was added carefully via syringe (gas evolution) followed by 1N aq. HCl solution (12.0 mL). The mixture was poured into EtOAc and the layers were separated. The aqueous layer was basified with 1N aq. NaOH solution (pH=12) and then extracted with CH2Cl2 (5×). The combined CH2Cl2 extracts were dried over MgSO4, filtered and concentrated in vacuo to give the title compound (288 mg, 28%) as a colorless oil. 1H NMR (CDCl3) δ 7.57-7.53 (m, 1H), 7.44-7.40 (m, 1H), 7.37-7.32 (m, 1H), 7.25-7.19 (m, 1H), 4.07 (s, 2H), 1.30 (s, 9H); MS(ESI+) m/z 196.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH:29]1[CH2:31][CH2:30]1>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:28][CH:29]3[CH2:31][CH2:30]3)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: BrCC1CC1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(OCC2CC2)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 90 °C
Yield: 39.7 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (25 mg, 0.095 mmol), potassium carbonate (26 mg, 0.19 mmol) and (bromomethyl)cyclopropane (14 μL, 0.14 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 90° C. for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography of the residue using hexanes/ethyl acetate/dichlrormethane (3.5:0.5:4) followed by trituration with diethyl ether afforded 12 mg (41%) of 3-(2-pyridyl)-5-(3-cyano-5-cylopropylmethoxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.86 (d, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 7.99 (s, 1H), 7.91 (t, 1H), 7.50 (m, 1H), 7.40 (s, 1H), 3.95 (d, 2H), 1.21 (m, 1H), 0.72 (m, 2H), 0.41 (m, 2H).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH2:12][C@H:11]1[C@:6]2([NH:17][CH3:18])[CH2:7][CH2:8][CH2:9][CH2:10]1.[NH4+].[OH-:20]>Br>[CH3:18][NH:17][C@@:6]12[CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:3]=[CH:4][C:5]2=1
Reactant: CN[C@]12CCCC[C@H]1CCc1ccc(OC)cc12
Reactant: [OH-]
Agent: Br
Agent: [NH4+]
Product: CN[C@@]12CCCC[C@@H]1CCc1cc(O)ccc12
Yield: 74 %

Procedure:
A solution of the product from Example 133 (150 mg) in 48% aqueous HBr was heated at reflux for 2.5 hours. The reaction mixture was poured into cold aqueous NH4OH solution. The resulting solution was extracted with ethyl acetate (3×25 ml), dried (MgSO4) and filtered. Evaporation of the solvent and drying in vacuo afforded the title compound as a tan solid (90 mg, 74%), mp 191° C.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][N:4]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:12]([CH2:20][CH2:21][C:22](OC)=[O:23])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:26]>ClCCl.CO>[CH3:1][NH:2][C:22](=[O:23])[CH2:21][CH2:20][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:26])[N:4]([CH3:3])[C:13]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)CCc1c(-c2ccccc2)n(C)c(=O)c2ccccc12
Reactant: CN
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)CCc1c(-c2ccccc2)n(C)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A stream of gaseous methylamine is passed into a 250 ml round-bottomed flask containing a solution of 1.25 g (3.85 mmol) of methyl 2-methyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-4-propanoate in 20 ml of dichloromethane and 80 ml of methanol until saturation and the mixture is left stirring at room temperature for 3 days. The solvents are evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate ranging from 100/0 to 80/20 and then with a 95/5 mixture of dichloromethane and methanol. After recrystallizing from acetonitrile, 0.85 g (2.65 mmol) of white crystalline solid is obtained. Melting point: 185°-186° C.
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1.[C:16]1([CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Mg]Br.[C:25]1([Mg]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC1C=CC=CC=1C.O1CCCC1.C(OCC)C>[OH:3][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[PH:2][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:24]1[CH:29]=[CH:30][CH:25]=[CH:26][C:27]=1[CH3:28]
Reactant: Cc1ccccc1[Mg]Br
Reactant: Br[Mg]c1ccccc1
Reactant: ClP1Oc2ccccc2-c2ccccc21
Solvent: CCOCC
Solvent: Cc1ccccc1C
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccccc1Pc1ccccc1-c1ccccc1O
Temperature: 25 °C
Yield: 100 %

Procedure:
16.4 g (70 mmol) of 6-chloro-6H-dibenz[c,e][1,2]oxaphosphorine in 50 ml of anhydrous o-xylene are introduced, in an argon atmosphere with stirring, and a solution of 70 mmol of 2-tolylmagnesium bromide in tetrahydrofuran are added dropwise at -10° C. The mixture is slowly heated to 25° C. and stirred for 3 hours. A solution of 70 mmol of phenylmagnesium bromide in 50 ml of diethyl ether is added dropwise and the mixture is then heated to 65° C., the diethyl ether being distilled off. The mixture is stirred for a further 2 hours at 120° C., cooled to room temperature and 100 ml of water are added. The mixture is neutralized with dilute hydrochloric acid, the organic phase is separated off, dried with sodium sulfate and concentrated under reduced pressure. 25.8 g of colorless crystals are obtained. By recrystallization from methanol/water, 10:1, 20.4 g (79%) of colorless crystals having melting point 98 at 101° C. are obtained.
Reaction SMILES: [C:1]([CH:3]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6])#[N:2].C(O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCC[Sn](O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC>>[C:1]([CH:3]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:4][C:5]([O:7][CH2:8][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:6])#[N:2]
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Reactant: OCc1ccccc1
Agent: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Product: N#CC(CC(=O)OCc1ccccc1)c1ccc(O)cc1
Reaction time: 0.5 h
Yield: 6 %

Procedure:
To the microwave vial was charged with isomer methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (+ve) (0.5 g, 2.4 mmole) & benzyl alcohol (0.5 mL, 4.8 mmol), was added tributyltinoxide (0.03 g, 5% W/W). Temperature was set 90° C. & energy is fixed at 250 W for 30 mins. After completion of the reaction (monitored by TLC), the RM mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine solution, dried over anhydrous Na2SO4 and evaporated to dryness gave the titled compound (0.040 g, yield: 6.0%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9](Cl)=[O:10])[O:5][CH:6]=1.[N-:12]=[N+:13]=[N-:14].[Na+].C(OCC)(=O)C>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([N:12]=[N+:13]=[N-:14])=[O:10])[O:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Cl)/C=C/c1cc(Br)co1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: [N-]=[N+]=NC(=O)/C=C/c1cc(Br)co1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.3 %

Procedure:
A solution of (E)-3-(4-bromofuran-2-yl)acryloyl chloride (4.0 g, 16.99 mmol) in 10 mL of 1,4-dioxane was added to a solution of sodium azide (2.21 g, 34.0 mmol) in 10 mL of water and 10 mL of 1,4-dioxane. The reaction mixture was stirred for 2.5 h at room temperature. The reaction mixture was mixed with ethyl acetate and water. Phases were separated and the aqueous phase was extracted with ethyl acetate (twice). The combined organic phases were washed with brine, dried, filtrated and concentrated to give 4 g of the title compound (yield: 97%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.Cl.C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:70](NCC4C=CC=CN=4)=[O:71])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[NH2:100][CH2:101][C:102]1[CH:107]=[CH:106][N:105]=[CH:104][CH:103]=1>>[OH:29][C@@H:17]1[C@H:18]([OH:28])[C@@H:19]([N:21]2[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[N:22]2)[CH2:20][C@H:16]1[N:13]1[CH:12]=[N:11][C:10]2[C:14]1=[N:15][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][C:70]([NH:100][CH2:101][C:102]3[CH:107]=[CH:106][N:105]=[CH:104][CH:103]=3)=[O:71])[CH2:3]1)=[N:8][C:9]=2[NH:30][CH2:31][CH:32]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)C1
Reactant: NCc1ccncc1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: O=C(NCc1ccncc1)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)C1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol. (Intermediate FB) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethylpyridine with 4-aminomethylpyridine. MS (ES+) m/e 730.55 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH2:11]([NH:15][CH2:16][CH:17]=[O:18])[CH2:12][CH:13]=[CH2:14]>C1C=CC=CC=1>[CH2:11]([N:15]([CH2:16][CH:17]=[O:18])[C:9]([NH:8][C:6]1[S:7][C:3]([O:2][CH3:1])=[N:4][N:5]=1)=[O:10])[CH2:12][CH:13]=[CH2:14]
Reactant: COc1nnc(N=C=O)s1
Reactant: C=CCCNCC=O
Solvent: c1ccccc1
Product: C=CCCN(CC=O)C(=O)Nc1nnc(OC)s1

Procedure:
A mixture of 5-methoxy-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the diethyl acetal of 2-but-3-enylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield the desired product the diethyl acetal of 2-[1-but-3-enyl-3-(5-methoxy-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[CH3:11]I>>[CH3:9][C:5]1[C:6]([C:7]#[N:8])=[C:2]([NH:1][CH3:11])[S:3][C:4]=1[CH3:10]
Reactant: Cc1sc(N)c(C#N)c1C
Reactant: CI
Product: CNc1sc(C)c(C)c1C#N

Procedure:
Prepared as in Example 21b from 2-amino-4,5-dimethylthiophene-3-carbonitrile and methyl iodide.
Reaction SMILES: [C:1](O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[NH:33][C:32]3[CH:34]=[CH:35][C:36]([C:38]([NH2:40])=[O:39])=[CH:37][C:31]=3[N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[NH:33][C:32]3[CH:34]=[CH:35][C:36]([C:38]([NH2:40])=[O:39])=[CH:37][C:31]=3[N:30]=2)=[CH:27][CH:28]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCCCN4)cc3)nc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCCCN4C(=O)c4ccccc4)cc3)nc2c1
Reaction time: 18 h
Yield: 46.8 %

Procedure:
A solution of benzoic acid (75 mg, 0.62 mmol) and EDC (59 mg, 0.31 mmol) in DMF (1 mL) was stirred for 2 h and then was treated with 2-[4-(2-piperidin-2-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide (75 mg, 0.21 mmol) and DMAP (65 mg, 0.53 mmol). The mixture was stirred for 18 h, and the crude material was purified by reverse phase HPLC (C18; H2O/CH3CN/0.01% TFA), providing 46 mg (66%) of the title compound. HPLC (Method C): Rt=5.15. MS (ESI+): mass calcd. for C28H28N4O3, 468.22; m/z found, 469.4 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.19 (s, 1H), 8.00-7.96 (m, 3H), 7.72 (d, J=8.6 Hz, 1H), 7.36-7.25 (m, 2H), 7.25-7.10 (m, 4H), 6.95-6.90 (m, 1H), 4.20-4.07 (m, 2H), 3.92-3.90 (m, 1H), 3.48-3.43 (m, 1H), 2.45-2.35 (m, 1H), 2.12-1.81 (m, 1H), 1.81-1.30 (m, 7H).