Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[C:12]=1[C:19]1[N:24]=[CH:23][C:22]([CH:25]=[O:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH3:10].[Cl-].[NH4+]>CCOCC>[CH:1]1([CH:25]([C:22]2[CH:23]=[N:24][C:19]([C:12]3[C:13]([CH2:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:9][CH3:10])=[CH:20][C:21]=2[O:27][CH2:28][CH3:29])[OH:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1cc(-c2c(CC)cccc2CC)ncc1C=O
Reactant: Cl[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOc1cc(-c2c(CC)cccc2CC)ncc1C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A cyclohexylmagnesium chloride solution (2 M in THF, 1 mL) is slowly added to a solution of 6-(2,6-diethyl-phenyl)-4-ethoxy-pyridine-3-carbaldehyde (prepared as described above) (142 mg, 0.5 mmol) in ether (2 mL) at 0° C., and the resulting mixture is stirred at room temperature for 30 minutes. Saturated ammonium chloride solution (1 mL) is added to quench the reaction. The organic layer is separated and dried over anhydrous Na2SO4. The solvents are removed in vacuo and the crude is purified with PTLC (hexanes/ethyl acetate 3:1) to give cyclohexyl-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-methanol. 1H NMR: (CDCl3) 8.40 (s, 1H), 7.28 (t, 1H), 7.16 (d, 2H), 6.76 (S, 1H), 4.54 (t, 1H), 4.08 (q, 2H), 2.32 (m, 4H), 2.05 (br, 1H), 1.75 (m, 4H), 1.40 (m, 4H), 1.05 (m, 10H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.[CH3:14][C:15]([S@@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6](/[CH:7]=[N:20]/[S@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
In a 50 ml round-bottomed flask, 3-(trifluoromethoxy)benzaldehyde (400 mg, 2.1 mmol) was dissolved in dichloromethane (12 ml) and (S)-2-methylpropane-2-sulfinamide (281 mg, 2.31 mmol) and anhydrous copper (II) sulfate (739 mg, 4.63 mmol) were added. The reaction mixture was stirred at room temperature overnight then filtered through a glass microfiber filter, rinsing with dichloromethane. The filtrate was concentrated and the residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-20% EtOAc) to afford 430 mg (70%) of (S)-2-methyl-propane-2-sulfinic acid 1-(3-trifluoromethoxy-phenyl)-meth-(E)-ylideneamide as a light yellow oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[C@@H:5]([CH3:36])[CH2:4]1.[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:40])[CH2:38][CH3:39])[CH2:4][C@@H:5]4[CH3:36])=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)C[C@@H]1C
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)[C@@H](C)C1

Procedure:
Starting from N-[(1S*,2S*,4S*)-4-amino-2-methylcyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f63) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:8]2=[NH:27])=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CO.O1CCOCC1>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]([CH2:16][CH2:17][CH2:18][O:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[C:8]3=[NH:27])=[CH:28][CH:29]=2)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1COCCO1
Product: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccc(-c2ccc(F)cc2)cc1
Temperature: 100 °C
Yield: 35.5 %

Procedure:
Nitrogen was bubbled through a mixture of 1-(4-bromo-benzyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (80 mg, 0.18 mmol) and 4-fluorophenyl boronic acid (37 mg, 0.26 mmol) in 3:1 MeOH/1,4-dioxane (3 ml) at rt for 10 min before a solution of 2M Na2CO3 (0.17 ml, 0.35 mmol) was introduced. The suspension was degassed for a further 2 min and then PdCl2(dppf) (14 mg, 0.02 mmol) was added. The reaction mixture was sealed and heated to 100° C. where it was maintained for 16 h. After this time, the suspension was cooled to rt and filtered through Celite®. The filtrate was concentrated under reduced pressure and the crude product that remained was purified by preparative HPLC to provide 1-(4′-fluoro-biphenyl-4-ylmethyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (30 mg, 36%). HPLC-MS 470 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>O.C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]([C:12]([C:11]2[CH:15]=[CH:16][C:8]([F:7])=[CH:9][CH:10]=2)=[O:13])=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1cccs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(=O)c2ccc(F)cc2)s1
Reaction time: 4 h

Procedure:
To a stirred mixture of 29.5 parts of 2-methylthiophene, 39.65 parts of p-fluorobenzoyl chloride and 280 parts of methylene chloride are added portionwise 40 parts of aluminium chloride while keeping the temperature at 20° C (water-bath). Upon completion, stirring is continued for 4 hours at room temperature. The reaction mixture is poured onto crushed ice and 50 parts of hydrochloric acid, while stirring vigorously. The layers are separated and the aqueous phase is washed with chloroform. The organic layers are dried and evaporated. The residue is taken up in benzene and the latter is evaporated again. The residue solidifies on triturating in petroleumether. The solid product is filtered off and crystallized from ethanol at -20° C, yielding p-fluorophenyl 5-methyl-2-thienyl ketone; mp. 68° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[CH3:26]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:13]([OH:15])=[O:14])=[CH:19][C:18]=1[CH3:26]
Reactant: COCCOc1ncc(C(=O)O)cc1Br
Reactant: Cc1cc(B(O)O)ccc1Cl
Product: COCCOc1ncc(C(=O)O)cc1-c1ccc(Cl)c(C)c1

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-(2-methoxyethoxy)-3-pyridinecarboxylic acid (CAN 912454-34-3) and B-(4-chloro-3-methylphenyl)-boronic acid (CAN 161950-10-3) as starting materials; LC-MS (UV peak area/ESI) 94%, 322.0842 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[C:10]([CH3:16])[CH:9]=1.C(N(C(C)C)CC)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.O>[CH3:26][S:27]([O:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9][C:10]=1[CH3:16])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2ccccc2Cl)ccc1CO
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ccccc2Cl)ccc1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2′-chloro-3-methylbiphenyl-4-yl)methanol from step 1 in CH2Cl2 (0.13M) at 0° C. was added diisopropyl ethylamine (1.5 eq.) then methanesulfonyl chloride (1.1 eq.). The reaction mixture was stirred at room temperature for 2 h, poured in water and extracted with EtOAc. The organic extract was washed with water, brine, dried over MgSO4 filtered and concentrated to afford the title compound which was used as such in the next step.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([SH:25])[N:19]=2)[CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:26](I)[CH2:27][CH3:28]>N>[OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([S:25][CH2:26][CH2:27][CH3:28])[N:19]=2)[CH:17]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cnc(S)nc1-c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1
Reactant: CCCI
Agent: N
Product: CCCSc1ncc(C)c(-c2c[nH]c(C(=O)N[C@H](CO)c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-mercapto-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (7.7 mmol, 2.74 mmol) in aqueous ammonia (15%) was added at room temperature n-propyliodide (11.6 mmol, 1.1 mL). The solution was stirred overnight at room temperature. The resulting solid was collected by filtration and used directly for the next step. 1H NMR consistent with the structure.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][CH2:16][C:17]1[CH:18]=[C:19]([C:23]#[N:24])[O:20][C:21]=1[CH3:22].[C:25]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:25]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:30]=[CH:29][C:28]([O:15][CH2:16][C:17]2[CH:18]=[C:19]([C:23]#[N:24])[O:20][C:21]=2[CH3:22])=[CH:27][CH:26]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: Cc1oc(C#N)cc1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1oc(C#N)cc1COc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 79.2 %

Procedure:
Diisopropylazodicarboxylate (1.84 g, 10.6 mmoles) was added to a solution of 4-hydroxymethyl-5-methyl-furan-2-carbonitrile (147) (1.32 g, 9.6 mmoles), biphenyl-4-ol (1.63 g, 9.6 mmoles) and triphenylphosphine (4.3 g, 16.35 mmoles) in tetrahydrofuran (50 mL) with stirring and cooling to 0° C. under an argon atmosphere. After 5 minutes, the cooling was removed and the mixture stirred at room temperature for 16 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The ethyl acetate phase was washed with brine and dried. After the solvent was evaporated, the residue was purified by flash chromatography (silica, gradient elution with 5% to 10% ethyl acetate in cyclohexane) to afford compound 148 as a white solid (2.2 g). IR (powder) CN st. 2225 cm−1.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([O:8][CH2:9]OC)[CH:5]=[C:4](OCOC)[C:3]=1[C:16](=[O:18])C>C(O)C>[CH3:9][O:8][C:6]1[CH:7]=[CH:2][C:3]([CH:16]=[O:18])=[CH:4][CH:5]=1
Reactant: COCOc1cc(O)c(C(C)=O)c(OCOC)c1
Solvent: CCO
Product: COc1ccc(C=O)cc1
Yield: 114.5 %

Procedure:
In 45 ml of ethanol were dissolved 6.00 g of the 2'-hydroxy-4',6'-bis(methoxymethoxy)acetophenone obtained in Production Example 11 and 3.65 g of the p-methoxybenzaldehyde obtained in Production Example 25, and the solution was cooled to 0° C. and 55 ml of a saturated solution of potassium hydroxide in ethanol was added to the solution. The mixture was stirred for 24 hours. After the reaction, the reaction liquid was diluted with water and neutralized with 6 N hydrochloric acid, and the formed precipitate was recovered by filtration to obtain 8.17 g (yield=86.3%) of 2'-hydroxy-4,4',6'-tris(methoxymethoxy)chalcone.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([CH3:17])=[C:10]([C:12]([O:14]CC)=[O:13])[N:11]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[CH3:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([CH3:17])=[C:10]([C:12]([OH:14])=[O:13])[N:11]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(-c2ccc(C)s2)sc1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nc(C(=O)O)c(C)s2)s1
Temperature: 60 °C
Yield: 80.6 %

Procedure:
To a solution of ethyl 2-(5-methyl-2-thienyl)-5-methyl-4-thiazolecarboxylate (1.47 g) in methanol (100 ml) was added 1N aqueous potassium hydroxide (16.5 ml) and the mixture was heated at 60° C. for 40 minutes. Then the solvent was removed from the reaction mixture. The residue was treated with water and acidified with 2N hydrochloric acid under ice-cooling. The deposited solids were filtered and washed with water, recrystallized from methanol-water to give yellowish crystals of 2-(5-methyl-2-thienyl)-5-methyl-4-thiazolecarboxylic acid (1.06 g, yield 80%), m.p. 160°-161° C.
Reaction SMILES: CC1[NH:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[CH3:11][C:12]1([CH:16]=O)[CH2:15][O:14][CH2:13]1>>[CH3:11][C:12]1([C:16]2[NH:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=2)[CH2:15][O:14][CH2:13]1
Reactant: CC1(C=O)COC1
Reactant: Cc1nc(C(F)(F)F)c[nH]1
Product: CC1(c2nc(C(F)(F)F)c[nH]2)COC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 16.2, except 3-methyloxetane-3-carbaldehyde was used in place of acetaldehyde. m/z (ES+) 207(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([Br:7])=[N:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Br:7][C:5]1[S:6][C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([F:13])=[CH:15][CH:16]=2)=[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:4]=1
Reactant: CCOC(=O)c1nc(Br)sc1N
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(Br)sc1NC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
To a mixture of ethyl 5-amino-2-bromothiazole-4-caboxylate (0.50 g, 1.99 mmol) and a catalytic amount of DMAP in pyridine (5 mL) was added a solution of 4-fluorobenzoyl chloride (0.377 g, 2.39 mmol) in pyridine (5 mL) at 0° C. The mixture was allowed to warm to rt, and stirred for 16 hrs. The reaction mixture was quenched with ice-water, and the resulting solids were collected. The solids were purified by silica gel column chromatography eluted with 20% EtOAc in hexane to give 0.70 g (93% yield) of the title compound.
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCCl>[F:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][CH:23]2[CH2:22][NH:21][CH2:24]2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Fc1ccc(OC2CNC2)cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
1-chloroethyl chloroformate (0.87 ml, 8.09 mmol) was added to an ice-cooled solution of 1-benzhydryl-3-(4-fluorophenoxy)azetidine (D21) (1.8 g, 5.39 mmol) in 1,2 dichloroethane (18 ml) and the resulting mixture was heated under reflux for 3 hours. The reaction mixture was evaporated in vacuo and the residue was re-dissolved in methanol (10 ml). This solution was heated under reflux overnight then cooled at room temperature and evaporated in vacuo. The obtained residue was loaded on SPE-SCX (20 g) cartridge. The ammonia fractions, after evaporation in vacuo, were loaded on by SPE-Si (5 g) cartridge eluting with a mixture dichloromethane/dichloromethane:NH3 (2M solution in MeOH) (from 100/0 to 80/20). Collected fractions after solvent evaporation afforded the title compound (D49) (0.9 g)
Reaction SMILES: [CH2:1](I)I.[Cl:4][C:5]1[CH:15]=[CH:14][C:8](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1>C(Cl)Cl.[Zn]>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C@@H:9]2[CH2:1][C@H:10]2[C:11]([OH:13])=[O:12])=[CH:14][CH:15]=1
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Reactant: ICI
Agent: [Zn]
Solvent: ClCCl
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of zinc dust (6.54 g, 0.1 mole) and cuprous chloride (1 g, 0.01 mole) in methylene chloride (30 mL) is stirred and heated to reflux under a nitrogen atmosphere for 30 min. After the mixture is cooled to room temperature, methylene iodide (13.4 g, 0.05 mole) is added to the mixture which is then refluxed for an additional hour. After cooling to 0° C., trans-4-chlorocinnamic acid (9.1 g) is added. The reaction is allowed to warm to room temperature over 2 hours and then refluxed for 3 days. The reaction is quenched at 0° C. by the addition of 30 ml of diethyl ether and 30 ml of ice cold 10% H2SO4 solution. The mixture is filtered washed with ether. The organic layer is dried over MgSO4 and concentrated to provide the desired product as a white solid. 1H NMR (CDCl3) 7.25 (d, J=7 Hz, 2H), 7.05 (d, J=7 Hz, 2H), 2.58 (m, 1H), 1.85 (m, 1H), 1.65 (m, 1H), 1.37 (m, 1H).
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)=[O:2].[Cl-].[Na+].C(O)(=[O:17])C>>[CH:1]([NH:3][CH:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[C:7](=[O:17])[CH2:6][CH2:5]1)=[O:2]
Reactant: O=CNC1CCCc2sccc21
Reactant: CC(=O)O
Agent: [Cl-]
Agent: [Na+]
Product: O=CNC1CCC(=O)c2sccc21

Procedure:
In 725 ml of 50% aqueous acetic acid, 39 g of N-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is stirred while 473 g of ceric ammonium nitrate is added over 15 minutes at about 25° C. After 15 minutes of additional stirring, sodium chloride is added and the mixture is extracted 3 times with dichloromethane (500, 500 and 250 ml). The combined extract is washed with brine and then with water. The water is extracted with 100 ml of dichloromethane and combined with the main dichloromethane solution. Evaporation of the dichloromethane in vacuo gives a sticky gum, which when triturated with 100 ml of ether affords 28.4 g. of the title compound, m.p. 96° C. to 106° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:20][O:21][CH:22]([O:27][CH3:28])[C:23](OC)=[O:24]>O1CCCC1.CCCCCC>[CH3:20][O:21][CH:22]([O:27][CH3:28])[C:23](=[O:24])[CH2:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(=O)C(OC)OC
Reactant: CC(=O)c1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(OC)C(=O)CC(=O)c1ccncc1
Temperature: -40 °C
Reaction time: 16 h

Procedure:
A solution of 4-acetylpyridine (12 g) in dry tetrahydrofuran (500 ml), under nitrogen and at −60° C., was treated with a solution of lithium bis(trimethylsilyl)amide in hexane (200 ml, 1M). The mixture was allowed to warm to −40° C. then treated with methyl dimethoxyacetate (12 ml). After standing at room temperature for 16 hours the reaction mixture was evaporated and the residue was triturated with diethyl ether to give the title compound as a yellow solid (22 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=O)=[CH:4][C:3]=1[CH2:12][O:13]C.[CH3:15][N:16]([CH3:27])[C:17]1[N:22]=[CH:21][C:20]([C:23](=[N:25]O)[NH2:24])=[CH:19][CH:18]=1>>[CH3:9][O:8][CH2:6][C:5]1[CH:4]=[C:3]([C:12]2[O:13][N:25]=[C:23]([C:20]3[CH:19]=[CH:18][C:17]([N:16]([CH3:27])[CH3:15])=[N:22][CH:21]=3)[N:24]=2)[CH:2]=[CH:11][C:10]=1[C:2]1[CH:11]=[CH:10][CH:5]=[CH:4][C:3]=1[CH3:12]
Reactant: CN(C)c1ccc(C(N)=NO)cn1
Reactant: COCc1cc(C(=O)OC)ccc1Br
Product: COCc1cc(-c2nc(-c3ccc(N(C)C)nc3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described in Method B starting from Intermediate A1 and 6-(dimethylamino)-N′-hydroxypyridine-3-carboximidamide (UkrOrgSynthesis, BBV-073023). After purification by flash chromatography (silica, EtOAc/cHex) followed by a crystallization from a hot mixture of MTBE and heptane, the title compound was obtained as a white powder. HPLC (Method A), Rt: 4.0 min (purity: 100%). UPLC/MS, M+(ESI): 401.1. Elemental analysis: [C24H24N4O2-0.1H20] calculated: C, 71.66%; H, 6.06%; N, 13.93%. found: C, 71.66%; H, 6.06%; N, 13.91%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[O:15])[S:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1
Reactant: Cc1cnn(C)c1-c1cc(C(=O)O)sc1C
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (207 mg, 0.83 mmol) [prepared according to the procedure of Example 164], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (279 mg, 0.83 mmol) [Prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (469 mg, 1.00 mmol) in chloroform (8 mL). DIEA (730 μL, 4.18 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (209 mg, 0.36 mmol, 43%): LC-MS (ES) m/z=517 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].I[CH2:12][CH2:13][CH3:14].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][CH3:14])=[CH:4][N:3]=1
Reactant: CCCI
Reactant: Oc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc(Br)nc1
Reaction time: 18 h
Yield: 87 %

Procedure:
2-Bromo-5-hydroxypyridine (6 mmol) is dissolved in DMF (10 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30 min 1-iodopropane (1.1 eq.) is added and the reaction solution is stirred 18 hours. The reaction solution is pored into water and extracted with methyltert.-butyl ether. The combined organic layers are dried over MgSO4 and the solvent is removed in vacuo. 2-Bromo-5-propoxy-pyridine is obtained as yellow oil in a yield of 87%; HPLC (method C): 1.93 min; LC-MS (method A): 1.78 min, 215.95 (M+H+).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH2:28])[CH2:24][N:25]([CH3:27])[CH3:26])=[CH:19][C:18]=1[F:29]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH:28][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:24][N:25]([CH3:27])[CH3:26])=[CH:19][C:18]=1[F:29]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CN(C)C[C@@H](N)c1ccc(Cl)c(F)c1
Agent: Cl
Product: CN(C)C[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(Cl)c(F)c1

Procedure:
Compound 53 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-1-(4-Chloro-3-fluoro-phenyl)-N2,N2-dimethyl-ethane-1,2-diamine hydrochloride to give the title compound as a white solid. LC/MS [390 (M+H)]; 1H NMR (400 MHz, Acetonitrile-d3) δ 10.34 (s, 1H), 8.96 (d, 1H), 8.49 (d, 2H), 8.35 (s, 1H), 7.46 (t, 1H), 7.35 (d, 1H), 7.28 (d, 1H), 6.62 (s, 1H), 5.26 (d, 1H), 2.93 (t, 1H), 2.60 (dd, 1H), 2.29 (s, 6H).