Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][SH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[N:15]=1.C(OCC)(=O)C>C1COCC1.O>[C:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([S:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:15]=1)#[N:21]
Reactant: N#Cc1cccc(Cl)n1
Reactant: SCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(SCCCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
3-Phenylpropylmercaptan (1.21 g, 7.94 mmol) and sodium hydride (60%, 0.35 g, 8.66 mmol) were added to THF (30 ml), and the mixture was stirred at room temperature for 1 hr. A solution of 2-chloro-6-cyanopyridine (1.00 g, 7.22 mmol) in THF (10 ml) was added dropwise to the mixture and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (1.84 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[CH2:24]Br>>[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[CH2:24][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([N+:18]([O-:20])=[O:19])[C:11]=2[N:10]=[C:9]1[C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8]
Reactant: O=[N+]([O-])c1cccc2nc(-c3c(F)cccc3F)[nH]c12
Reactant: Fc1cccc(F)c1CBr
Product: O=[N+]([O-])c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F

Procedure:
2-(2,6-difluorophenyl)-4-nitrobenzimidazole (7.7 g, 28 mmol) was reacted with 2,6-difluorobenzylbromide (6.95 g, 33.6 mmol). The crude product was purified by recrystallization from diethylether:hexane (3:1), 9.8 g (24.4 mmol, 87%), yielding white crystals 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-nitrobenzimidazole. M.p. 168-170° C. 1H-NMR (300 MHz, CD2Cl2): δ 8.13 (dd, J=8.1, 0.9 Hz, 1H, H5), 7.86 (dd, J=8.1, 0.9 Hz, 1H, H7), 7.59 (m, 1H, H4′), 7.43 (dd, J=8.1 Hz, H6), 7.28 (m, 1H, H4″), 7.12 (m, 2H, H3″,5″), 6.84 (m, 2H, H3″,5″), 5.44 (s, 2H, CH2).
Reaction SMILES: C(NC(C)C)(C)C.[CH:8]1([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:18]1(=[O:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.CCCCCC>[CH:8]1([CH:13]([C:18]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)CC1CCCC1
Reactant: O=C1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C1CCCC1)C1(O)CCCCC1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 100.6 %

Procedure:
Diisopropylamine (12.7 g, 0.125) was dissolved in 150 mls of dry THF and cooled to -70° C. under N2. n-Bulb (80 ml of 1.6M solution in hexane, 0.125 moles) was added and the solution stirred for 5 minutes at -70° C. Methyl cyclopentaneacetate (17 g, 0.125 mole) in 50 mls of THF was added at -70° C. over 15 minutes and the reaction was stirred at -70° C. for 15 more minutes. A solution of cyclohexanone (11.3 g, 0.115 moles) in THF (50ml) was then added at -70° C. over 1/2 hour and stirred in the cold for 1 hour. The reaction was warmed to room temperature over 1 hour and quenched with 5 mls of 1N HCl. The solvent was removed on the rotary evaporator and ethyl acetate added. The solution was then washed with saturated NaHCO3 and the layers were separated. The organic layer was dried over Na2SO4. The drying agent was filtered and the filtrate stripped to give a residue which was chromatographed on silica gel using 7% ethyl acetate/hexane to give 27.8 g (92% yield) of the title compound.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]2)(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:1].[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]2
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)CCC(=O)N2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
500 ml of 3 N HCl in dioxane was added to the mixture of 40 g of the product of Step 1 in 500 ml of DCM and the solution was stirred overnight at RT. The solvent was evaporated, and the residue was washed with Et2O (1000 ml) to afford 6-(aminomethyl)-3,4-dihydroquinolin-2(1H)-one hydrochloride (30 g, 95% yield). 1H-NMR (300 MHz, DMSO-d6) δ: 10.17 (s, 1H), 7.28-7.23 (m, 2H), 6.88-6.86 (m, 1H), 3.90 (s, 2H), 2.89-2.84 (m, 2H), 2.53-2.42 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[N:12]=[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:10]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH:15]=[O:16])=[C:13]([CH3:17])[N:12]=[C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:10]=1
Reactant: Cc1nc(-c2ccccc2)nc(-c2ccc(Cl)cc2Cl)c1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2)nc(-c2ccc(Cl)cc2Cl)c1C=O
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a stirred solution of (4-(2,4-dichlorophenyl)-6-methyl-2-phenylpyrimidin-5-yl)methanol (75 mg, 0.2 mmol) in CH2Cl2 (6 mL) was added Dess-Martin periodinane (102 mg, 0.24 mmol). The reaction was kept for 2 hrs and was diluted with EtOAc (10 mL). The organic layer was washed with saturated NaHCO3 solution (10 mL), and brine (10 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give the crude product as a white solid (75 mg). The crude product was purified by flash chromatography (silica gel, 30% EtOAc/hexane) to give 4-(2,4-dichlorophenyl)-6-methyl-2-phenylpyrimidine-5-carbaldehyde (65 mg, 91% for 2 steps) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>O1CCCC1>[Cl:1][C:2]1[C:3]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[C:4]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH:5]=[C:6]([CH:10]=1)[C:7]([N:60]1[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]1)=[O:8]
Reactant: COc1ccc(COc2cc(C(=O)O)cc(Cl)c2OCc2ccc(OC)cc2)cc1
Reactant: CN1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(C(=O)N3CCN(C)CC3)cc(Cl)c2OCc2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of 5-chloro-3,4-bis(p-methoxybenzyloxy)benzoic acid (0.75 g: 1.75 mMol.) and 1-hydroxybenzotriazole (0.26 g: 1.1 Eq.) in tetrahydrofuran (15 ml) is added dicyclohexylcarbodiimide (0.40 g: 1.1 Eq.). After 1 hour stirring, to the mixture is added N-methylpiperazine (0.44 ml: 2.3 Eq.), and the mixture is stirred for 1 hour. The reaction mixture is filtered to remove solid and concentrated under reduced pressure to give 1-(5-chloro-3,4-bis(p-methoxybenzyloxy)benzoyl)-4-methylpiperazine (0.86 g). Yield: 96%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[O:30])[CH2:25][CH2:24]2)[CH:18]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:34]2[CH2:35][CH2:36][N:31]([C:29]([CH:26]3[CH2:27][CH2:28][N:23]([C:19]4[CH:18]=[C:17]([Cl:16])[N:22]=[CH:21][N:20]=4)[CH2:24][CH2:25]3)=[O:30])[CH2:32][CH2:33]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C(C1CCN(c2cc(Cl)ncn2)CC1)N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CCN(c2cc(Cl)ncn2)CC1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
4-Trifluoromethylphenylsulphonyl chloride (1.32 g) was added to a mixture 1-[1-(6-chloro-pyrimidin-4-yl)-4-piperidylcarbonyl]piperazine hydrochloride (2.60 g) and triethylamine (5.00 ml) in dichloromethane (100 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 1.5% methanol in dichloromethane to give 1-(4-trifluoromethylphenylsulphonyl)-4-[1-(6-chloro-pyrimidin-4-yl)-4-piperidylcarbonyl]piperazine (1.80 g) as a solid.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:20])[C:4](=[O:19])[CH:5]=[CH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[CH3:21]S(C)=O>[H-].[Na+]>[CH3:1][O:2][N:3]([CH3:20])[C:4]([C@@H:5]1[CH2:21][C@H:6]1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:19]
Reactant: COc1ccc2cccc(C=CC(=O)N(C)OC)c2c1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2cccc([C@@H]3C[C@H]3C(=O)N(C)OC)c2c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
5.8 g (21.4 mmol) of the compound obtained in Step F dissolved in 30 ml of DMSO are added to a suspension of ylid produced starting from 10.6 g (2 eq) of Me3SOI dissolved while hot in 50 ml of DMSO and 1.25 g of NaH. After 15 hours' stirring at room temperature and 4 hours at 50° C., the title cyclopropane amide is obtained in the form of a brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6].[CH3:12][N:13](C=O)C>[C-]#N.[C-]#N.[Zn+2]>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[C:8]([O:10][CH3:11])[CH:7]=1)[C:12]#[N:13])=[O:6]
Reactant: COc1cc(Br)cc(C=O)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(C#N)cc(C=O)c1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
step 3—A solution of 3-bromo-5-methoxy-benzaldehyde (1 mmol) in DMF (2 mL) is added to a round bottomed flask containing Zn(CN)2 (0.7 equivalents), Pd(PPh3)4(0) (0.2 equivalents) in DMF (15 mL). The reaction is stirred at 90° C. under an atmosphere of argon for 48 h. The reaction mixture is cooled and evaporated to dryness. The crude residue is dissolved in EtOAc, washed with brine solution, dried (MgSO4) and evaporated. The crude product is purified by SiO2 chromatography to afford 3-formyl-5-methoxy-benzonitrile.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][CH2:30][S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:33])=[O:32])[CH:27]=2)[NH:22][CH:21]=1)=O.[OH-].[Na+]>O>[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][CH2:30][S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:32])=[O:33])[CH:27]=2)[NH:22][CH:21]=1
Reactant: CN1CCC[C@@H]1C(=O)c1c[nH]c2ccc(CCS(=O)(=O)c3ccccc3)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(CCS(=O)(=O)c3ccccc3)cc12
Temperature: 2.5 °C
Yield: 75 %

Procedure:
To a suspension of LAH and THF was slowly charged (R)-(1-methylpyrrolidin-2-yl)(5-(2-(phenylsulfonyl)ethyl)-1H-indol-3-yl)methanone at 0° C. and then the reaction was slowly heated to reflux. Upon completion of the reaction in about 3-5 h, the reaction was cooled to 0-5° C. and 1N NaOH soln and H2O were sequentially charged. The solids were filtered and the precipitate washed with additional THF. The filtrate was distilled to dryness under reduced pressure. The residue was dissolved in water and the aqueous layer extracted with dichloromethane and dried over sodium sulfate and distilled to give the title compound in 75-80% yield.
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[C:29]([C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:53])[O:39][CH2:40][CH2:41][C:42]2[C:47]([CH2:48][CH3:49])=[CH:46][C:45](Br)=[CH:44][C:43]=2[CH2:51][CH3:52])[CH:34]=[CH:35][CH:36]=1)#[N:30]>>[C:29]([C:31]1[CH:32]=[C:33]([NH:37][C:38]([O:39][CH2:40][CH2:41][C:42]2[C:47]([CH2:48][CH3:49])=[CH:46][C:45]([B:25]([OH:27])[OH:26])=[CH:44][C:43]=2[CH2:51][CH3:52])=[O:53])[CH:34]=[CH:35][CH:36]=1)#[N:30]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: CCc1cc(Br)cc(CC)c1CCOC(=O)Nc1cccc(C#N)c1
Product: CCc1cc(B(O)O)cc(CC)c1CCOC(=O)Nc1cccc(C#N)c1
Yield: 45 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 37D (670 mg, 1.7 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 37E (278 mg, 45%) as a brown oil. 1H NMR (400 MHz, CD3OD) δ ppm 1.16 (t, J=7.45 Hz, 6 H) 2.68 (q, J=7.41 Hz, 4 H) 3.03 (t, J=7.83 Hz, 2 H) 4.14 (t, J=7.82 Hz, 2 H) 7.13-7.29 (m, 2 H) 7.30-7.45 (m, 2 H) 7.59 (d, J=7.83 Hz, 1 H) 7.80 (s, 1 H) 9.42 (s, 1 H).
Reaction SMILES: CC(C)([O-])C.[K+].[Si:7]([O:14][CH2:15][CH2:16][OH:17])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Cl:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1F>C1COCC1>[C:10]([Si:7]([O:14][CH2:15][CH2:16][O:17][C:24]1[CH:23]=[CH:22][C:21]([N+:26]([O-:28])=[O:27])=[CH:20][C:19]=1[Cl:18])([CH3:9])[CH3:8])([CH3:12])([CH3:13])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCCO
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.2 %

Procedure:
Potassium tert-butoxide (354 mg, 3.2 mmol) was added in one portion to a stirred solution of 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (506 mg, 2.9 mmol) in THF (3 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 30 min then 3-chloro-4-fluoronitrobenzene (251 mg, 1.4 mmol) was added in one portion (reaction turned dark color). The mixture was stirred at 0° C. for 10 min then the ice-bath removed, the reaction was allowed to warm to room temperature (10 min) and stirred for 1 hr. The solvent was removed under vacuum and the residue partitioned between EtOAc (50 mL) and H2O (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic layers dried (Na2SO4), filtered and the solvent removed under vacuum to leave the product as an oil (yield assumed quantitative=475 mg). The product was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:16]([CH:17]([OH:20])[C:18]#[CH:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[N:9]3[N:8]=2)=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:16]([C:17](=[O:20])[C:18]#[CH:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[N:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: C#CC(O)c1c(-c2ccc(Br)o2)nn2c(Cl)cccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C#CC(=O)c1c(-c2ccc(Br)o2)nn2c(Cl)cccc12
Yield: 32 %

Procedure:
In a similar manner as described in Example 25 from 2-(5-bromo-2-furyl)-7-chloropyrazolo[1,5-a]pyridine-3-carbaldehyde (2.54 g, 7.8 mmol) was obtained 1-[2-(5-bromo-2-furyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol. To the solution of 1-[2-(5-bromo-2-furyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol in dichloromethane was added manganese dioxide as described in example 25. 1-[2-(5-Bromo-2-furyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (0.86 g, two steps 32%) was obtained as a yellow solid. 1H NMR (CDCl3): δ 8.53 (d, 1H), 7.52–7.48 (m, 2H), 7.22 (d, 1H), 6.51 (d, 1H), 3.36 (s, 1H). MS m/z 349 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:17])[CH2:6][C:7](=O)[CH2:8][NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:3].C(O)(C)(C)C.[C:23]([S-:25])#[N:24].[K+]>O>[CH2:2]([O:4][C:5](=[O:17])[CH2:6][C:7]1[NH:24][C:23](=[S:25])[N:9]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=1)[CH3:3]
Reactant: N#C[S-]
Reactant: CCOC(=O)CC(=O)CNC1CCCCC1
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)Cc1cn(C2CCCCC2)c(=S)[nH]1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
200 g (0.758 mol) 4-Cyclohexylamino-3-oxo-butyric acid ethyl ester hydrochloride were dissolved in 360 ml water and 120 ml tert-butanol and were heated to 90° C. Then 88.4 g (0.91 mol) KSCN were added and the mixture was heated for 20 s, thereby a phase separation occurred. After cooling to RT, the phases were separated and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with Brine, dried with MgSO4 and concentrated. The solid was digested in MTBE and filtered to yield 192 g (0.715 mol, 94%) of (1-Cyclohexyl-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)-acetic acid ethyl ester as a beige solid. HPLC: tR=1.16 min (YMC J′ sphere ODS H 80 20×2.1 mm, 4 μm, A: H2O+0.05% TFA, B: MeCN, 4%→95% B in 2 min, 1 ml/min, 30° C.); Mass (ES+) (C13H20N2O2S): calculated. 268. found 269 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:57])[N:8]([CH2:49][C:50]2[O:51][CH:52]=[CH:53][C:54]=2[C:55]#[N:56])[C:9](=[O:48])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[N:28](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:27]=[N:26][N:25]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:57])[N:8]([CH2:49][C:50]2[O:51][CH:52]=[CH:53][C:54]=2[C:55]#[N:56])[C:9](=[O:48])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[NH:28][N:27]=[N:26][N:25]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(Cc2occc2C#N)c(=O)c1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc(C)n(Cc2occc2C#N)c(=O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 5 °C
Yield: 96.9 %

Procedure:
A suspension of 40 g of 2-[[4-butyl-2-methyl-6-oxo-5-[[2'[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-1(6H)-pyrimidinyl]methyl]-3-furancarbonitrile in 400 ml of CH3OH is refluxed to complete reaction. The residue obtained by evaporation of the solvent under reduced pressure, is taken up into 330 ml of 1% NaOH and extracted with Et2O. The aqueous phase is cooled at 5° C., acidified to pH 3 with 20% HCl and the resulting solid is filtered, washed thoroughly with water and dried under vacuum over P2O5. 26.2 g of a whitish solid are obtained (90% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[CH:18][C:17]=3[CH3:24])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[CH3:32][O:33][C:34]1[CH:38]=[C:37]([CH2:39]O)[N:36]([CH3:41])[N:35]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:17]([CH3:24])=[CH:18][C:19]([O:23][CH2:39][C:37]4[N:36]([CH3:41])[N:35]=[C:34]([O:33][CH3:32])[CH:38]=4)=[CH:20][C:21]=3[CH3:22])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CCc1ccc(NCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1F
Reactant: COc1cc(CO)n(C)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(NCc2cccc(-c3c(C)cc(OCc4cc(OC)nn4C)cc3C)c2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
To a solution of ethyl 3-(2-fluoro-4-{[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methyl]amino}phenyl)propanoate (0.50 g, 1.2 mmol), (3-methoxy-1-methyl-1H-pyrazol-5-yl)methanol (0.17 g, 1.2 mmol) and tributylphosphine (0.59 mL, 2.4 mmol) in tetrahydrofuran (30 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.60 g, 2.4 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, diisopropyl ether was added to the residue, and the resultant insoluble material was filtered off. The filtrate was concentrated and the residue was purified by silica gel column chromatography (40% ethyl acetate/hexane) to give the title compound (0.44 g, yield 68%) as a colorless oil.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:5](=[O:17])[NH:6][C:7]([S:11][CH:12]([CH3:16])[C:13](=O)[CH3:14])=[N:8][C:9]=1[CH3:10].[BrH:18]>C(O)(=O)C>[BrH:18].[Br:18][CH2:2][CH2:3][C:4]1[C:5](=[O:17])[N:6]2[C:13]([CH3:14])=[C:12]([CH3:16])[S:11][C:7]2=[N:8][C:9]=1[CH3:10]
Reactant: CC(=O)C(C)Sc1nc(C)c(CCO)c(=O)[nH]1
Agent: Br
Solvent: CC(=O)O
Product: Cc1nc2sc(C)c(C)n2c(=O)c1CCBr
Temperature: 90 °C

Procedure:
A mixture of 36 parts of 5-(2-hydroxyethyl)-6-methyl-2-[(1-methyl-2-oxopropyl)thio]-4(3H)-pyrimidinone and 240 parts of a hydrobromic acid solution 60% in acetic acid was stirred and heated for 4 hours at 90° C. The reaction mixture was evaporated and the residue was suspended in 400 parts of 2-propanone. The solid product was filtered off, washed with 2-propanone and dried, yielding 44 parts of 6-(2-bromoethyl)-2,3,7-trimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one monohydrobromide; mp. 172° C. (intermediate 7).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:13]=O)(C)(C)C.[C:16](#[N:20])[CH2:17][C:18]#[N:19]>C(O)C.N1CCCCC1>[NH2:19][C:18]1[N:7]=[C:8]2[CH:12]=[CH:11][S:10][C:9]2=[CH:13][C:17]=1[C:16]#[N:20]
Reactant: CC(C)(C)OC(=O)Nc1ccsc1C=O
Reactant: N#CCC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1cc2sccc2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
(2-Formyl-thiophen-3-yl)-carbamic acid tert-butyl ester described in Preparation Example U-2 (500 mg, 2.20 mmol) and malononitrile (153 mg, 2.31 mmol) were dissolved in a solution of ethanol (10 mL) to which piperidine (catalytic amount) had been added, and the mixture was stirred for 1 hour under reflux. The reaction mixture was cooled to room temperature, the precipitated solid was filtered, and title compound (215 mg, 1.23 mmol, 56%) was obtained as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[OH:7][C:8]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=1[CH:10]=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH3:6][O:5][C:3]([C:2]1[O:7][C:8]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=2[CH:10]=1)=[O:4]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2ccc(OC)cc2o1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of methyl bromoacetate (1.53 g, 10 mmol), 2-hydroxy-4-methoxybenzaldehyde (1.52 g, 10 mmol) and Cs2CO3 (6.5 g, 20 mmol) in DMF (100 mL) was stirred vigorously at 50° C. for 3 hrs and then at 150° C. for 5 min. The reaction was cooled, diluted with ethyl acetate and washed with water. The organic phase was dried and concentrated to give essentially pure 6-methoxy-benzofuran-2-carboxylic acid methyl ester as a solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=1.[CH3:17][NH:18][CH3:19].C(N(CC)CC)C>ClCCl.CN(C=O)C>[Cl:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([N:18]([CH3:19])[CH3:17])=[O:16])=[N:12][CH:13]=1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)c1cnc(Cl)cn1
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (1.7 mL, 19 mmol) was added to a suspension of 5-chloropyrazine-2-carboxylic acid (CAS no. 36070-80-1) (2.53 g, 16.0 mmol) in dichloromethane (25 mL) and DMF (4 drops) at RT and under argon. The mixture was allowed to stir for 1.5 h, concentrated in vacuo to and the residue was re-dissolved in dichloromethane (25 mL). Dimethylamine (2M in THF, 8.77 mL, 17.6 mmol) was then added dropwise followed by triethylamine (4.9 mL, 35 mmol) and allowed to stir for a further 5.5 hours. The reaction mixture was concentrated in vacuo and the residue was re-dissolved in dichloromethane and filtered. The filtrate was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexanes to give the desired compound (1.88 g).