Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[CH:4]=1)[CH3:2].CO[CH2:15][Cl:16].C(O)(=O)C>O>[CH2:11]([C:5]1[CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[CH2:15][Cl:16])[CH3:12]
Reactant: COCCl
Reactant: CCc1cc(CC)cc(CC)c1
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(CC)c(CCl)c(CC)c1
Temperature: 120 °C
Reaction time: 7 h
Yield: 64.6 %

Procedure:
A mixture of 81.1 g of 1,3,5-triethylbenzene, 60.4 g of chloromethyl methyl ether and 6.0 g of acetic acid was stirred in a sealed tube at 120° C. for 7 hours. The reaction mixture was poured into 500 ml of water and extracted with hexane. The organic layer was washed with an aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was distilled under reduced pressure to obtain 68.07 g of 2,4,6-triethylbenzyl chloride. Boiling point: 88 to 98° C. (0.18 kPa).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:23][CH2:22]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: ClCCCCn1cnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc(N2CCN(CCCCn3cnc4ccccc43)CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(2-pyrimidinyl) piperazine (4.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.1 g compound (I-14) with a yield of 60.1%. ESI-MS [M+H]+: m/z 337.2.
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:13]([NH2:15])=[O:14].[O-:16][C:17]#[N:18].[Na+]>C(O)(=O)C.O>[CH2:10]([N:7]1[CH2:8][CH2:9][C:4]2[C:3]([C:13]([NH2:15])=[O:14])=[C:2]([NH:1][C:17]([NH2:18])=[O:16])[S:12][C:5]=2[CH2:6]1)[CH3:11]
Reactant: N#C[O-]
Reactant: CCN1CCc2c(sc(N)c2C(N)=O)C1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCN1CCc2c(sc(NC(N)=O)c2C(N)=O)C1
Reaction time: 2 h
Yield: 23.3 %

Procedure:
To a stirred mixture of compound F4 (451 mg, 2.00 mmol) in acetic acid (6 mL) at room temperature was added a solution of sodium cyanate (169 mg, 2.60 mmol) in water (2.5 mL) dropwise over 2 min. After addition, the reaction mixture was stirred for another 2 h and then concentrated under reduced pressure. The resulting residue was mixed with saturated aqueous sodium bicarbonate (50 mL) and extracted with methylene chloride (3×150 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with methanol/methylene chloride (15:85) to afford compound M1 as a yellow solid (125 mg, 23%): 1H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.31 (bs, 1H), 6.77 (bs, 3H), 3.41 (s, 2H), 2.73 (d, J=4.8 Hz, 2H), 2.63 (d, J=4.8 Hz, 2H), 2.50-2.45 (m, 2H), 1.06 (t, J=7.0 Hz, 3H). MS (M+H) 269.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.[C:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][CH:66]([NH2:69])[CH2:65][CH2:64]1)=[O:62])([CH3:59])([CH3:58])[CH3:57]>ClCCl>[C:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][CH:66]([NH:69][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:65][CH2:64]1)=[O:62])([CH3:59])([CH3:57])[CH3:58]
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a suspension of 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (3.53 g; 10.0 mmol) from example A67 in dry dichloromethane (50 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.0 mmol), triethylamine (15.0 mmol) and 1-hydroxybenzotriazole (10.0 mmol). The suspension is stirred at ambient temperature for one hour. To the resulting solution, 4-amino-piperidine-1-carboxylic acid tert-butyl ester (12.0 mmol) is added and stirring is continued overnight at ambient temperature. The reaction mixture is loaded onto a silica gel column and purified by flash chromatography using acetic acid ethyl ester/2-propanol (98:2 v/v). The eluate containing the product fraction is collected and evaporated. The product is triturated with n-hexane and dried in high vacuo at 50° C. to yield 3.85 g of the title compound as white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([I:11])=[C:4]([OH:10])[C:5]([I:9])=[CH:6][C:7]=1[I:8].[F:12][C:13]([F:24])([C:17]([F:23])([Br:22])[C:18]([F:21])([F:20])[Br:19])[C:14](Cl)=[O:15]>N1C=CC=CC=1>[I:11][C:3]1[C:2]([Br:1])=[C:7]([I:8])[CH:6]=[C:5]([I:9])[C:4]=1[O:10][C:14](=[O:15])[C:13]([F:12])([F:24])[C:17]([F:23])([Br:22])[C:18]([F:21])([F:20])[Br:19]
Reactant: O=C(Cl)C(F)(F)C(F)(Br)C(F)(F)Br
Reactant: Oc1c(I)cc(I)c(Br)c1I
Solvent: c1ccncc1
Product: O=C(Oc1c(I)cc(I)c(Br)c1I)C(F)(F)C(F)(Br)C(F)(F)Br

Procedure:
20.3 grams of 3-bromo-2,4,6-triiodophenol (m.p. 155°-157° C.) were dissolved in 50 ml of pyridine 13.0 grams of 2,2,3,4,4-pentafluoro-3,4-dibromo-butyryl chloride were added dropwise through a dropping funnel with stirring. The mixture was stirred overnight at room temperature. The mixture was washed in a separatory funnel twice with 250 ml of DI water, then filtered through a column of silica and the solvent evaporated. The material was then chromatographed on a column of silica using FREON 113 (trichlorotrifluroethane) as eluent. The sample (25 grams), which slowly crystallized at room temperature, was shown to be pure ester (97%) by gc/ms. It is suitable for use as a fluid above its melting point of 56-57° C. m/e (chemical ionization) 129 (21%, CF2Br); 131 (100, CF2Br and C3F5); 140 (13%, C5HBr); 142 (13%, C5HBr); 188 (14%, C5HI); 267, 269 (11%, 10% C5BrIH); 315 (4%, C5I2H); 422, 424 (6%, 7%, C6I2HBrO); 549, 551 (5%, 4%, C6I3HBrO); 866, 868, 870, 872 (0.2%, 0.6%, 0.4%, 0.2%, molecular ion). I.R.(ν, in cm-1)=3080 (Ar--H); 1800 (C=O); 1550, 1520 (Ar C=C).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]1([CH3:24])[CH:17]=[CH:16][C:15]([S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:24][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][CH:3]=2)=[O:23])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2ccc(C(F)(F)F)cc2)cc1
Yield: 84.3 %

Procedure:
A solution of 8.0 g (49.65 mmoles) of 4-aminobenzotrifluoride in 10 ml of methylene chloride was added to a solution of 9.85 g (49.95 mmoles) of p-toluenesulfonyl isocyanate in 75 ml of methylene chloride with stirring. The mixture became quite warm and a heavy white precipitate formed. An additional 100 ml of methylene chloride were added. The reaction mixture was stirred an additional 15 minutes, and the precipitate was recovered by filtration affording 15.0 g of the title product as a white solid. A small amount of the material was crystallized from diethyl ether to provide the title compound (87% yield) with a melting point of 194-197° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34](=[N:36]O)[NH2:35]>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34]1[N:35]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:25][N:36]=1
Reactant: NC(Cc1ccccc1Cl)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(Cc4ccccc4Cl)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 41 mg (0.22 mmol, 1.1 eq.) of 2-(2-chlorophenyl)-N′-hydroxyethanimidamide were reacted according to the General Method 1. Yield: 10 mg (10% of theory)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.N1C=CC=CC=1>[CH3:20][S:21]([O:1][C:2]1[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[C:4]([CH2:5][NH:6][C:7]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:13])[CH:3]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1cc(O)cc(CNC(=O)OC(C)(C)C)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1cc(CNC(=O)OC(C)(C)C)cc(OS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 81 %

Procedure:
To a stirring solution of 91.8 mg of tert-butyl 3-hydroxy-5-isopropylbenzylcarbamate in 3 mL of CH2Cl2 and 300 μL of pyridine at 0° C. was added 30 μL (0.386 mmol) of MsCl. The ice bath was removed, and after stirring at r.t. for 75 min. 50 μL of Et3N was added. After 30 min., the solution was concentrated and EtOAc and H2O were added. The organic layer was washed with 15 mL of brine, and the aqueous layer was extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (40% EtOAc/hexanes) provided 96.2 mg of 3-((tert-butoxycarbonylamino)methyl)-5-isopropylphenyl methanesulfonate as a pale yellow oil in about 80% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:32]([CH:40]=O)[NH:31][C:30]=2[CH3:42])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[C:32]([CH:40]=[C:13]3[C:12]4[C:16](=[CH:17][C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])=[CH:10][CH:11]=4)[NH:15][C:14]3=[O:18])[NH:31][C:30]=2[CH3:42])=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)NCCN1CCCC1
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C)c(C(=O)NCCN2CCCC2)c1-c1ccccc1
Yield: 34.8 %

Procedure:
6-(2-Methoxyphenyl)-1,3-dihydroindol-2-one (50 mg, 0.21 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (70 mg) to give 0.04 g (35%) of the title compound as a yellow-orange solid.
Reaction SMILES: CO[CH:3]([O:27][CH3:28])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH2:13][C:14]3[N:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:17][C:18]=3[CH3:19])=[CH:10][C:9]=2[CH:26]=1.C[Si]([C:33]#[N:34])(C)C.B(F)(F)F.CCOCC>ClCCl>[CH3:28][O:27][CH:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH2:13][C:14]3[N:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:17][C:18]=3[CH3:19])=[CH:10][C:9]=2[CH:26]=1)[C:33]#[N:34]
Reactant: C[Si](C)(C)C#N
Reactant: COC(Cc1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1)OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(C#N)Cc1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1
Yield: 85.9 %

Procedure:
To a solution of 5-(2,2-dimethoxyethyl)-2-[(5-methyl-2-phenyl-4-oxazolyl)methyl]benzofuran (0.75 g, 2.0 mmol) in dichloromethane (15 ml) were added trimethylsilyl cyanide (0.80 ml, 6.0 mmol) and boron trifluoride etherate (50 μl, 0.5 mmol). After 1 hour the solution was diluted with dichloromethane, washed with 5% sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated. The product was purified by flash-chromatography (hexanes/ethyl acetate, 2:1) and isolated as a solid (0.64 g, mp 107°-109° C.).
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]([CH3:22])([CH3:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.CN.[CH:30]([N:33](CC)C(C)C)(C)C>ClCCl>[CH3:21][C:20]1([CH3:22])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=2)[N:12]=[C:11]1[C:8]1[CH:9]=[CH:10][C:5]([S:2](=[O:4])(=[O:3])[NH:33][CH3:30])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(S(=O)(=O)Cl)cc1)=N2
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(C2=Nc3ccc(C(=O)OC)cc3CC2(C)C)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 49.2 %

Procedure:
To a round bottom flask, a mixture of methyl 2-(4-(chlorosulfonyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (396 mg, 1.0 mmol) in dichloromethane (10 mL) was added dropwise to a mixture of methylamine hydrochloride (68 mg, 1.0 mmol) and N,N-diisopropyl ethylamine (0.54 mL, 3.0 mmol) in dichloromethane (10 mL). The resultant mixture was allowed to stir at room temperature for 10 hours. The reaction mixture was washed by water several times, dried over anhydrous magnesium sulfate. Filtered and concentrated to provide methyl 3,3-dimethyl-2-(4-(N-methylsulfamoyl)phenyl)-3,4-dihydroquinoline-6-carboxylate as a yellow oil (190 mg). MS (ES+APCI) M+1=389.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:20][C@H:21]([C:23]1[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][C@H:21]([C:23]2[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)=[N:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: N#Cc1cccc(Oc2ncc(Cl)cc2C(=O)O)c1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1cccc(C#N)c1)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(3-cyanophenoxy)nicotinic acid (step 1) and tert-butyl 4-[(1S)-1-aminoethyl]benzoate (step 3 of Example 44): 1H-NMR (CDCl3) δ 8.56 (1H, d, J=2.7 Hz), 8.13 (1H, d, J=2.7 Hz), 7.98–7.95 (2H, m), 7.89–7.86 (1H, m), 7.64–7.38 (6H, m), 5.42–5.31 (1H, m), 1.61–1.58 (12H, m); MS (ESI) m/z 476 (M−H)−.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]C)[C:4]=1[NH2:5])C.Cl[CH2:13][CH:14]=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:3]([CH3:1])[C:4]=1[NH:5][CH2:13][CH:14]=[O:15]
Reactant: O=CCCl
Reactant: CCc1cccc(CC)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cccc(C)c1NCC=O
Temperature: 150 °C

Procedure:
2,6-Diethylaniline (100 grams), the dimethyl acetal of 2-chloroacetaldehyde (37.5 grams) and sodium carbonate (31.8 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at 150° C. for a period of about 30 hours. After this time the mixture was filtered and the filtrate was distilled to yield the desired product the dimethyl acetal of 2-(2,6-dimethylanilino)acetaldehyde having a boiling point of 120° C. at 1 mm of Hg pressure.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[CH2:15][N:16]1[CH2:21][CH2:20][N:19](CC2C=CC=CC=2)[CH2:18][CH2:17]1)[CH3:2].[H][H]>[Pd].CO>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[CH2:15][N:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1)[CH3:2]
Reactant: CCOCCn1c(CN2CCN(Cc3ccccc3)CC2)nc2ncccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOCCn1c(CN2CCNCC2)nc2ncccc21
Yield: 46.1 %

Procedure:
A mixture of 8.3 parts of 1-(2-ethoxyethyl)-2-[[4-(phenylmethyl)-1-piperazinyl]methyl]-1H-imidazo[4,5-b]pyridine and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 3.2 parts (46.1%) of 1-(2-ethoxyethyl)-2-(1-piperazinylmethyl)-1H-imidazo[4,5-b]pyridine as a residue (compound 31).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:20][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17](O)=[O:18])=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1>CN(C)C=O>[CH3:3][CH:2]([C:4]1[S:20][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17]([NH:34][C:35]4[NH:39][N:38]=[N:37][N:36]=4)=[O:18])=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:1]
Reactant: Nc1nnn[nH]1
Reactant: CC(C)c1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cc2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc2s1
Temperature: 105 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
2.88 g (0.01 mol) of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]-thieno[2,3-d]pyrimidin-7-carboxylic acid (Example 18) and 3.31 g (0.02 mol) of 1,1' carbonyldiimidazole (Aldrich Chemical Company) in 100 ml of dimethylformamide are stirred and heated in a wax bath at 105° C. for ninety minutes under nitrogen. The mixture is cooled and stirred at room temperature for thirty minutes and 1.03 g (0.01 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company) is added and the resulting mixture is stirred and heated at 105° C. for one hundred thirty-five minutes under nitrogen. The mixture is allowed to stand overnight at room temperature, the precipitate is filtered and the filtrate is evaporated in vacuo. The residue is slurried in boiling methanol, the mixture cooled and filtered. This precipitate is combined with the previous precipitate to give 1.8 g of 2-(1-methylethyl)-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]-thieno[2,3-d]pyrimidine-7 -carboxamide; mp 307° C. (dec) after recrystallization from pyridine.
Reaction SMILES: [O:1]([C:9]1[CH:10]([CH:18]([CH:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[C:21]2[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH3:19])[C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[Li]CCCC.Cl[Si:43]([CH3:46])([CH3:45])[CH3:44]>C1COCC1.CCCCCC>[CH3:44][Si:43]([CH3:46])([CH3:45])[CH:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]([Si:2]([CH3:5])([CH3:4])[CH3:3])[C:21]=2[O:29][Si:30]([C:33]([CH3:35])([CH3:34])[CH3:36])([CH3:31])[CH3:32])[CH3:19])=[C:9]1[O:1][Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C1C(O[Si](C)(C)C(C)(C)C)=Cc2ccccc21)C1C(O[Si](C)(C)C(C)(C)C)=Cc2ccccc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C1=C(O[Si](C)(C)C(C)(C)C)C([Si](C)(C)C)c2ccccc21)C1=C(O[Si](C)(C)C(C)(C)C)C([Si](C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of bis(2-(tert-butyldimethylsiloxy)indenyl)ethane (10.38 g, 20.0 mmol) in THF (100 mL) at −20° C. was added dropwise n-BuLi (16.1 mL of a 2.5 M solution in hexane, 40.2 mmol) and the reaction mixture was stirred for 3 hours at room temperature. To the resulting solution was added dropwise chlorotrimethylsilane (6.85 g, 63.0 mmol, 8.0 mL) at 0° C. After completed addition the reaction mixture was stirred overnight at room temperature and the solvents were evaporated. The remaining orange solid was extracted with CH2Cl2 and filtrated through celite. The solvent was evaporated and the product was dissolved in Et2O (150 mL). Concentration and cooling to 0° C. gave 10.29 g (77.6%) of a 2:1 diastereomeric mixture of the title compound as off-white crystals. EIMS (calcd/found): m/e 662.3827/662.3834. 1H NMR (CD2Cl2, δ, major/minor diastereomer): 7.51-7.49 (m, 2H, major); 7.42-7.40 (m, 2H, minor); 7.29-7.24 (m, 4+2H, major/minor); 7.22-7.17 (m, 2H, minor); 7.08-7.02 (m, 2+2H, major/minor); 3.29 (s, 1H, minor); 3.27 (s, 1H, major); 3.00-2.96 (m, AA′, 2H, minor); 2.72-2.65 (m, AA′BB′, 4H, major); 2.44-2.40 (m, BB′, 2H, minor); 1.02 (s, 18H, major); 1.01 (s, 18H, minor); 0.20 (s, 6H, minor); 0.19 (s, 6H, major); 0.10 (s, 6H, minor); 0.05 (s, 6H, major); 0.02 (s, 18H, minor); 0.01 (s, 18H, major). 13C NMR (CD2Cl2, δ, major diastereomer): 158.32; 144.56; 139.24; 125.09; 122.74; 121.98; 119.89; 118.08; 45.08; 26.14; 24.06; 18.52; −2.39; −3.40; −4.66. 13C NMR (CDCl3, δ, minor diastereomer): 158.08; 144.50; 139.14; 124.97; 122.62; 121.95; 119.95; 118.50; 45.13; 26.14; 23.86; 18.47; −2.29; −3.40; −4.24.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH3:6][C:7]([CH2:9][OH:10])=O.C(N(CC)CC)C>CO>[NH2:4][C:3]1[O:10][CH:9]=[C:7]([CH3:6])[C:2]=1[C:1]#[N:5]
Reactant: CC(=O)CO
Reactant: N#CCC#N
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1coc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
To a mixture of malononitrile (0.96 g, 14.6 mmol), acetol (1.08 g, 14.6 mmol) in methanol (10 mL) at 0° C. was added, dropwise, triethylamine (2.0 mL). The reaction mixture was stirred at room temperature overnight. After removal of solvent under reduced pressure the crude solid washed with cold isopropanol to give product as white powder (0.54 g, 30%). HPLC/MS: (M+H)+ 123.3 m/z. Retention time (LC-MS)=1.81 min. 1H NMR (CD3OD): 6.58(s, 1H,); 1.95 (s, 3H).