Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])/[CH:13]=[CH:14]\[C:15](OC)=[O:16])=[C:7]([C:20](=[O:27])[NH:21][CH:22]([CH:24]2[CH2:26][CH2:25]2)[CH3:23])[CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:13]2[CH2:14][C:15](=[O:16])[NH:3][NH:2]2)=[O:19])=[C:7]([C:20](=[O:27])[NH:21][CH:22]([CH:24]2[CH2:26][CH2:25]2)[CH3:23])[CH:6]=1
Reactant: NN
Reactant: COC(=O)/C=C\C(=O)Nc1ccc(Cl)cc1C(=O)NC(C)C1CC1
Solvent: O
Solvent: CCO
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(=O)NN1)C1CC1
Reaction time: 5.5 h
Yield: 52 %

Procedure:
3.58 g of hydrazine monohydrate was dropwise added to a mixed liquid comprising 25 g of methyl 4-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylamino)-4-oxoisocrotonate and 250 ml of ethanol, followed by reflux with heating. After stirring for 5.5 hours, the reaction liquid was stood to cool. The precipitated crystals were subjected to suction filtration. The crystals collected after the filtration were washed with ethyl acetate and then with hexane and air dried to obtain 13 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:12]([OH:14])=O)[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]=1[O:17][CH3:18].[ClH:19].Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37])[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[ClH:19].[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:12]([N:30]3[CH2:29][CH2:28][N:27]([CH2:26][C:25]4[CH:33]=[C:34]([O:38][CH3:39])[C:35]([O:36][CH3:37])=[C:23]([O:22][CH3:21])[CH:24]=4)[CH2:32][CH2:31]3)=[O:14])[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]=1[O:17][CH3:18]
Reactant: COc1ccc2c(c1OC)CCCC(C(=O)O)=C2
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(CN2CCN(C(=O)C3=Cc4ccc(OC)c(OC)c4CCC3)CC2)cc(OC)c1OC
Yield: 42.7 %

Procedure:
Using a mixture of 3,4-dimethoxy6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (0.6 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (1.3 g), triethylamine (1.5 g), N,N-dimethylformamide (20 ml) and diethyl phosphorocyanidate (0.6 ml), an amidation as that described in Example 6 is carried out. The product is purified by silica gel column chromatography (hexane:acetone=1:1), and converted to the hydrochloride in a mixture of ethyl acetate and ethyl ether to yield 1-(3,4-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.55 g) as colorless crystals, m.p. 225°-229° C. (decomp.).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][O:32][CH3:33])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1)=O.[CH3:34][NH2:35].[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:34][NH:35][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][O:32][CH3:33])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CCOC)CC4)c3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.9 %

Procedure:
To a solution of 5-(3-formylphenyl)-3-(1-{[2-(methyloxy)ethyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (25 mg, 0.053 mmol) in MeOH/CH2Cl2 (1 mL/1 mL) was added methyl amine (0.15 mL, 0.33 mmol). The reaction mixture was stirred at room temperature for 2 hours before NaBH4 (13.2 mg, 0.33 mmol) was added. The reaction mixture was stirred at room temperature overnight and evaporated all the solvent. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (10.0 mg, 39%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[F:15][C:16]([F:37])([S:33](F)(=[O:35])=[O:34])[C:17]([F:32])([F:31])[C:18]([F:30])([F:29])[C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22]>C1(C)C=CC=CC=1>[C:16]([S:33]([NH:7][CH2:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])(=[O:35])=[O:34])([C:17]([C:18]([C:19]([C:20]([C:21]([F:23])([F:24])[F:22])([F:25])[F:26])([F:28])[F:27])([F:30])[F:29])([F:32])[F:31])([F:37])[F:15]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CN(C)CCCN
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)CCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A mixture of dimethylaminopropylamine, H2NC3H6N(CH3)2 (12.2 g, 0.12 mole), triethylamine, (C2H5)3N (8.1 g, 0.08 mole) and toluene (60 g) was first prepared at ambient temperature and about atmospheric pressure in an inert atmosphere of nitrogen. To this mixture was added perfluorohexanesulfonyl fluoride, C6F13SO2F (41.0 g, 0.10 mole). The total mixture was then heated in a stainless steel reaction vessel at 90° C. for a period of about 3 hours forming a homogeneous reactant solution. During this period the aforementioned Reaction (a) takes place to produce intermediate N-[3-(N',N'-dimethylamino)propyl]perfluorohexane sulfonamide, C6F13SO2N(H)C3H6N(CH3)2.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[C:18]3[C:17](=[O:19])O[C:15](=[O:20])[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>C(O)(=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:18]=2[C:17](=[O:19])[N:35]([CH2:34][CH2:33][N:30]2[CH2:29][CH2:28][N:27]([C:24]4[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=4)[CH2:32][CH2:31]2)[C:15]3=[O:20])=[O:8])=[CH:4][CH:3]=1
Reactant: NCCN1CCN(c2ccncc2)CC1
Reactant: O=C(Nc1cccc2c1C(=O)OC2=O)c1ccc(Cl)s1
Solvent: CC(=O)O
Product: O=C(Nc1cccc2c1C(=O)N(CCN1CCN(c3ccncc3)CC1)C2=O)c1ccc(Cl)s1
Reaction time: 24 h

Procedure:
310 mg (1 mmol) of 5-chloro-N-(1,3-dioxo-1,3-dihydro-2-benzofuran-4-yl)-2-thio-phenecarboxamide and 0.64 g (1 mmol) of 2-[4-(4-pyridinyl)piperazino]ethylamine (obtainable by heating 4-chloropyridine with aminoethylpiperazine or according to German Offenlegungschrift 2024350) are boiled in 40 ml of glacial acetic acid overnight. 340 mg of 5-chloro-N-(1,3-dioxo-1,3-dihydro-2-benzofuran-4-yl)-2-thiophenecarboxamide are added and the mixture is then boiled for another 24 h and subsequently concentrated under reduced pressure, water is added, the aqueous phase is extracted four times with ethyl acetate and the combined organic phases are dried with Na2SO4, admixed with silica gel and concentrated under reduced pressure. Chromatography on silica gel using a toluene/ethyl acetate->toluene/ethanol gradient gives 140 mg (28.2% of theory) of the target compound of m.p. 168° C. and Rf (SiO2, toluene/ethanol=1:1)=0.28.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[CH:24][O:23][CH:22]=1.[Br:26]N1C(=O)CCC1=O>O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[CH:24][O:23][C:22]=1[Br:26]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccoc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccoc1Br
Reaction time: 2 h

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(furan-3-yl)pyrazole (0.600 g) in tetrahydrofuran (20 ml) was added N-bromosuccinimide (0.288 g). The mixture was left at room temperature for 2 hours and then poured onto a column of silica gel (30 g) and eluted with hexane:dichloromethane (1:1). Combination and evaporation of suitable fractions gave a red oil which was further purified by column chromatography on silica gel (30 g) eluted with hexane:dichloromethane (1:1), then dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:26]([O:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCBr
Reactant: Cc1cc2c(cc1-c1ccc(O)c(C=O)c1)C(C)(C)CCC2(C)C
Product: CCCCCCCOc1ccc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1C=O
Yield: 65.7 %

Procedure:
In a similar manner to Exmaple 10(b), by reaction of 2 g (9.3 mmol) of 2-hydroxy-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)benzaldehyde [prepared in Example 16(a)] with 1.1 ml (6.8 mmol) of 1-bromoheptane, 1.88 g (72%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[C:11]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:12][C:11]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: N#Cc1cccc(C=O)c1
Product: N#Cc1ccc(C(=O)C=Cc2cccc(C#N)c2)cc1

Procedure:
Part A. Employing methods similar to Example 1 Part A but using m-cyano benzaldehyde (0.91 gm, 6.89 mmol) and 4-acetyl benzonitrile (1.0 gm, 6.89 mmol), 4-[3-(3-cyanophenyl)-1-oxo-2-propenyl]benzonitrile was isolated as a pale yellow powder, 1.4 gm (79%), 1H NMR (CDCl3) 8.53(s,1H), 8.35(d,2H), 8.15-8.20(m,3H), 7.92(d, 1H), 7.82(d, 1H), 7.67(t, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH:11]=[CH:10]2.[CH2:24]([NH:26][CH2:27][CH2:28][OH:29])[CH3:25]>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([N:12]2[C:13]3[C:9](=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]([CH2:24][CH3:25])[CH2:27][CH2:28][OH:29])=[C:15]([F:16])[CH:14]=3)[CH:10]=[CH:11]2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(-n2ccc3cc(OCCCCBr)c(F)cc32)cc1
Reactant: CCNCCO
Product: CCN(CCO)CCCCOc1cc2ccn(-c3ccc(F)cc3)c2cc1F

Procedure:
In analogy to example 23.7, 5-(4-Bromo-butoxy)-1-(4-fluoro-phenyl)-6-fluoro-1H-indole and 2-(ethylamino)ethanol were converted to yield 2-({4-[1-(4-Fluoro-phenyl)-6-fluoro -1H-indol-5-yloxy]-butyl}-ethyl-amino)-ethanol as light yellow oil, MS: 389 (MH+).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH2:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]=[C:41]=[O:42])[CH3:32]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:41]([NH:40][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[O:33][CH2:31][CH3:32])=[O:42])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: CCOc1ccccc1N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccccc1NC(=O)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 34.9 mg (0.21 mmol) of 2-ethoxyphenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 10 mg (18.7% of theory) of the title compound are obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:2]1.C(Cl)(=O)OCC.[CH3:17][O:18][C:19]1[CH:24]=[C:23]2[C:25]([NH2:35])=[N:26][C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:28][C:22]2=[CH:21][C:20]=1[O:36][CH3:37]>C(N(CC)CC)C.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]([N:32]2[CH2:33][CH2:34][N:29]([C:27]3[N:26]=[C:25]([NH2:35])[C:23]4[C:22](=[CH:21][C:20]([O:36][CH3:37])=[C:19]([O:18][CH3:17])[CH:24]=4)[N:28]=3)[CH2:30][CH2:31]2)=[O:10])=[CH:2]1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C(O)C=Cc1ccoc1
Agent: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCN(C(=O)C=Cc4ccoc4)CC3)nc(N)c2cc1OC
Reaction time: 3 h
Yield: 59 %

Procedure:
To a mixture of 276 mg. (2 mM) of 3-(furan-3-yl)acrylic acid, and 242 mg. (2.4 mM) of triethylamine in 10 ml. of ethyl acetate was added dropwise under ice-cooling a solution of 260 mg. (2.4 mM) of ethyl chlorocarbonate in 5 ml. of ethyl acetate. The resulting mixture was stirred for 3 hours and 761 mg. (2 mM) of 2-piperazine-4-amino-6,7-dimethoxyquinazoline and 484 mg. (4.8 mM) of triethylamine were odded thereto. Stirring was continued at room temperature for further one day. The precipitate thus separated was recovered by filtration and washed well with water to give 480 mg. of the desired product.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[N:11]=[CH:12][C:13]3[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:14]=3[N:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:21]([CH2:28][CH2:29][CH2:30]Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[O:21]([CH2:28][CH2:29][CH2:30][N:16]1[C:14]2[N:15]=[C:10]([NH:9][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:11]=[CH:12][C:13]=2[CH:19]=[CH:18][C:17]1=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1ccc2cnc(Nc3ccccc3)nc2[nH]1
Reactant: BrCCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc2cnc(Nc3ccccc3)nc2n1CCCOc1ccccc1
Temperature: 50 °C

Procedure:
To a suspension of NaH (51 mg of a 60% suspension of NaH in mineral oil) in 6 mL of dimethylformamide was added 2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one (200 mg, 0.84 mmol). The reaction mixture was heated to 50° C. resulting in a yellow solution. The solution was cooled slightly, and 3-phenoxypropyl bromide (230 μL, 1.47 mmol) was added. The reaction mixture was heated at 50° C. for 10 minutes, then cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Methanol and ethyl acetate were added to the residue, and 60 mg (19%) of 8-(3-phenoxypropyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one was collected by filtration, mp 175-176° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)[CH2:13][C:14](O)=[O:15].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:40]([NH:42][NH2:43])=[O:41]>O1CCCC1>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)[CH2:13][C:14]([NH:43][N:42]=[C:40]=[O:41])=[O:15]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OC
Reactant: NNC=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NN=C=O)N2C(=O)c3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
A mixture of 3-(1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (3.0 g, 8.1 mmol) and carbonyidiimidazole (1.45 g, 8.94 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for 2 hours. To the solution was added formic hydrazide (644 mg, 10.7 mmol). The mixture was stirred for 18 hours. The resulting suspension was filtered and washed with ether. The isolated solid was stirred in a mixture of ethyl acetate (40 mL) and water (10 mL) for 1 hour. The suspension was filtered and washed with water and ether to give crude 3-(1,3-dioxoisoindolin-2-yl)-N-carbonylamino-3-(3-ethoxy-4-methoxyphenyl)propanamide (1.3 g, 39% yield). A solution of 3-(1,3-dioxoisoindolin-2-yl)-N-carbonylamino-3-(3-ethoxy-4-methoxyphenyl)propanamide (600 mg, 1.46 mmol) and phosphorus oxychloride (POCl3, 0.54 mL, 5.8 mmol) in acetonitrile (20 mL) was heated to reflux for 2 hours. This solution was poured into water (10 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography gave an oil. The oil was slurried in ether (10 mL). The resulting suspension was filtered to yield 2-[1-(3-ethoxy-4-methoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]isoindoline-1,3-dione as a white solid (250 mg, 43% yield): mp, 132.0-134.0° C.; 1H NMR (CDCl3); δ 1.46 (t, J=6.9 Hz, 3H, CH3), 2.82 (dd, J=6.0, 15.6 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.11 (q, J=7.0 Hz, 2H, CH2), 4.37 (dd, J=10.3, 15.7 Hz, 1H, CHH), 5.81 (dd, J=6.0, 10.3 Hz, 1H, NCH), 6.62 (d, J=7.9 Hz, 1H, Ar), 7.13-7.17 (m, 2H, Ar), 7.67-7.72 (m, 2H, Ar), 7.75-7.62 (m, 2H, Ar), 8.29 (s, 1H, Ar); 13C NMR (CDCl3)δ 14.69, 27.70, 51.85, 55.90, 64.42, 111.32, 112.51, 120.32, 123.44, 130.14, 13163, 134.13, 148.39, 143.43, 153.03, 163.99, 167.93; Anal Calcd for C21H29N3O5: C, 64.12; H, 4.87; N, 10.68. Found: C, 63.84; H, 4.90; N, 10.48.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[N+:11]([C:14]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:25][O:24][CH2:23]2)[CH:18]=[CH:17][C:15]=1[NH2:16])([O-:13])=[O:12]>>[N+:11]([C:14]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:23][O:24][CH2:25]2)[CH:18]=[CH:17][C:15]=1[NH:16][CH:8]=[O:10])([O-:13])=[O:12]
Reactant: O=CO
Reactant: Nc1ccc(OC2COC2)cc1[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: O=CNc1ccc(OC2COC2)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 50.6 %

Procedure:
A stirred mixture of acetic anhydride (15 mL, 161 mmol) and formic acid (6 mL, 161 mmol) was heated at 60° C. for 5 h. The mixture was cooled to rt, then 2-nitro-4-(oxetan-3-yloxy)aniline (1.69 g, 8.02 mmol) was added and the mixture was heated at 70° C. for 15 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aq NaHCO3. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 20% EtOAc in hexanes to 100% EtOAc to afford N-(2-nitro-4-(oxetan-3-yloxy)phenyl)formamide (967 mg, 51%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 10.36 (br s, 1H), 8.29 (m, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.36 (d, J=1.8 Hz, 1H), 7.24 (dd, J=9.0, 3.0 Hz, 1H), 5.38 (pentet, J=4.9 Hz, 1H), 4.92-4.94 (m, 2H), 4.53-4.56 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC(S(O[CH2:36][CH2:37][C:38]2[S:39][CH:40]=[CH:41][CH:42]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]3[N:17]([CH2:36][CH2:37][C:38]4[S:39][CH:40]=[CH:41][CH:42]=4)[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Reactant: c1ccc(CCN2CCC(Nc3nc4ccccc4[nH]3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: c1ccc(CCN2CCC(Nc3nc4ccccc4n3CCc3cccs3)CC2)cc1
Yield: 23.2 %

Procedure:
A mixture of 3.2 parts of N-[1-(2-phenylethyl)-4-piperidinyl]-1H-benzimidazol-2-amine, 2.9 parts of [2-(2-thienyl)ethyl] 4-methylbenzenesulfonate, 1 part of sodium carbonate and 135 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and 2-propanone, yielding 1 part (23.2%) of N-[1-(2-phenylethyl)-4-piperidinyl]-1-[2-(2-thienyl)ethyl]-1H-benzimidazol-2-amine; mp. 118.3° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36]
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: C[C@H](O)C(=O)NC1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from cis-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A141) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[C:6]([O:16]CC)(=O)[CH:7]([CH2:9][C:10]([O:12]CC)=O)[OH:8]>>[CH2:1]([NH:5][C:6](=[O:16])[CH:7]([CH2:9][C:10]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:12])[OH:8])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: CCOC(=O)CC(O)C(=O)OCC
Product: CC(C)CNC(=O)CC(O)C(=O)NCC(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 29 %

Procedure:
N,N′-Di-iso-butyl DL-malamide was prepared by the reaction of iso-butylamine with diethyl DL-malate. To a round-bottomed flask were added diethyl DL-malate (5.229 g, 1 eq) and iso-butylamine (14.058 g, 7 eq). The clear light yellow solution was stirred for 24 hours at room temperature, after which point a white solid had precipitated from solution. The solid was filtered, washed with hexane (3×25 mL), and dried under vacuum (1.96 g, 29% yield). The product was >99% pure as determined by NMR analyses.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([C:13]#[N:14])[C:11]#[N:12].O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:11]([NH2:12])=[N:16][NH:17][C:13]=1[NH2:14]
Reactant: N#CC(C#N)Cc1cccc(Cl)c1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c(N)c1Cc1cccc(Cl)c1Cl
Yield: 46.8 %

Procedure:
To a mixture of malononitrile (2.64 g, 40 mmol) in 95% Ethanol (50 mL) was added 2,3-dichlorobenzaldehyde (7.00 g, 40.0 mmol). The reaction was stirred at rt for 18 h. EtOH (20 mL) was added and the mixture was stirred at rt for 20 min and cooled to 0° C. in an ice bath. Sodium borohydride (0.424 g, 11.20 mmol) was introduced to the vigorously stirred mixture and the reduction was complete in about 10 min. To the reaction mixture was added water (40 mL). 1N HCl was added in to quench the excess hydride. More water was added in until precipitation was complete. Filtration gave [(2,3-dichlorophenyl)methyl]propanedinitrile (7.86 g, 87%). To a solution of [(2,3-dichlorophenyl)methyl]propanedinitrile (7.86 g, 34.9 mmol) in Ethanol (80 mL) was added hydrazine hydrate (2.57 mL, 52.4 mmol). The mixture is heated at reflux temperature for 8 h. The reaction mixture was concentrated. The crude material was purified on a silica column (MeOH/DCM: 0˜10%) to give the product (4.2 g, 47%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 3.77 (s, 2H) 7.09 (m, 1H) 7.19 (t, J=7.96 Hz, 1H) 7.38 (m, 1H); LC/MS: MS (ES+) m/e 257.0 [M+H]+.