Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>C1COCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:13]=2)=[O:18])=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Yield: 50.9 %

Procedure:
Reaction of 4-aminoacetophenone (75 mg, 0.55 mmol) in THF (6 mL) with 4-biphenylcarbonyl chloride (147 mg, 0.68 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave biphenyl-4-carboxylic acid (4-acetyl-phenyl)-amide (90 mg, 0.28 mmol, 50% yield) as a white powder after washing by water and ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[C:16]1([N:22]2[CH:26]=[CH:25][C:24](=[O:27])[NH:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[OH:14][CH:3]1[CH:4]([O:27][C:24]2[CH:25]=[CH:26][N:22]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:23]=2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11][C:2]1([CH3:15])[CH3:1]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: O=c1ccn(-c2ccccc2)[nH]1
Product: CC1(C)Oc2ccc(C#N)cc2C(Oc2ccn(-c3ccccc3)n2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 1-phenyl-1,2-dihydro-pyrazol-3-one as starting materials, the title compounds were prepared as white solids.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]2[C:74]([CH2:77][F:78])([CH2:75][F:76])[O:73][B:72]([OH:79])[C:71]=2[CH:80]=1>CN(C=O)C>[F:78][CH2:77][C:74]1([CH2:75][F:76])[O:73][B:72]([OH:79])[C:71]2[CH:80]=[C:67]([CH2:66][NH:65][C:24]([C:21]3[C:20]4[N:16]([CH:17]=[CH:18][CH:19]=4)[C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=5)([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=4)=[CH:23][CH:22]=3)=[O:25])[CH:68]=[CH:69][C:70]1=2
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: NCc1ccc2c(c1)B(O)OC2(CF)CF
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc2c(c1)B(O)OC2(CF)CF)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.22 mmol) and DIPEA (114 mg, 0.88 mmol) in DMF (5 mL) can be stirred at rt for 5 min and then HATU (169 mg, 0.44 mmol) can be added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-bis(fluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (116 mg, 0.44 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified by prep-TLC to provide the title product.
Reaction SMILES: NCCCCN.[S:7](S(Cl)(=O)=O)([C:10]1[CH:26]=[CH:25][C:13]([N:14]=[N:15][C:16]2[CH:24]=[CH:23][C:19]([N:20]([CH3:22])[CH3:21])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[NH2:31][CH:32]([CH3:36])[CH:33]([NH2:35])[CH3:34]>C(#N)C>[S:7]([CH2:34][CH:33]([NH2:35])[CH:32]([NH2:31])[CH3:36])([C:10]1[CH:26]=[CH:25][C:13]([N:14]=[N:15][C:16]2[CH:24]=[CH:23][C:19]([N:20]([CH3:22])[CH3:21])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)S(=O)(=O)Cl)cc2)cc1
Reactant: CC(N)C(C)N
Agent: NCCCCN
Solvent: CC#N
Product: CC(N)C(N)CS(=O)(=O)c1ccc(N=Nc2ccc(N(C)C)cc2)cc1

Procedure:
1,4-diaminobutane was dissolved in acetonitrile. Dabsyl sulfonyl chloride was slurred in acetonitrile. The Dabsyl sulfonyl chloride slurry was added to the diaminobutane solution and reacted for 15 minutes. The reaction was quenched with water, diluted to 40% water and filtered. The filtrate was diluted to 60% water and re-filtered. The resulting filter cake was dried under high vacuum. The dry filter cake was dissolved in acetonitrile and dried in a rotoevaporator. The dried material was subject to further characterization. Calculated mass 375.49. Observed m+1 376.3. Elemental analysis—Calculated: % C, 57.57; % H, 6.71; % N, 18.65. Observed: % C, 57.48; % H, 6.35; % N, 18.33.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH:12]=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl.Cl.[CH3:16][N:17]([CH3:30])[C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(B)#N.[Na]>CO.C(O)(=O)C.CO.C(Cl)(Cl)Cl>[CH3:16][N:17]([CH3:30])[C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:20][N:21]([CH2:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:22][CH2:23]1
Reactant: CN(C)C1(c2ccccc2)CCNCC1
Reactant: CN(CCC=O)C(=O)OC(C)(C)C
Agent: BC#N
Agent: Cl
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: CN(CCCN1CCC(c2ccccc2)(N(C)C)CC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.4 %

Procedure:
11.1 g (1.3 eq.) tert-butyl methyl(3-oxopropyl)carbamate were added to a solution of 11 g (1 eq.) N,N-dimethyl-4-phenylpiperidin-4-amine dihydrochloride in 110 ml methanol at 0° C. and the reaction mixture was stirred for 15 min at 0° C. 6.2 g (3 eq.) sodium cyanoboron hydride were then added in portions and the mixture was stirred for 30 min at room temperature. The reaction mixture obtained was adjusted to a pH of 5-6 with acetic acid and stirred for 12 h at room temperature. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCl3). As the conversion was still not complete, 2.4 g sodium cyanoboron hydride were added and the reaction mixture obtained was adjusted to pH 5-6 with acetic acid and stirred for 60 min at room temperature. Once the conversion was complete, the methanol was distilled off, the mixture was made alkaline with saturated NaHCO3 solution, the mixture obtained was extracted with chloroform (3×100 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 5% MeOH/CHCl3). 9 g (60%) of product were obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[S:9][CH:10]=1)=[O:5])C.C(O)(=O)C.Cl>O1CCOCC1>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([N:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)[C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1)=[O:30]
Reactant: CCOC(=O)c1csc(N(C(=O)c2ccccc2Cl)c2ccc(OC)c(OC)c2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1ccc(N(C(=O)c2ccccc2Cl)c2nc(C(=O)O)cs2)cc1OC
Temperature: 60 °C

Procedure:
A mixture of 2.09 g (4.68 mmol) 2-[(2-Chloro-benzoyl)-(3,4-dimethoxy-phenyl)-amino]-thiazole-4-carboxylic acid ethyl ester, 2.5 ml acetic acid and 7.5 ml HCl conc. in 10 ml dioxane was heated to 60° C. for 2 h. The mixture was subjected to reversed phase HPLC purification eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 1.1 g (56%) of the title compound. MS (m/e): 419.2 (MH+, 100%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=O)[NH:14][CH2:15][CH2:16][NH:17][C:18](=O)[CH3:19])=[O:5])[CH3:2]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][NH:17][CH2:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCCNC(C)=O
Solvent: C1CCOC1
Product: CCNCCNCCc1[nH]cc(C)c1C(=O)OCC
Yield: 88.3 %

Procedure:
A stirred solution of 2-[(2-acetylamino-ethylcarbamoyl)-methyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (500 mg, 1.695 mmol) in anhydrous tetrahydrofuran (10 ml) was added dropwise slowly with 1M borane-tetrahydrofuran complex in tetrahydrofuran (6.75 ml, 6.75 mmol) under an argon atmosphere. Upon completion of the addition, the mixture was heated to reflux for 7 hours The mixture was concentrated under reduced pressure. The residue was added with water (10 ml) and adjusted to pH 3 with 2N hydrochloric acid. The resulting mixture was adjusted to pH 14 with 2N aqueous sodium hydroxide solution and extracted with ethyl acetate (10 ml×3). The combined organic extracts were washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-[2-(2-ethylamino-ethylamino)-ethyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (400 mg, 88%) as a brown solid.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:10]1[CH:31]=[C:30]([O:32][CH3:33])[C:13]2[N:14]([CH2:26][CH2:27][O:28][CH3:29])[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[N:16][C:12]=2[CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CCOC(C)=O>C(O)(=O)C>[CH2:3]([C:10]1[CH:31]=[C:30]([O:32][CH3:33])[C:13]2[N:14]([CH2:26][CH2:27][O:28][CH3:29])[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[N:16][C:12]=2[C:11]=1[Br:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Cc3ccccc3)cc(OC)c21
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(Cc3ccccc3)cc(OC)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
6 μl (0.122 mmol) bromine are added to a solution of 48 mg (0.116 mmol) 5-benzyl-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole in 6 ml glacial acetic acid. The reaction mixture is stirred at room temperature for 10 min. 25 ml EtOAc are added and this solution is washed 4N NaOH (2×), water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is recrystallized from dichloromethane/diethyl ether/hexane to afford 40 mg of the title compound as colorless crystals.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([O:9][CH:10]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:11]=[O:12])[CH2:6][CH2:7][CH3:8]>C(O)CCC>[C:1]([C:2]([CH:11]([OH:12])[CH:10]([O:9][CH2:5][CH2:6][CH2:7][CH3:8])[O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH2:3])#[N:4]
Reactant: CCCCOC(C=O)OCCCC
Reactant: C=CC#N
Solvent: CCCCO
Product: C=C(C#N)C(O)C(OCCCC)OCCCC

Procedure:
0.17 mole acrylonitrile and 30 g (0.15 mole) of 95.5% by weight dibutoxyethanal in butanol were reacted using the method of example 1to form 22 g of 2-cyano-4,4-dibutoxy-3-hydroxy-1-butene which distilled at 108° C. under 0.1 mbar.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].C(N)CN.C(O)(=[O:13])CC>>[C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:2]([OH:13])(=[O:3])[C:1]([OH:5])=[O:4]
Reactant: CCC(=O)O
Reactant: O=C(O)CO
Solvent: NCCN
Product: O=C(O)C(=O)O
Product: O=CC(=O)O
Temperature: 15 °C
Reaction time: 377 h

Procedure:
Into a Kontes Airlift Bioreactor was placed 400 mL of a solution of 0.75M glycolic acid, 0.86M ethylenediamine, 0.075M propionic acid (HPLC internal standard), and 0.01 mM flavin mononucleotide (pH 9.0). Wet oxygen was bubbled through the solution in the bioreactor, and a peristaltic pump was used to recirculate the oxygenated solution (at 40 mL/min) from the bioreactor through a jacketed 1-cm ID×30-cm chromatography column containing spinach glycolate oxidase (13.9 IU) and Aspergillus niger catalase (56,000 IU) co-immobilized on Eupergit C oxirane acrylic beads (21-mL fixed bed volume). The contents of the bioreactor and jacketed chromatography column were maintained at 15° C. by recirculating 50:50 ethylene glycol/water through the jacket of the reactor and column using a refrigerated bath/circulator set at 10° C. After 377 hours, the yields of glyoxylic acid, oxalic acid, and formic acid were 93%, 0%, and 0.3%, respectively, with a 94% conversion of glycolic acid. The final activities of glycolate oxidase and catalase were 48% and 69% of their initial values.
Reaction SMILES: Br[CH:2]1[CH2:8][NH:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]2[C:13]([CH3:16])=[N:14][N:15]=[C:3]12.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=2)O1.[C:33]([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][C:13]1[N:4]2[C:5]3[CH:12]=[CH:11][C:10]([C:25]4[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=4)=[CH:9][C:6]=3[N:7]([CH3:33])[CH2:8][CH2:2][C:3]2=[N:15][N:14]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1nnc2n1-c1ccccc1NCC2Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1N(C)CC2
Yield: 38.4 %

Procedure:
A solution of bromo-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (50 mg, 0.17 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (75 mg, 0.34 mmol), Tetrakis(triphenylphosphine)palladium(0)(10 mg) and Cs2CO3 (110 mg, 0.34 mmol) in dioxane (5 mL) and water (1 mL) was heated at 120° C. under microwave for 20 min. The reaction mixture was concentrated to give the crude product, which was purified by prep-TLC (DCM:MeOH=10:1) to afford 5-(1,6-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyridin-2-amine (20 mg, yield 38%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:30])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([CH2:27][NH:28][CH3:29])[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:31]([NH2:33])=O)=[N:10]2)=[CH:5][CH:4]=1>CN(C=O)C.S(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:30])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([CH2:27][NH:28][CH3:29])[CH2:25][CH2:26]5)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:31]#[N:33])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CNCC1(c2ccc(N3CCc4c(C(N)=O)nn(-c5ccc(OC)cc5)c4C3=O)cc2)CC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CNCC1(c2ccc(N3CCc4c(C#N)nn(-c5ccc(OC)cc5)c4C3=O)cc2)CC1
Reaction time: 0.17 h
Yield: 76.4 %

Procedure:
The product of Example 67 (15 mg) was stirred in DMF (0.5 mL) at RT in a capped vial. Two drops of thionyl chloride was added. The reaction was completed in 10 min. The mixture was purified by RP-prep LC-MS (5–98% CH3CN/H2O in a 10-min run) to give pure 1-(4-methoxyphenyl)-6-(4-{1-[(methylamino)methyl]cyclopropyl}phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile (11 mg, yield: 76.2%). LC/MS (ESI+) 428.4 (M+H)+, tR=4.49 min.
Reaction SMILES: [Cl:1][C:2]1[C:18]([F:19])=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:13]=[CH:12][S:11][C:10]=2[C:14](O)=[O:15])=O)=[C:4]([F:20])[CH:3]=1.S(Cl)(Cl)=O.C[N:26](C=O)C>>[Cl:1][C:2]1[C:18]([F:19])=[CH:17][C:5]([C:6]2[NH:8][C:9]3[CH:13]=[CH:12][S:11][C:10]=3[C:14](=[O:15])[N:26]=2)=[C:4]([F:20])[CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(Nc1ccsc1C(=O)O)c1cc(F)c(Cl)cc1F
Solvent: O=S(Cl)Cl
Product: O=c1nc(-c2cc(F)c(Cl)cc2F)[nH]c2ccsc12
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
After a mixture of 3-[(4-chloro-2,5-difluorobenzoyl)amino]thiophene-2-carboxylic acid, thionyl chloride and DMF was stirred for 1.5 hours at 75° C., the solvent was removed under reduced pressure and 1,4-dioxane was added. After the reaction solution was added to 28% ammonia water under ice cooling and stirred at room temperature for 3 hours, the solvent was removed under reduced pressure. MeOH and 1M NaOH aq were added to the obtained residue and stirred for 2.5 hours at 90° C. to give 2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4(1H)-one.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][C:10]1[CH:11]=[C:12]([CH:38]=[CH:39][CH:40]=1)[C:13]([NH:15][C:16]1[CH:17]=[C:18]([CH:34]=[CH:35][C:36]=1[CH3:37])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20])=[O:14].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)(=O)C>[CH3:37][C:36]1[CH:35]=[CH:34][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[CH:23]=2)=[O:20])=[CH:17][C:16]=1[NH:15][C:13](=[O:14])[C:12]1[CH:38]=[CH:39][CH:40]=[C:10]([CH2:9][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:11]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(CCl)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Temperature: 60 °C
Yield: 41.6 %

Procedure:
N-Methylpiperazine (0.036 g) was added to a mixture of 3-(3-chloromethylbenzamido)-4-methyl-N-(3-morpholinophenyl)benzamide (0.15 g), potassium carbonate (0.09 g) and acetone (5 ml) and the resultant mixture was stirred and heated to 60° C. for 16 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica gel using methanol as eluent. The product so obtained was dissolved in ethyl acetate and precipitated by the addition of isohexane. There was thus obtained the title compound (0.071 g); NMR Spectrum: (DMSOd6) 2.1 (s, 3H), 2.3 (s, 3H), 2.2-2.4 (m, 8H), 3.1 (t, 4H), 3.55 (s, 2H), 3.75 (t, 4H), 6.65-6.7 (m, 1H), 7.18 (t, 1H), 7.3-7.35 (m, 1H), 7.38-7.55 (m, 4H), 7.78-7.8 (m, 1H), 7.85-7.9 (m, 2H), 7.95 (s, 1H); Mass Spectrum: M+H+ 528.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29].O>C1(C)C=CC=CC=1.C1COCC1>[Cl:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[CH:11]/[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)/C=C/c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 1.19 g (29.64 mmol, 60%) of sodium hydride were suspended in 25 ml of toluene and 25 ml of THF, and the mixture was cooled to 0° C. 7.28 ml (30.99 mmol) of tert-butyl (diethoxyphosphoryl)acetate were then slowly added dropwise, and the mixture was stirred at 0° C. for 30 min. 5 g (26.94 mmol) of 4-chloro-3-nitrobenzaldehyde were then added to the reaction mixture, and the mixture was subsequently warmed to room temperature. The mixture was stirred at room temperature for 2 h, and 50 ml of water were then added. The organic phase was separated off, and the aqueous phase was then extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 9:1). This gave 6.77 g (23.86 mmol, 77% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[C:5](=[O:16])[NH:4][CH2:3]1.Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[CH3:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:13])[F:14])=[CH:9][CH:10]=2)[C:5](=[O:16])[N:4]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][C:24]=2[CH3:25])[CH2:3]1
Reactant: Cc1ccncc1Br
Reactant: CC1(C)CNC(=O)c2cc(C(F)(F)F)ccc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CC(C)(C)c2ccc(C(F)(F)F)cc2C1=O
Yield: 5.5 %

Procedure:
Using analogous reaction conditions as described in Example 1, 4,4-dimethyl-7-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-20d: 200 mg, 0.8230 mmol) was reacted with 3-bromo-4-methyl-pyridine (91.9 mL, 0.8230 mmol), 1,4-dioxane (3 mL), copper iodide (15.6 mg, 0.0823 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (38.8 mL, 0.2469 mmol) and potassium phosphate (436.1 mg, 2.0575 mmol) to afford the crude product. Purification by column chromatography on silica gel (50% ethylacetate in hexane) afforded 15 mg of the product (5.44% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:11]2[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][C@H:12]2[C:18]#N)[CH2:9][OH:10])=[CH:4][CH:3]=1.C(=O)(O)[O-:21].[Na+].C(Cl)(Cl)Cl.Cl.[CH2:30]([OH:32])[CH3:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:11]2[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][C@@H:12]2[C:18]([O:32][CH2:30][CH3:31])=[O:21])[CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: CCO
Reactant: N#C[C@@H]1CCCC(=O)N1[C@@H](CO)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H]1CCCC(=O)N1[C@@H](CO)c1ccc(F)cc1

Procedure:
A solution of (S*)-1-[(R*)-1-(4-fluorophenyl)-2-hydroxyethyl]-6-oxopiperidine-2-carbonitrile (1.17 g) in saturated hydrochloric acid-ethanol (20 mL) was stirred at room temperature for two days. A saturated sodium bicarbonate solution and chloroform were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 290 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
50 g (0.247 Mol) of 1-Bromo-4-nitro-benzene and 55 mL. (0.495 Mol) of 1-methyl-piperazine are heated for 26 h at 80° C. After cooling, the reaction mixture is taken up in water and extracted with CH2Cl2CH3OH (8:2). The combined organic layers are dried (Na2SO4), filtered and evaporated under reduced pressure. The crude product is recrystallized from ethanol to obtain 1-methyl-4-(4-nitro-phenyl)-piperazine. Title compound: ES-MS: 443.0 [M+H]+; Rf=0.38 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[CH3:13][NH:14]C.C12[C:22](=[CH:23]C=CC=1)[NH:21][C:20](=O)OC2=O>>[NH:21]1[CH2:20][CH2:13][N:14]=[C:22]1[CH2:23][NH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: CNC
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CN(C)C(=O)c1ccccc1N
Product: CN(C)C(=O)c1ccccc1NCC1=NCCN1

Procedure:
2-Amino-N,N-dimethylbenzamide (prepared from dimethylamine [2M in tetrahydrofuran]and isatoic anhydride, using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give 2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]-N,N-dimethylbenzamide.