Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:28].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][Si:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][O:20][CH2:19][N:10]1[C:11]2[C:18]3[CH:17]=[CH:16][S:15][C:14]=3[CH2:13][C:12]=2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:33]=[CH:34][C:29]([C:27]#[N:28])=[CH:30][CH:31]=3)=[CH:3][CH:4]=2)=[N:9]1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(-c3ccc(C#N)cc3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 50 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.4 g, 0.9 mmol), 4-cyanophenylboronic acid (0.2 g, 1.35 mmol), Na2CO3 (2 M, 2.0 mL), and Pd(PPh3)2Cl2 (8 mg, 0.075 mmol) in toluene/ethanol (1:1, 6 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (30% EtOAc in hexane) to give 4′-[4-(2-Trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta [a]pentalen-6-yl]-biphenyl-4-carbonitrile as brown solid in 50% yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([O:20][CH3:21])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:21][O:20][C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:19]=[N:18][CH:17]=1
Reactant: COc1cncc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Product: COc1cncc(N2CCNCC2)n1

Procedure:
Prepared in analogy to example 4.10(c) from 6′-Methoxy-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester and trifluoroacetic acid. MS (m/e): 195.1 (MH+, 80%)
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:9]2[CH:4]([CH2:5][NH:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>CC(C)=O.O>[C:13]([O:12][C:10]([N:1]1[CH:9]2[CH:4]([CH2:5][N:6]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:7][CH2:8]2)[CH2:3][CH2:2]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: ClCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC2CNCCC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2CN(CCCCl)CCC21
Yield: 77 %

Procedure:
To a solution of tert-butyl octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (0.63 g) in acetone (15 mL) was added K2CO3 (1.54 g) and 1-bromo-3-chloropropane (1.45 mL). The reaction mixture was heated to reflux overnight, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 for 1 h and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 10:1 (v/v) CH2Cl2/MeOH) to give the title compound as pale yellow liquid (0.65 g, 77.00%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.Cl.[CH3:33][NH:34][O:35][CH3:36]>C(Cl)(Cl)Cl.O>[CH3:36][O:35][N:34]([CH3:33])[C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: CNOC
Reactant: Cc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CON(C)C(=O)c1ccccc1C
Temperature: 25 °C
Yield: 50 %

Procedure:
2-Methylbenzoic acid (1.00 g, 7.34 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.69 g, 8.81 mmol) in chloroform (10 mL) stirred with N,N-diisopropylethylamine (1.50 mL, 8.81 mmol) for 10 minutes under cooling with ice and then stirred with N,O-dimethylhydroxylamine hydrochloride (860 mg, 8.81 mmol) and N,N-diisopropylethylamine (1.50 mL, 8.81 mmol) for one day while the temperature was gradually raised to room temperature. After addition of water, the reaction mixture was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a pale yellow oil (658 mg, yield 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:20]=[C:19]([C:21]#[C:22][CH2:23][CH2:24][OH:25])[S:18][C:13]=3[N:14]([CH2:16][CH3:17])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1>[Pd].C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[S:18][C:13]=3[N:14]([CH2:16][CH3:17])[CH:15]=2)=[O:9])=[CH:27][CH:28]=1
Reactant: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCCO)sc21
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCCO)sc21
Yield: 81 %

Procedure:
A solution of N-(4-chlorobenzyl)-7-ethyl-2-(4-hydroxy-1-butynyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Example No. 15) (0.257 g) in 1/1 CH2Cl2/CH3OH (50 mL) is hydrogenated over 10% Pd/C (75 mg) at 35 psi for 2 h. The reaction mixture is filtered through a Celite pad, and the filtrate is concentrated in vacuo. The resulting pale yellow solid is purified via column chromatography (CH2Cl2:CH3OH; 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 0.209 g (81%) of the title compound as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:17]=[CH:16][CH:15]=[C:9]2[C:10]([NH:12][C:13](=[O:14])[C:8]=12)=[O:11].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(OCC)C>[N:18]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[CH:17]=[CH:16][CH:15]=[C:9]3[C:10]([NH:12][C:13](=[O:14])[C:8]=23)=[O:11])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: O=C1NC(=O)c2c(CCCCCBr)cccc21
Solvent: CCOCC
Product: O=C1NC(=O)c2c(CCCCCN3CCOCC3)cccc21

Procedure:
5-Bromopentylphthalimide (432 mg; 2.0 mmoles) and morpholine (0.35 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]=[N:12]2)=[CH:7][C:4]=1[CH:5]=O.[CH3:20][NH2:21]>ClCCl.C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]=[N:12]2)=[CH:7][C:4]=1[CH2:5][NH:21][CH3:20]
Reactant: CN
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1C=O
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNCc1cc(-n2nnnc2C(F)(F)F)ccc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In 40 ml of dichloromethane was dissolved 2.72 g of 2-methoxy-5-(5-trifluoromethyltetrazole-1-yl)benzaldehyde, and added thereto was 2.5 ml of 8 M methylamine in ethanol solution, 0.572 ml of acetic acid and 3.12 g of triacetoxy sodium borohydride, the mixture was stirred at room temperature for 6 hours. The reaction mixture was washed with saturated aqueous sodium hydrocarbonate solution, and the organic layers were dried and concentrate. The residue was purified by silica gel column chromatography (chloroform:methanol=49:1 to 4:1), to give 2.2 g of N-{2-methoxy-5-(5-trifluromethyltetrazole-1-yl)benzyl}-N-methylamine as shown in Table 136 below.
Reaction SMILES: C1C(=O)N(Br)C(=[O:4])C1.CC([Si](C)(C)[O:14][C@@H:15]1[CH2:28][C@@H:27]2[C@H:18]([C@H:19]3[C@H:24]([CH2:25][CH2:26]2)[CH2:23][C@:22]2([CH3:34])[C:29](=[N:32][OH:33])[CH2:30][CH2:31][C@H:21]2[CH2:20]3)[CH2:17][CH2:16]1)(C)C.[BH4-].[Na+].Cl>O1CCOCC1>[CH3:34][C@@:22]12[C@@H:29]([N+:32]([O-:4])=[O:33])[CH2:30][CH2:31][C@H:21]1[CH2:20][C@@H:19]1[C@H:24]([CH2:25][CH2:26][C@H:27]3[C@H:18]1[CH2:17][CH2:16][C@H:15]([OH:14])[CH2:28]3)[CH2:23]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H]2[C@H](CC[C@@H]3C[C@]4(C)C(=NO)CC[C@H]4C[C@H]32)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@]12C[C@H]3CC[C@@H]4C[C@@H](O)CC[C@H]4[C@@H]3C[C@@H]1CC[C@@H]2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of NBS (210 mg, 1.3 mmol) in dioxane (4 mL) was added aqueous KHCO3 (260 mg, 2.6 mmol, 4 mL) at room temperature. The mixture was stirred for 30 min at room temperature. Compound 5 (105 mg, 0.26 mmol) in dioxane (10 mL) was added. The reaction was stirred for 14 h at room temperature and then NaBH4 was added (200 mg in 5 portions). The reaction was stirred for 3 h at room temperature. 6 N HCl (10 mL) was added and stirring at room temperature continued for 1 h. The product was extracted into EtOAc (50 mL×2). The combined extracts were dried, filtered, and removed. The residue was purified by flash column chromatography (silica gel eluted with 20% EtOAc in hexanes) to afford compound 6 (62 mg, 56%): mp 157-159° C.; [α]D20 +32.4 (c 0.21, CHCl3); 1H NMR (CDCl3) δ 4.40 (t, J=8.2 Hz, 1H), 4.05-4.10 (m, 1H), 2.56-2.51 (m, 1H), 0.73 (s, 3H); 13C NMR (CDCl3) δ 94.4, 66.3, 47.9, 47.2, 47.0, 45.8, 45.1, 40.4, 38.3, 36.1, 33.9, 33.8, 32.7, 28.4, 25.7, 24.6, 2.32, 12.1; IR νmax 3385, 2212, 1542 cm−1. Anal. Calcd for (C18H29NO3): C, 70.32; H, 9.51; N, 4.56. Found: C, 70.12; H, 9.32; N, 4.33.
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH:8][C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([N:8]([N:3]1[C:4]([CH3:7])=[CH:5][CH:6]=[C:2]1[CH3:1])[C:9]1[N:10]=[N:11][C:12]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:13][CH:14]=1)(=[O:23])[CH3:22]
Reactant: Cc1ccc(C)n1Nc1ccc(N2CCOCC2)nn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(c1ccc(N2CCOCC2)nn1)n1c(C)ccc1C
Temperature: 110 °C

Procedure:
A mixture of 6 g (22 m mol) of N-(2,5-dimethyl-1H-pyrrol-yl)-6-morpholino-3-pyridazineamine, 30 ml of acetic anhydride, and 6 ml of pyridine is heated for one hour at 110° C. The reaction mixture is evaporated to dryness under vacuum and the oily residue is dissolved in 150 ml of ethyl acetate. The organic solution is washed first with 50 ml of an aqueous solution of sodium bicarbonate and then with 50 ml of water.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[N:18]=2)[C:7]([NH:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1)([O-])=O>[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[N:18]=2)[C:7]([NH:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1
Reactant: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccc(Cl)cc3)ccc2o1
Agent: [Zn]
Product: CCCNc1ccc(N)cc1-c1nc2cc(-c3ccc(Cl)cc3)ccc2o1

Procedure:
Prepared by the method of Example 47b), from 2-(3-nitro-6-propylaminophenyl)-5-(4-chlorophenyl)benzoxazole (284 mg, 0.70 mmol) and zinc (455 mg, 7.0 mmol) the subtitle compound was obtained (264 mg, 99%). The product was used directly in the next step without purification
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].BrC[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[O:19][CH3:20].[C:21](=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[CH3:18][O:17][C:14]1[CH:15]=[C:16]([CH:11]=[C:12]([O:19][CH3:20])[CH:13]=1)[CH2:21][O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(CBr)c(OC)c1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(COc2cccc(O)c2)cc(OC)c1
Yield: 27.1 %

Procedure:
Resorcinol (0.21 g, 1.87 mmol), 4-bromomethyl-1,3-dimethoxybenzene (0.39 g, 1.70 mmol), potassium carbonate (0.26 g, 1.87 mmol) and 18-crown-6-ether (0.09 g, 0.34 mmol) were stirred together in acetone (15 cm3, 99%) under nitrogen at room temperature for 20 hours. The solution was evaporated under reduced pressure, and the residue was taken up in dichloromethane (10 cm3) and water (10 cm3). The aqueous layer was extracted with dichloromethane (2×10 cm3), and the combined extracts were washed with water (2×20 cm3), dried (MgSO4), and evaporated under reduced pressure. The residue was chromatographed (SiO2, dichloromethane) to give the phenol, (0.12 g, 27%), as an oil.
Reaction SMILES: [CH3:1][O:2][Si:3]([O:10][CH3:11])([O:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH2:7].[C:12](=S)=[S:13].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>O1CCCC1>[N:7]([CH2:6][CH2:5][CH2:4][Si:3]([O:8][CH3:9])([O:10][CH3:11])[O:2][CH3:1])=[C:12]=[S:13]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CO[Si](CCCN=C=S)(OC)OC
Temperature: 0 °C
Reaction time: 5 h

Procedure:
In a reaction container mixed were 53.8 g of 3-(trimethoxysilyl)propylamine and 600 ml of dry tetrahydrofuran (THF), with cooling to 0° C. To this solution, 34.2 g of carbon disulfide was added dropwise, and the mixture was stirred at 0° C. for 5 hours in a nitrogen atmosphere. Then, a solution of 61.9 g of dicyclohexyl carbodiimide in 180 ml of dry THF and 3 g of triethylamine were added thereto, and the mixture was allowed to react at 40° C. for 5 hours. THF was removed from the reaction mixture obtained, and the residue was extracted with n-hexane. Then n-hexane was removed from the extract under reduced pressure, and the residue was distilled under reduced pressure, to obtain γ-isothiocyanatopropyltrimethoxysilane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[C:18]3=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]3[CH:16]=[CH:15][CH:14]=1)[CH:7]=[CH:6]2>C1COCC1.CO.[Pt](=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]1[C:18]3=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]3[CH2:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C3=CC=CN4CCS(=O)(=O)N=C34)ccc2c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2cc(C3CCCN4CCS(=O)(=O)N=C34)ccc2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-(6-methoxynaphthalen-2-yl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (218 mg) in THF (dry) (75 mL) and MeOH (75 mL) and the mixture was stirred at room temperature under hydrogen overnight and at 50° C. overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). The filtrate was concentrated and the residue was crystallized from MeCN-THF/IPE to give the title compound (153 mg) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2].[I:23]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>ClCCl.CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([I:23])[C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2]
Reactant: N#Cc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)ccc1O
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(I)c1O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-(3-cyano-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole was dissolved in dichloromethane (27 mL) and methanol (3 mL), and N-iodosuccinimide (1.79 g) and trifluoromethanesulfonic acid (5 droplets) was added to the solution, and then the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-ethyl acetate to obtain the title compound (1.30 g) as a colorless crystal.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:22])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:25]I.O>CN(C)C=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:22])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1
Reactant: CI
Reactant: O=c1[nH]c2cnc3ccc(Br)cc3c2n1-c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(-c2ccccc2Cl)c2c3cc(Br)ccc3ncc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
300 mg (0.8 mmol) of 8-bromo-1-(2-chloro-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one [see under B)] are dissolved in 5 ml of anhydrous N,N-dimethylformamide and 35 mg (0.8 mmol) of NaH are added portionwise. The suspension is stirred for 90 min at room temperature and 113 mg (0.8 mmol) of methyl iodide dissolved in 3 ml of N,N-dimethylformamide are added. After stirring for 18 h at room temperature, the solution is cooled at 0° C. and 20 ml of water are added slowly to the stirred suspension. The suspension is extracted with ethyl acetate and the water phase is discarded. The organic phase is washed with brine, dried with Na2SO4 and evaporated to dryness. The crude compound is purified by flash-chromatography (dichloromethane with 2% methanol) to provide the title compound: Analytical HPLC: tret=7.64 min (Grad. 2); ES-MS: m/e0=388.0, 390.0.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[O:14][CH:13]=1.[OH-].[Na+]>ClC(Cl)C>[CH:8]([C:13]1[O:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:16][C:12]=1[CH3:11])=[O:9]
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2cc(C)co2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2cc(C)c(C=O)o2)cc1
Temperature: 0 °C

Procedure:
Phosphorus oxychloride (12 ml) was added slowly to dimethylformamide (9.85 ml) with stirring at 0° C., and the mixture stirred at 0° C. for 30 minutes. A solution of 3-methyl-5-(4-methylphenyl)furan (22 g) in 50 ml of dichloroethane was added dropwise over a period of 15 minutes, maintaining the temperature at 0° C. The mixture was then stirred at room temperature for 11/2 hours. Ice water was then added, and the pH of the aqueous layer adjusted to about 8 with dilute sodium hydroxide. The organic layer was separated, the aqueous layer extracted with dichloromethane, the organic portions combined and solvent removed under reduced pressure. The solvent was removed from the filtrate under reduced pressure, and the residue flash chromatographed on silica gel, eluting with 10% ethyl acetate in heptane, to yield 19.2 g of 2-formyl-3-methyl-5-(4-methylphenyl)furan.
Reaction SMILES: [CH2:1]([N:3]([CH3:23])[C:4]([N:6]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][CH:8]([C:20]([OH:22])=O)[CH2:7]1)=[O:5])[CH3:2].O[N:25]=[C:26]([NH2:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>>[C:27]([C:26]1[N:31]=[C:20]([CH:8]2[CH2:9][CH:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=3)[CH2:11][N:6]([C:4]([N:3]([CH2:1][CH3:2])[CH3:23])=[O:5])[CH2:7]2)[O:22][N:25]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)C(N)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N(C)CC)C2)cc1
Product: CCc1ccc(C2CC(c3nc(C(C)(C)C)no3)CN(C(=O)N(C)CC)C2)cc1

Procedure:
64 mg (0.20 mmol) of 1-[ethyl(methyl)carbamoyl]-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 45A) and 26 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2,2-dimethylpropanimidamide were reacted according to the General Method 1. Yield: 52 mg (65% of theory)
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[OH:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[OH:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:16]([C:13]2[S:14][CH:15]=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[N:12]=2)=[O:17])[CH2:23][CH2:22]1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: OCC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCC(CO)CC3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (200 mg, 0.66 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 4-(Hydroxymethyl)piperidine (Maybridge)(76.3 mg; 0.66 mmol; 1 eq.) and triethylamine (0.19 ml; 1.33 mmol; 2 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is crystallized in MeOH, affording Compound (27) as a brown solid (106.3 mg; 42%). 1H NMR (DMSO-d6, 300 MHz) δ 1.05-1.30 (m, 2H), 1.65-1.87 (m, 3H), 2.14 (s, 3H), 2.50 (s, 3H), 2.86 (m, 1H), 3.20 (m, 1H), 3.28 (m, 2H), 4.48 (m, 1H), 4.52 (t, J=4.5 Hz, 1H), 5.16 (m, 1H), 7.97 (s, 1H), 12.16 (s, 1H). M− (ESI): 379.20; M+ (ESI): 381.19. HPLC (method A), Rt: 2.47 min (purity: 99%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[NH2:38])[CH2:22][CH2:21]1.Cl.O1CCOCC1>CO>[N:23]1([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:28][C:27]=2[NH:38][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:3]=2[CH3:19])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: Cc1c(-c2cccc(F)c2)nc2ccccc2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2cccc(F)c2)nc2ccccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4-chloro-2-(3-fluorophenyl)-3-methylquinoline (127 mg, 467 μmol), 2,5-dimorpholinobenzenamine (123 mg, 467 μmol) and 4N hydrochloric acid solution in dioxane (0.12 mL, 467 μmol) in MeOH (3.00 mL) to afford product as a colorless solid after purification by chromatography on silica gel, eluting with MeOH gradient in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 8.16 (1H, d, J=8.2 Hz), 7.90 (1H, dd, J=8.0, 1.0 Hz), 7.66-7.75 (1H, m), 7.43-7.56 (2H, m), 7.32-7.43 (2H, m), 7.25 (1H, s), 7.07-7.22 (2H, m), 6.45 (1H, dd, J=8.6, 2.7 Hz), 6.03 (1H, d, J=2.7 Hz), 3.88-3.99 (4H, m), 3.67-3.80 (4H, m), 3.01-3.14 (4H, m), 2.88-2.99 (4H, m), 2.32 (3H, s). Mass Spectrum (ESI) m/e=499.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.[CH3:17]OC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C1COCC1>[Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH:12]([CH3:17])[CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)NC(=O)Nc1cc(C(N)=S)c(Br)cn1

Procedure:
The title compound was synthesized by a method analogous to the synthesis of Intermediate 42 starting with Intermediate 46 and Lawesson's reagent in THF.