Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:13]4[CH:20]=[C:19]([C:21](O)=[O:22])[NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:10][C:4]=2[S:3]1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([C:21]([C:19]2[NH:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][C:9]4[CH:8]=[CH:7][C:5]5[NH:6][C:2](=[O:1])[S:3][C:4]=5[CH:10]=4)[C:13]=3[CH:20]=2)=[O:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1cc2c(Nc3ccc4[nH]c(=O)sc4c3)ncnc2[nH]1
Product: O=C(c1cc2c(Nc3ccc4[nH]c(=O)sc4c3)ncnc2[nH]1)N1CCCCC1

Procedure:
150 mg (458 μmol) 4-[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (prepared according to example 30) were transformed in analogy to example 4 using piperidine to give after working up and purification 47.0 mg (26%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([CH:14]=O)=[C:6]2Cl)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[SH:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]>>[CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]3[CH:14]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[S:23][C:6]2=3)[CH2:2][CH2:3]1
Reactant: O=Cc1c(Cl)n(CC2CC2)c2ccccc12
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc2c3ccccc3n(CC3CC3)c2s1

Procedure:
Prepared from (4) (6.5 g), K2CO3 (10 g) and methyl 2-mercaptoacetate (3.2 ml) yielding (7) (6 g), m.p. 110°-111° C.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1.[CH3:20][C:21]1[O:22][C:23]([CH3:26])=[CH:24][CH:25]=1>C1(C)C=CC=CC=1>[CH3:20][C:21]12[O:22][C:23]([CH3:26])([CH:24]=[CH:25]1)[CH:6]1[CH:5]2[C:4](=[O:7])[N:3]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:17])([F:19])[F:18])[CH:9]=2)[C:2]1=[O:1]
Reactant: N#Cc1ccc(N2C(=O)C=CC2=O)cc1C(F)(F)F
Reactant: Cc1ccc(C)o1
Solvent: Cc1ccccc1
Product: CC12C=CC(C)(O1)C1C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C12
Temperature: 60 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A slurry of 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-2-trifluoromethyl-benzonitrile (30 g, 113 mmol) and 2,5-dimethylfuran (70 mL) was stirred at 60° C. for 0.5 h. After toluene (40 mL) was added, the reaction mixture was stirred at 60° C. for 3 h. The mixture was then cooled in ice bath. The solid was collected by filtration and washed with cold toluene (30 mL) to give Preparation 1 as an off white solid (36.8 g, 102 mmol, 90% yield).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:29])[NH:12][C@@H:13]2[CH2:18][CH2:17][C@H:16]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:54][NH2:55]>C1COCC1>[CH3:54][NH:55][C:24](=[O:25])[C:23]1[CH:22]=[CH:21][C:20]([O:19][C@H:16]2[CH2:17][CH2:18][C@@H:13]([NH:12][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:30])[F:31])=[CH:5][CH:6]=3)=[O:29])[CH2:14][CH2:15]2)=[CH:28][CH:27]=1
Reactant: CN
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)N[C@H]1CC[C@@H](Oc2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(O[C@H]2CC[C@@H](NC(=O)Nc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1686 (0.22 g, 0.5 mmol), EDC HCl (0.12 g, 0.63 mmol), HOBT (0.09 g, 0.63 mmol), TEA (0.17 mL, 0.63 mmol) in THF (10 mL) was added 2M MeNH2 in THF (1.25 mL, 2.5 mmol) at 0° C. The reaction mixture was allowed to slowly warm to room temperature overnight. The solvent was removed in vacuo and then purified by recrystallization with EtOAc/Hexanes gave the title compound, 0.2 g (89%) as a white solid. mp 207.3-208.4° C. 1H NMR (300 MHz, DMSO-d6): δ 8.55 (s, 1H), 8.26 (q, J=4 Hz, 1H), 7.78 (d, J=9 Hz, 2H), 7.47 (d, J=9 Hz, 2H), 7.21 (d, J=9 Hz, 2H), 7.00 (d, J=9 Hz, 2H), 6.40 (d, J=8 Hz, 1H), 4.62-4.53 (m, 1H), 3.73-3.60 (m, 1H), 2.75 (d, J=4 Hz, 3H), 1.89-1.50 (m, 8H).
Reaction SMILES: [CH2:1]([C:8]1[C:12]2[C:13](=[O:30])[N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=3)[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]=2[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)(Cl)(Cl)Cl.O.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[NH2:27][C:23]1[CH:22]=[C:21]([N:14]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]3[NH:10][N:9]=[C:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:12]=3[C:13]2=[O:30])[CH:26]=[CH:25][CH:24]=1
Reactant: O=c1c2c(Cc3ccccc3)n[nH]c2c2cccnc2n1-c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: Nc1cccc(-n2c(=O)c3c(Cc4ccccc4)n[nH]c3c3cccnc32)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.6 %

Procedure:
To a solution of 3-benzyl-5-(3-nitrophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (98 mg, 0.25 mmol) in conc. hydrochloric acid (7 ml) was added tin chloride.2H2O (500 mg, 5-fold weights), and the mixture was stirred at room temperature for 1.5 hour, admixed with water, then treated with sodium carbonate to make it to pH8-9, and extracted with chloroform 8 times. The organic layer was dried over anhydrous magnesium sulfate, and evaporated to give 5-(3-aminophenyl)-3-benzyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (63 mg, 70%).
Reaction SMILES: [C:1](=[NH:24])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:25]([CH:27]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:28](OC)=O)=[O:26].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:28]=[C:27]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:25](=[O:26])[N:24]=3)=[CH:11][CH:10]=2)=[CH:14][C:15]=1[C:20]([F:23])([F:22])[F:21]
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: COC(=O)CC(C=O)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)Cc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Temperature: 130 °C

Procedure:
To a solution of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl imidocarbamate (437 mg, 0.861 mmol) and dimethyl 2-formylbutanedioate (450 mg, 2.58 mmol) in NMP (5 mL) was added K2CO3 (357 mg, 2.58 mmol). The mixture was heated at 130° C. for 1.5 h. Purification via reverse phase flash chromatography then afforded the title compound, together with ethyl ester (102 mg, 0.211 mmol, 24.55% yield).
Reaction SMILES: [OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:39]2[CH2:43][CH2:42][C:41](=[O:44])[CH:40]=2)O1>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([C:39]4[CH2:43][CH2:42][C:41](=[O:44])[CH:40]=4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CC1(C)OB(C2=CC(=O)CC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Product: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(C4=CC(=O)CC4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 125 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3-methyl-cyclohexylmethyl)-amide, cesium carbonate, 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclopent-2-enone and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II). 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.70 (t, J=6.04 Hz, 1H), 8.28-8.22 (m, 2H), 8.12 (d, J=9.21 Hz, 1H), 7.86 (d, J=9.03 Hz, 1H), 7.13 (t, J=1.64 Hz, 1H), 4.21 (s, 1H), 3.22-3.20 (m, 2H), 2.56-2.54 (m, 2H), 1.73 (t, J=3.41 Hz, 1H), 1.62-1.56 (m, 4H), 1.48-1.45 (m, 1H), 1.32-1.25 (m, 1H), 1.06-1.00 (m, 1H), 0.84 (d, J=6.63 Hz, 3H), 0.77-0.74 (m, 1H). m/z: 413.2 [M+H]+
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18]([O:21][CH3:22])[C:19]#[CH:20].O>C(COC)OC.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.[Cu]I>[CH3:22][O:21][CH2:18][C:19]#[C:20][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C#CCOC
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1nc(-c2ccccc2)sc1C#CCOC
Temperature: 25 °C
Yield: 87.1 %

Procedure:
Nitrogen was bubbled through a solution of Ethyl 5-bromo-2-phenylthiazole-4-carboxylate (13.1 g, 41.9 mmol) and methyl propargyl ether (7.1 mL, 83.9 mmol) in dimethoxyethane (DME) (200 mL). Dichlorobis(triphenylphosphine)palladium (II) (1.47 g, 2.2 mmol), copper (I) iodide (0.2 g, 1.1 mmol), and TEA (29 mL, 210 mmol) were added and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to room temperature, poured into H2O (200 mL) and extracted with EtOAc (2×200 mL). The combined organics were washed with brine, dried (MgSO4), and concentrated. The crude product was purified by MPLC eluting with pentane/EtOAc (0-50% gradient) to give ethyl 5-(3-methoxyprop-1-ynyl)-2-phenylthiazole-4-carboxylate as a tan solid (11 g, 88% yield).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)C>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:18][CH:19]=2)=[N:7][CH:6]=1
Reactant: Brc1cnc(Br)nc1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Brc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Yield: 96.6 %

Procedure:
10.43 g (0.044 mol) of 2,5-dibromopyrimidine, 10 g (0.044 mol) of 4-(phenylmethoxy)benzeneboronic acid, 98.8 mg (0.00044 mol) of palladium(II) acetate, (0.001752 mol) of TPPTS and 9.3 g (0.0876 mol) of sodium carbonate are heated at 80° C. in 100 ml of toluene, 50 ml of ethanol and 30 ml of water for 48 hours. The palladium catalyst is subsequently separated off from the reaction mixture by filtration at 80° C. The lower aqueous phase of the reaction mixture is separated off at 80° C. before the organic phase is freed of the solvents on a rotary evaporator and is dried in a high vacuum. The crude product thus obtained is crystallized from acetonitrile (300 ml), giving 14.5 g (93% yield, based on 2,5-dibromopyrimidine) of 5-bromo-2-[4-(phenylmethoxy)phenyl]-pyrimidine (content according to HPLC: 98%). ##STR18##
Reaction SMILES: [CH:1]([NH:3][CH:4](P(OCC)(OCC)=O)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6])=[S:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:32][C:33](=O)[CH3:34]>CC(C)=O>[CH3:32][C:33]1[CH2:34][S:2][CH:1]=[N:3][C:4]=1[C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)=[O:6]
Reactant: CC(=O)CCl
Reactant: CCOP(=O)(OCC)C(NC=S)C(=O)OCc1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(C)CSC=N2)cc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
A mixture of p-methoxybenzyl α-thioformamidodiethylphosphonoacetate (188 mg., 0.5 mmole), powdered potassium carbonate (1.52 mg., 1.1 mmole) and chloro-2-propanone (44μl., 0.55 mmole) in acetone (2.5 ml.) is stirred at room temperature and under a nitrogen atmosphere. After 22 hours stirring, the mixture is filtered and the salts washed with acetone. The combined filtrate and washings are evaporated in vacuo to a dark residue which is shaken with csrbon tetrachloride (3 × 2 ml.). The combined extracts are washed with water (2 × 2 ml.) and saturated brine (2 ml.), dried over magnesium sulfate and evaporated in vacuo to give p-methoxybenzyl 5-methyl-6H-1,3-thiazine-4-carboxylate (116 mg.) as an orange oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:24])=[C:6]([C:17]2[CH:18]=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:7]=1[C:8]1[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=1[F:16].[CH3:25][O-:26].[Na+].CO>O>[Cl:23][C:20]1[N:19]=[CH:18][C:17]([C:6]2[C:7]([C:8]3[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=3[F:16])=[C:2]([O:26][CH3:25])[N:3]=[N:4][C:5]=2[CH3:24])=[CH:22][CH:21]=1
Reactant: C[O-]
Reactant: Cc1nnc(Cl)c(-c2c(F)cc(F)cc2F)c1-c1ccc(Cl)nc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nnc(C)c(-c2ccc(Cl)nc2)c1-c1c(F)cc(F)cc1F

Procedure:
A mixture of 3-chloro-5-(6-chloro-pyridin-3-yl)-6-methyl-4-(2,4,6-trifluorophenyl)-pyridazine (Compound No. I.a.11, 700 mg), sodium methoxide (30% solution in methanol, 750 mg) and 10 ml of methanol is heated for 6 h to 60° C. Subsequently the reaction mixture is cooled, diluted with water and extracted with ethyl acetate. The combined organic layer is washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The remainder is purified by chromatography on silica gel, using a mixture of heptane/ethyl acetate 3:1 as eluent to obtain 4-(6-chloro-pyridin-3-yl)-6-methoxy-3-methyl-5-(2,4,6-trifluoro-phenyl)-pyridazine (Compound I.a.12), m.p. 123-124° C.
Reaction SMILES: [CH:1]1([C:6]2[S:7][CH2:8][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(#N)C.[O-2].[O-2].[Mn+4]>[CH:1]1([C:6]2[S:7][CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)C1CSC(C2CCCC2)=N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: CCOC(=O)c1csc(C2CCCC2)n1
Reaction time: 2 h

Procedure:
Manganese dioxide (24 g) was added to a solution of ethyl 2-cyclopentyl-4,5-dihydrothiazole-4-carboxylate [Carboxylic Acid 2, step b] (3.2 g) in acetonitrile (100 mL) and the resulting mixture heated at reflux overnight. The reaction was allowed to cool and filtered through a pad of Celite. The filter pad was washed with acetonitrile (2×100 mL) and the combined filtrate and washings evaporated. The residue was purified by silica gel chromatography eluting with 9:1 isohexane:ethyl acetate. The fractions containing the product were combined, evaporated and redissolved in ethanol (20 mL). A slurry of palladium on carbon (5%, 0.66 g) in water (0.5 mL) was added and the resulting suspension stirred under an atmosphere of hydrogen at 5 bar pressure for 2 h. The mixture was filtered through a pad of Celite which was washed with ethanol (3×50 mL). The combined filtrate and washings were evaporated to give the subtitled compound as a clear oil. Yield 0.9 g.
Reaction SMILES: C(OCC)(=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([O:21][C:22](=[O:32])[CH2:23][CH:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:25](O)=O)(C)(C)C>C1COCC1>[CH2:28]([CH:24]1[CH2:25][O:32][C:22](=[O:21])[CH2:23]1)[CH:29]([CH3:30])[CH3:31]
Reactant: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CC1COC(=O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.8 %

Procedure:
Ethyl acetate (0.12 mL, 1.22 mmol) in THF (2 mL) was added dropwise to a stirring solution of lithium bis(trimethylsilyl)amide (1.22 mL of a 1 M solution in THF, 1.22 mmol) at −78° C. under argon. After 20 minutes, 3 (0.21 g, 1.16 mmol) in THF (1 mL) was added, and the mixture was stirred for 2 hours. The mixture was quenched by addition of saturated ammonium chloride solution (3 mL) and allowed to warm to room temperature. The mixture was diluted with ether (20 mL) and dilute hydrochloric acid (15 mL) was added. The organic layer was separated, and the aqueous layer was further extracted with ether (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 99:1) to give the nitro-ester 4 (0.13 g, 41%) as a colorless liquid; Rf(heptane/ethyl acetate, 9:1) 0.32; vmax(film)/cm−1 1731 (C═O), 1547 (NO2), 1375 (NO2); δH (400 MHz; CDCl3): 4.73 (2H, s, CH2NO2), 4.14 (2H, q, J=7.1, CO2CH2Me), 2.58 (2H, s, CH2CO2Et), 2.07 (2H, m), 1.71–1.66 (4H, m), 1.60–1.24 (8H, m), 1.26 (3H, t, J=7.2, CO2CH2Me); m/z (ES+) 270 (M+H, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[O:12])=[CH:7][C:6]=2[CH:13]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc2cc(Br)ccc2o1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2cc3cc(Br)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
5-Bromo-benzofuran-2-carboxylic acid (0.346 g) in THF (7 mL) was treated with carbonyldiimidazole (0.214 g) and stirred at ambient temperature for 2 h whereupon methyl-piperazine (0.129 g) was added. The mixture was stirred at ambient temperature for 18 h and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution, whereupon the organic portion was separated out, dried over sodium sulfate and filtered. The solvent was evaporated, and the residue was purified via silica gel chromatography (5% 2 M ammonina in methanol/dichloromethane) to afford the title compound (0.222 g). 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J=1.9 Hz, 1H), 7.45 (dd, J=8.8, 1.9 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 3.83 (br s, 4H), 2.48 (t, J=4.8 Hz, 4H), 2.33 (s, 3H). 13C NMR (400 MHz, CDCl3) δ 159.4, 153.4, 150.3, 129.6, 129.0, 124.9, 116.8, 113.5, 111.3, 55.3, 54.9, 46.8, 46.1, 42.9.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:43])=[O:42]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:50]3[CH2:51][CH2:52][CH:47]([CH2:46][CH2:45][CH2:44][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:48][CH2:49]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)CCCC1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-(3-methanesulfonyl-propyl)-piperidine dihydrochloride to give the title compound. HR-MS (ES, m/z) calculated for C38H49Cl2N4O4S [(M+H)+] 727.2846, observed 727.2848.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:18][C:19](=O)[CH3:20]>C(O)C>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:7]1[C:2]2[N:3]([CH:18]=[C:19]([CH3:20])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)CCl
Reactant: Cc1ccccc1CNc1cccnc1N
Solvent: CCO
Product: Cc1cn2cccc(NCc3ccccc3C)c2n1

Procedure:
A solution of 2-amino-3-(2-methylbenzylamino)pyridine (3.25 g) and chloroacetone (1.26 ml) in ethanol (65 ml) was refluxed for 18 hours and then evaporated in vacuo. To the residue was added aqueous sodium bicarbonate solution and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was purified by column chromatography on silica gel (40 g) with a mixture of methylene chloride and ethyl acetate (10:1) as an eluent to give 8-(2-methylbenzylamino)-2-methylimidazo[1,2-a]pyridine (1.80 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1>>[S:19]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)=[CH:20]1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: OB(O)c1ccsc1
Product: c1cc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cs1

Procedure:
The title compound was prepared from the product of Example 65A and thien-3-ylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 312.0 (M+H)+, retention time 1.25 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=O)=[C:17]([CH3:24])[CH:16]=1>>[Br:14][C:15]1[CH:23]=[CH:22][C:18]([CH3:19])=[C:17]([CH2:24][C:11]2[S:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:13][CH:12]=2)[CH:16]=1
Reactant: COc1ccc(-c2cccs2)cc1
Reactant: Cc1cc(Br)ccc1C(=O)O
Product: COc1ccc(-c2ccc(Cc3cc(Br)ccc3C)s2)cc1

Procedure:
The above 2-(4-methoxyphenyl)thiophene and 4-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) were treated in a manner similar to Reference Example 5 to give 5-bromo-1-(5-(4-methoxyphenyl)-2-thienylmethyl)-2-methylbenzene as a pale yellow solid. APCI-Mass m/Z 373/375 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[NH:12][CH3:13].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[S:32](Cl)(=[O:34])=[O:33].C(Cl)Cl>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:32]([C:24]1[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:23]=1[O:22][CH3:21])(=[O:33])=[O:34])[C:6](=[O:11])[C:5]2([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[NH:12][CH3:13]
Reactant: CNC1(CC2CCCCC2)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC1(CC2CCCCC2)C(=O)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2OC)c2ccc(Cl)cc21
Yield: 58 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 16 from 1.49 g of 5-chloro-3-(cyclohexylmethyl)-1,3-dihydro-3-(methylamino)indol-2-one and 1.8 g of 2-methoxy-4-nitrobenzenesulfonyl chloride. Chromatography on silica using DCM and then a DCM/AcOEt mixture (95/5; v/v) as the eluent gives 1.5 g of the expected product after crystallization from AcOEt. M.p.=207° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C@H:12]([CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH2:13][OH:14].C(N(CC)CC)C>ClCCl>[CH3:11][C@H:12]([CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH:13]=[O:14]
Reactant: COc1ccccc1SC[C@@H](C)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccccc1SC[C@@H](C)C=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
0.61 ml (0.007 mol) of oxalyl chloride and 20 ml of dichloromethane are introduced into a round-bottomed flask kept under an inert atmosphere. The mixture is cooled to −78° C. and then 1 ml (0.014 mol) of dimethyl sulfoxide is introduced. After stirring at −78° C. for 15 minutes, 1.5 g (0.007 mol) of 2-(S)-methyl-3-(2-methoxyphenylthio)propan-1-ol (XXb-1), in solution in 15 ml of dichloromethane, are added dropwise. The mixture is stirred at −78° C. for 1 hour and then 2 ml (0.014 mol) of triethylamine are added. After 15 minutes at −78° C., the mixture is reheated to −10° C. and stirred at this temperature for 45 minutes. The aldehyde is not isolated at this stage but is used in situ in the following reductive amination reaction.