Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Cu][C:10]#[N:11]>CN(C)C=O.C(OCC)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]#[N:11])=[N:3][CH:4]=1
Reactant: N#C[Cu]
Reactant: Brc1ccc(Br)nc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,5-Dibromopyridine (20.0 g, 84.4 mmol) was dissolved in dimethylformamide (422 mL). To the stirred solution was added copper(I) cyanide. After refluxing for 5 h, the mixture was cooled to room temperature and stored overnight. The reaction mixture was diluted with ethyl acetate (1200 mL) and filtered through a Buchner funnel containing sand, Celite, and silica gel layers. The filtrate was concentrated to a volume of 400 mL. This organic liquid was diluted with water (300 mL) and the resulting liquid was extracted with ethyl acetate (2×200 mL). The organic extracts were combined, washed with water (2×300 mL) and brine (1×250 mL), and dried over magnesium sulfate. After concentration, the product was purified via silica gel chromatography (50:50 ethyl acetate/CH2Cl2) to afford the title compound (9.79 g).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48](O)=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)C(C)C)C.[Cl:60][C:61]1[CH:66]=[CH:65][C:64]([CH:67]([NH2:72])[CH2:68][CH2:69][O:70][CH3:71])=[CH:63][CH:62]=1>CN1C(=O)CCC1.CCOC(C)=O>[Cl:60][C:61]1[CH:62]=[CH:63][C:64]([CH:67]([NH:72][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:34][CH2:35][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:37][CH2:38]2)=[O:49])[CH2:68][CH2:69][O:70][CH3:71])=[CH:65][CH:66]=1
Reactant: COCCC(N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (55.2 mg, 0.15 mmol) was added to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (50 mg, 0.14 mmol) and N-ethyldiisopropylamine (0.029 mL, 0.17 mmol) in NMP (5 mL). The resulting solution was stirred at 50° C. for 10 minutes then cooled to ambient temperature. 1-(4-Chlorophenyl)-3-methoxypropan-1-amine (Intermediate 100) (27.6 mg, 0.14 mmol) was added as a solution in NMP (2 mL). The resulting mixture was stirred at 22° C. for 16 hours. The reaction mixture was diluted with EtOAc (75 mL) and washed sequentially with water (6×75 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 1 to 4% (10:1 MeOH/conc. NH3 (aq)) in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 4-(1-(4-chlorophenyl)-3-methoxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (52.0 mg, 69.2%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16](OS(C)(=O)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:28]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:27][CH3:28])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OS(C)(=O)=O
Reactant: CCNc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)N(CC)c1ccccc1

Procedure:
Reaction and post-treatment were carried out according to Reference example 5(a) using 4.50 g of ethyl 3-(4-benzyloxyphenyl)-2-methanesulfonyloxypropionate and 5.6 ml of N-ethylaniline to obtain 6.30 g of a mixture of the desired compound and N-ethylaniline as a syrup.
Reaction SMILES: C([NH:4][C:5]1[C:14](=[S:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:12]=2)[O:7][CH:6]=1)(=O)C.Cl.C(=O)(O)[O-].[K+]>CO>[NH2:4][C:5]1[C:14](=[S:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:12]=2)[O:7][CH:6]=1
Reactant: CC(=O)Nc1coc2ccc(C(C)(C)C)cc2c1=S
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: CC(C)(C)c1ccc2occ(N)c(=S)c2c1
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A solution of 3-acetamido-6-tert.-butyl-thiochromone (31 g) in a 2 N solution (350 ml) of hydrochloric acid in methanol is heated gradually to the reflux temperature and kept at this temperature (70° C.) for 2 hours. After cooling, the reaction medium is poured into an excess of a 10% strength aqueous solution of potassium bicarbonate. A yellow solid precipitates which is filtered off, washed with water and dried. 3-Amino-6-tert.-butyl-thiochromone (26.2 g), which melts at 168° C., is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH2:21][CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)=[C:15]([Cl:32])[CH:14]=1)[NH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8]>Cl.O1CCOCC1>[ClH:19].[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:12][C:13]1[CH:14]=[C:15]([Cl:32])[C:16]([O:20][CH2:21][CH2:22][CH2:23][NH2:24])=[C:17]([Cl:19])[CH:18]=1)[NH:5][C:6](=[O:11])[C:7]([F:10])([F:8])[F:9]
Reactant: COC(=O)[C@H](Cc1cc(Cl)c(OCCCNC(=O)OC(C)(C)C)c(Cl)c1)NC(=O)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1cc(Cl)c(OCCCN)c(Cl)c1)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 200.4 %

Procedure:
8% Hydrochloric acid/dioxane (10 ml) was added to O-[3-(t-butoxycarbonylamino)propyl]-3,5-dichloro-N-trifluoroacetyl-L-tyrosine methyl ester (891 mg, 1.72 mmol) and the mixture was stirred at room temperature for 3 hrs. The solvent of the reaction mixture was distilled off under reduced pressure. To the residue was added a mixture of methanol and diisopropyl ether. The insoluble material was triturated, collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give O-(3-aminopropyl)-3,5-dichloro-N-trifluoroacetyl-L-tyrosine methyl ester hydrochloride (782 mg, 100%) as a colorless powder.
Reaction SMILES: [CH:1]([CH:3]1[C:12]2[C:7](=[C:8]([N+:13]([O-])=O)[CH:9]=[CH:10][CH:11]=2)[CH2:6][O:5][CH2:4]1)=[CH2:2].[NH4+].[Cl-]>CCO.O.[Fe]>[CH:1]([CH:3]1[C:12]2[C:7](=[C:8]([NH2:13])[CH:9]=[CH:10][CH:11]=2)[CH2:6][O:5][CH2:4]1)=[CH2:2]
Reactant: C=CC1COCc2c1cccc2[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C=CC1COCc2c(N)cccc21

Procedure:
A mixture of 4-ethenyl-8-nitro-3,4-dihydro-1H-isochromene (630 mg, 3.07 mmol), Fe (860 mg, 15.3 mmol) and NH4Cl (1.642 g, 30.7 mmol) in EtOH/H2O (2:1, 40 mL) was stirred at reflux under N2 protection for 2 h. The mixture was filtered, and the filtrate was evaporated to give 4-ethenyl-3,4-dihydro-1H-isochromen-8-amine. 1H-NMR (400 MHz, DMSO) δ 6.88 (t, J=8.0 Hz, 1H), 6.47 (d, J=8.0 Hz, 1H), 6.34 (d, J=8.0 Hz, 1H), 5.74˜5.83 (m, 1H), 5.03˜5.17 (m, 2H), 4.46 (s, 2H), 3.78˜3.82 (m, 1H), 3.61˜3.65 (m, 1H), 3.36˜3.38 (m, 1H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27]CC2C=CC=CC=2)=[C:23]([NH:35][CH3:36])[CH:22]=1)[OH:20].CO.C(Cl)(Cl)Cl>CO.[Pd]>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH:19]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([NH:35][CH3:36])[CH:22]=1)[OH:20]
Reactant: CNc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1O

Procedure:
According to the procedures as given in Example 2, the compound of Example 26 (in a solution of 200 mg of the compound in 25 ml of methanol) was subjected to a hydrogenolysis using 10% palladium/carbon black (100 mg), whereby the above-identified compound (153 mg) was obtained. Rf=0.09 (methanol/chloroform of 1/10).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:19])[C:5]1([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[C:20]1([C:26]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:27]2[CH:31]=[C:30]([CH:32]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=3)[C:33](O)=[O:34])[N:29]=[CH:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=C2C(N(O)N=NC2=CC=1)=O.C(N(CC)CC)C.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH3:2][O:3][C:4](=[O:19])[C:5]1([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:6][CH2:7][N:8]([C:33](=[O:34])[CH:32]([C:30]2[N:29]=[CH:28][N:27]([C:26]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:31]=2)[CH2:36][C:37]2[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[CH:41][CH:42]=2)[CH2:9][CH2:10]1
Reactant: N#Cc1ccc(CC(C(=O)O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: COC(=O)C1(Cc2ccccc2C)CCNCC1
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C1(Cc2ccccc2C)CCN(C(=O)C(Cc2ccc(C#N)cc2)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 4-(2-methylbenzyl)-isonipecotic acid methyl ester hydrochloride (72 mg, 0.25 mmol), and 2-{1-(triphenylmethyl)-1H-imidazol-4-yl}-2-(4-cyanobenzyl)-acetic acid(123 mg, 0.25 mmol), HOOBT (42 mg, 0.25 mmol) and triethylamine (0.088 ml, 0.636 mmol) in DMF (3 ml), was added EDC (54 mg, 0.25 mmol) and the reaction stirred at room temperature for 18 hrs. The reaction was diluted with EtOAc and washed with saturated NaHCO3 solution, the organic extracts were dried (Na2SO4), and the solvent evaporated in vacuo. The residue was purified by chromatography(SiO2, gradient elution, 1-5% MeOH in CH2Cl2) to afford the product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C1C(=O)N([Br:19])C(=O)C1>C1COCC1>[Br:19][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[Cl:1]
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Nc1ccc(Br)c(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 11.5 %

Procedure:
3-Chloro-2-nitro aniline (5.0 g, 28.97 mmol) and NBS (5.42 g, 30.42 mmol) were combined in THF (200 mL) and stirred at rt for 15 h. Concentration and purification (SiO2, EtOAc/hexanes) afforded the title compound (0.84 g): 1HNMR (400 MHz, CDCl3) δ 7.46 (d, J=8.9 Hz, 1H), 6.63 (d, J=8.9 Hz, 1H), 4.7 (s, 2H); MS (ESI) m/z 253 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].[I-].[K+].Br[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20]>CO.C1C=CC=CC=1.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:18]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)[C:19]([O:21][CH3:22])=[O:20])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 3.75 g of 4-tert-butylphenol and 1.19 g of sodium methoxide and a few crystals of potassium iodide in 40 ml of methanol is added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The mixture is refluxed overnight. On cooling, a white solid separates. The entire mixture is poured into 100 ml of water and extracted with two 100 portions of ether. The combined extracts are washed with 100 ml of 5% NaOH, 100 ml of water and saturated brine, and dried over MgSO4. Evaporation of the solvent affords a white solid, which is crystallized from hexane to give the product as fine white needles, mp 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([NH2:7])[N:3]=1.[O:8](C(OC(C)(C)C)=O)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O.CN(C=O)C.[H-].[Na+]>[NH4+].[Cl-].O.CCOC(C)=O>[Cl:1][C:2]1[S:6][N:5]=[C:4]([NH:7][C:9](=[O:8])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:3]=1
Reactant: Nc1nsc(Cl)n1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nsc(Cl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
To a stirred solution of 5-chloro-1,2,4-thiadiazol-3-amine (0.93 g, 6.9 mmol) and BOC2O (2.9 mL, 12 mmol) in DMF (10 mL, 129 mmol) was added sodium hydride (60%) (0.55 g, 14 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was carefully diluted with aqueous NH4Cl and water (20 mL each) and diluted with EtOAc (15 mL). The separated aqueous layer was extracted with EtOAc (15 mL×2) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a residue which was purified with flash column chromatography (ISCO Combiflash system, pure hexanes→10% EtOAc in hexanes) to obtain the desired product (0.87 g, 54%) as an off-white solid. LCMS (API-ES) m/z (%): 180.6 (100%, (M++H)-tert-Bu); 1H NMR (400 MHz, CD3OD) δ ppm (1.55, s, 9H).\
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:2]3[CH:16]=[CH:15][CH:14]=[C:4]([O:5][CH2:6][CH2:7][CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)[CH:3]=3)=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: Ic1cccc(OCCCN2CCCC2)c1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3cccc(OCCCN4CCCC4)c3)nc2)cc1

Procedure:
Prepared according to general working method I from 1-[3-(3-iodo-phenoxy)-propyl]-pyrrolidine (124 mg, 0.37 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (80 mg, 0.37 mmol).
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]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=1.FC(F)(F)C([O-])=O.[Cl:24][C:25]1[C:29]([Cl:30])=[C:28]([CH3:31])[NH:27][C:26]=1[C:32]([NH:34][CH:35]1[CH2:40][CH2:39][NH2+:38][CH2:37][CH2:36]1)=[O:33].C([O-])([O-])=O.[K+].[K+]>C(O)(C)(C)C>[Cl:24][C:25]1[C:29]([Cl:30])=[C:28]([CH3:31])[NH:27][C:26]=1[C:32]([NH:34][CH:35]1[CH2:40][CH2:39][N:38]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=2)[CH2:37][CH2:36]1)=[O:33]
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Reactant: Cc1[nH]c(C(=O)NC2CC[NH2+]CC2)c(Cl)c1Cl
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c2ccccc2n1
Yield: 47.7 %

Procedure:
As described for the synthesis of Example 264, ethyl 4-chloroquinazoline-2-carboxylate (690 mg), 4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidinium trifluoroacetate (Intermediate 86; 1.7 g), and K2CO3 (1.7 g) in 20 ml tert-butanol were combined to yield 662 mg grey solid.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[C:24]([CH2:28]O)[CH:25]=[CH:26][CH:27]=2)=[N:20][CH:21]=1.[F:30][C:31]1[CH:32]=[C:33]([C:38]2[CH:39]=[CH:40][C:41](=[O:44])[NH:42][N:43]=2)[CH:34]=[C:35]([F:37])[CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:30][C:31]1[CH:32]=[C:33]([C:38]2[CH:39]=[CH:40][C:41](=[O:44])[N:42]([CH2:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:19]4[CH:18]=[CH:17][C:16]([CH3:15])=[CH:21][N:20]=4)[CH:23]=3)[N:43]=2)[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: Cc1ccc(-c2cccc(CO)c2)nc1
Reactant: O=c1ccc(-c2cc(F)cc(F)c2)n[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4.2 134 mg (0.66 mmol) of diisopropyl azodicarboxylate are added to a solution of 88 mg (0.44 mmol) of [3-(5-methylpyridin-2-yl)phenyl]methanol, 138 mg (0.66 mmol) of 6-(3,5-difluorophenyl)-2H-pyridazin-3-one and 174 mg (0.66 mmol) of triphenylphosphine in 3.5 ml of THF. The reaction mixture is stirred at room temperature for 18 hours. The mixture is evaporated, and the residue is chromatographed on a silica gel column with dichloromethane/methanol as eluent: 6-(3,5-difluorophenyl)-2-[3-(5-methylpyridin-2-yl)benzyl]-2H-pyridazin-3-one (“A9”) as colourless crystals; ESI 390.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[N:14]([CH3:30])[C:15]([CH2:28][CH3:29])=[C:16]([C:26]#[N:27])[C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=1)=[O:12])[CH3:9].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH2:8]([O:10][C:11]([C:13]1[N:14]([CH3:30])[C:15]([CH2:28][CH3:29])=[C:16]([C:26]#[N:27])[C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:20][CH:19]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1c(-c2ccc(CO)cc2)c(C#N)c(CC)n1C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(COS(C)(=O)=O)cc2)c(C#N)c(CC)n1C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Add triethyl amine (0.053 g, 0.53 mmol) to a solution of 4-cyano-5-ethyl-3(4-hydroxymethyl-phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.15 g, 0.48 mmol, prepared directly above) in dichloromethane (5 mL) at 0° C. under nitrogen, followed by drop-wise addition of methanesulfonyl chloride (0.06 g, 0.53 mmol). Stir at 0° C. for 1.5 h. Add ice-water and dichloromethane. Separate phases and wash organics with water. Combine aqueous layers and back-extract aqueous phase with more dichloromethane. Combine organic phases, wash with brine, dry (sodium sulfate), filter and concentrate in vacuo, to give 0.181 g of title compound for use without further purification. 1H NMR (CDCl3, δ (ppm)): 7.46-7.38 (m, 4H); 5.28 (s, 2H), 4.09 (q, J=7.1 Hz, 2H); 3.89 (s, 3H); 2.93 (s, 3H); 2.85 (q, J=7.5 Hz, 2H); 1.30 (t, J=7.7 Hz, 3H); 1.00 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:36](Cl)=[O:37])[C:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)([CH3:28])[C:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([CH3:20])[N:19]=2)=[C:11]([O:39][CH2:40][CH3:41])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:44]1([CH2:50][C:51]([NH2:53])=[O:52])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:36]([N:47]3[CH2:48][CH2:49][N:44]([CH2:50][C:51]([NH2:53])=[O:52])[CH2:45][CH2:46]3)=[O:37])[C@@:17]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)([CH3:28])[C@@:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([CH3:20])[N:19]=2)=[C:11]([O:39][CH2:40][CH3:41])[CH:10]=1)(=[O:7])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: NC(=O)CN1CCNCC1
Reactant: CCOc1cc(S(=O)(=O)NC(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(S(=O)(=O)NC(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butylsulfamoyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C36H44N6O5SCl2 [(M+H)+] 743.2544, observed 743.2538.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:20]=[O:21].O>O1CCCC1>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH:20]=[O:21])=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)c2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(Br)c2ccccc12
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
To a solution of 1,4-dibromonaphthalene (1.00 g, 3.50 mmol) in tetrahydrofuran (15 mL) were added n-butyllithium (1.6 mol/L; 3.1 mL) and dimethylformamide (0.54 mL, 7.0 mmol) sequentially at −78° C. under nitrogen atmosphere, and the mixture was stirred for 15 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was combined, washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (8:1 hexane/ethyl acetate) to afford 4-bromo-1-naphthalenecarboxaldehyde (458 mg, 56%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[C:28]1[N:33]=[C:32]2[S:34][C:35]([NH:37][C:38](=[O:40])[CH3:39])=[N:36][C:31]2=[CH:30][CH:29]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([C:28]3[N:33]=[C:32]4[S:34][C:35]([NH:37][C:38](=[O:40])[CH3:39])=[N:36][C:31]4=[CH:30][CH:29]=3)[CH:15]=[CH:16][CH:17]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Reactant: CC(=O)Nc1nc2ccc(Br)nc2s1
Product: CC(=O)Nc1nc2ccc(-c3cccc(NS(=O)(=O)c4ccc(C)cc4)c3)nc2s1

Procedure:
This compound was made using 4-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide and N-(5-bromothiazolo[5,4-b]pyridin-2-yl)acetamide and following the procedure in Example 146, Method N, step 2 above. MS (ESI pos. ion) m/z: 439. Calculated exact mass for C21H18N4O3S2 438.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:9][CH2:10][C:11](Cl)=[O:12].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:9][CH2:10][C:11]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[Cl:1])=[O:12]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)Nc1ccccc1Cl
Temperature: 0 °C
Reaction time: 12 h

Procedure:
2-Chloroaniline (5 g) was dissolved in dichloromethane (100 ml) and chloroacetyl chloride (3.11 ml) and N,N-diisopropylethylamine (13.65 ml) were added at 0° C. under a nitrogen atmosphere. The mixture was stirred for 1 hour at 0° C. and 12 hours at room temperature, then quenched with water. The product was extracted with dichloromethane. The organic layer was washed with water, brine, dried (MgSO4) and concentrated under reduced pressure to leave the subtitle product as a beige solid. Yield 7.5 g. This was used in the next step without further purification.