Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13](=[O:29])[N:14]([CH2:18][C:19]1[CH:24]=[C:23]([CH2:25][CH2:26][OH:27])[CH:22]=[CH:21][C:20]=1[Cl:28])[CH:15]1[CH2:17][CH2:16]1)([CH3:11])([CH3:10])[CH3:9].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:8]([O:12][C:13]([N:14]([CH2:18][C:19]1[CH:24]=[C:23]([CH2:25][CH2:26][O:27][S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])[CH:22]=[CH:21][C:20]=1[Cl:28])[CH:15]1[CH2:16][CH2:17]1)=[O:29])([CH3:11])([CH3:9])[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CCO)ccc1Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(Cl)c(CN(C(=O)OC(C)(C)C)C3CC3)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83 %

Procedure:
Et3N (2.56 mL, 18.4 mmol) and DMAP (153 mg, 1.23 mmol) were added to a sol. of [2-chloro-5-(2-hydroxy-ethyl)-benzyl]-cyclopropyl-carbamic acid tert-butyl ester (4.00 g, 12.3 mmol) in CH2Cl2 (110 mL) at 0° C. A sol. of p-toluenesulfonyl chloride (2.80 g, 14.7 mmol) in CH2Cl2 (18 mL) was added dropwise, and the mixture was stirred for 3 days while warming up to rt. The mixture was partitioned between CH2Cl2 and water, and the aq. layer was extracted with CH2Cl2 (3×). The combined org. layers were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane/EtOAc 8:2) yielded the title compound (4.90 g, 83%). LC-MS: tR=1.13 min; ES+: 480.53.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20](O)=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[CH2:20][OH:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccsc2C(=O)O)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccsc2CO)CC1

Procedure:
The product from Step 2 is reduced with borane in THF to give 3-(1-tert-butyloxycarbonylpiperidin-4-ylamino)-2-hydroxymethylthiophene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH-:19].[Na+].OO>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)[C:5]([C:8]([NH2:9])=[O:19])=[N:6][CH:7]=1
Reactant: [OH-]
Reactant: Cc1cc(C)nc(Nc2cc(Br)cnc2C#N)c1
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)nc(Nc2cc(Br)cnc2C(N)=O)c1
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile (PrepEx 1.4) (2.6 g, 8.6 mmol) in DMSO (60 mL) was added sodium hydroxide (6.0 M in water, 1.4 mL, 8.6 mmol). The reaction mixture was cooled in an ice bath, and hydrogen peroxide (30% w/w solution in water, 2.0 mL, 20 mmol) was added. After 2 hours, the reaction mixture was diluted with water (100 mL) and stirred. After 10 min, the reaction mixture was filtered, and the collected solids were washed with water (2×50 mL) and dried under reduced pressure to afford 5-bromo-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide. 1H NMR (600 MHz, CD3OD) δ 9.63 (d, J=2.4 Hz, 1H), 8.07 (d, J=2.4 Hz, 1H), 6.63 (s, 1H), 6.48 (s, 1H), 2.40 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [Cl:1][CH:2]([Cl:8])[C:3](=O)[CH:4]=[CH:5]Cl.[CH3:9][N:10](C)[NH2:11]>C(OC)(C)(C)C>[Cl:1][CH:2]([Cl:8])[C:3]1[CH:4]=[CH:5][N:10]([CH3:9])[N:11]=1
Reactant: CN(C)N
Reactant: O=C(C=CCl)C(Cl)Cl
Solvent: COC(C)(C)C
Product: Cn1ccc(C(Cl)Cl)n1
Temperature: 34 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
At 20° C., 1,1,4-trichloro-3-buten-2-one (15 g, 0.078 mol) was added dropwise over a period of 37 min to a solution of 1,1-dimethylhydrazine (9.5 g, 0.156 mol) in methyl tert-butyl ether (MTBE, 500 ml), with warming to 34° C. After 2 h, a sticky brown suspension had formed, which was filtered through kieselguhr. The filtrate was concentrated under reduced pressure. The residue (7.6 g of a viscous oil) was subjected to fractional distillation under reduced pressure. As the main fraction, 3 g of 3-dichloromethyl-N-methylpyrazole were obtained in a purity of 96.4% (GC area) (boiling point 65° C./0.3 mbar), and the product crystallized on standing. Recrystallization gave a sample having a purity of >99% (GC area).
Reaction SMILES: Br[C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>C(#N)C.[F-].[K+].O>[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:24]2[CH:2]=[CH:3][C:4]3[C:8]4[CH:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=4[N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]=3[N:23]=2)=[CH:29][CH:28]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(Br)cnc21
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2ccc(-c3ccc(CO)cc3)nc21
Temperature: 140 °C
Yield: 172.5 %

Procedure:
A mixture of 3-bromo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (700 mg, 0.87 mmol), 4-hydroxymethylbenzeneboronic acid (400 mg, 1.32 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (52.5 mg, 0.064 mmol) in acetonitrile (21 mL) and 2N aqueous potassium fluoride solution (21 mL) was devided equally across two 25 mL microwave vials. Each vial was degassed with nitrogen for 10 minutes before the mixtures were heated under microwave irradiation at 140° C. for 30 minutes. The reaction mixtures were allowed to cool to ambient temperature, combined and diluted with water (50 mL). The precipitate was collected by filtration, washed with water (50 mL) and left to air dry. The resultant grey solid was purified by flash column chromatography (silica, 40 g column, ISCO, 0-100% ethyl acetate in cyclohexane). The isolated solid was then triturated with hot t-BME to afford the title compound as a light grey solid (646 mg, 26%). LCMS (Method B): RT=4.11 min, M+H+=431.
Reaction SMILES: [NH2:1][C@H:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[CH2:3][NH:4][C:5](=[O:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15].C(N(C(C)C)CC)(C)C.[Br:36][CH2:37][C:38](Br)=[O:39].C(OCC)(=O)C>O1CCCC1>[Br:36][CH2:37][C:38]([NH:1][C@H:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[CH2:3][NH:4][C:5](=[O:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:39]
Reactant: COc1ccccc1CCC(=O)NC[C@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(Br)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1CCC(=O)NC[C@@H](Cc1c[nH]c2ccccc12)NC(=O)CBr
Reaction time: 2 h

Procedure:
To a stirring solution of (R)-2-amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane (7.51 g, 21.369 mmol) in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere at 0° C. were added diisopropylethylamine (4.1 ml, 23.537 mmol) and bromoacetyl bromide (2.05 ml, 23.530 mmol). After 2 hours, ethyl acetate was added and the reaction mixture washed with water twice, 1.0 N hydrochloric acid (2×), saturated sodium bicarbonate solution (2×), and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to a tan foam on a rotary evaporator. In this manner the 2-[(2-bromo)acetyl]amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane was obtained in quantitative yield. No further purification was necessary.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][N:14]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.O>[Cl:12][C:13]1[N:14]=[CH:15][C:16]([C:17]2[NH:11][C:10]3[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=3[N:1]=2)=[CH:19][CH:20]=1
Reactant: Nc1cccc(C(=O)O)c1N
Reactant: O=Cc1ccc(Cl)nc1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc2[nH]c(-c3ccc(Cl)nc3)nc12
Temperature: 100 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
2,3-Diaminobenzoic acid (1; 200 mg, 1.31 mmol), 6-chloronicotinaldehyde (5; 186 mg, 1.31 mmol), and Na2S2O5 (324 mg, 1.7 mmol) were taken up in DMF (10 mL) and stirred at 100° C. for 18 h. The reaction mixture was cooled to room temperature and diluted with H2O. The resulting mixture was stirred for 1 h at room temperature and filtered. The collected solids were washed with water, MeOH, and dried to afford 2-(6-chloropyridin-3-yl)-1H-benzo[d]imidazole-4-carboxylic acid 6 as a pale solid (340 mg, yield: 95%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([S:9][CH3:10])[CH:8]=1.Cl.[NH+]1C=CC=CC=1.[Cl-].[NH4+].Cl>>[CH3:10][S:9][C:7]1[CH:8]=[C:3]([OH:2])[CH:4]=[N:5][CH:6]=1
Reactant: COc1cncc(SC)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CSc1cncc(O)c1
Yield: 47 %

Procedure:
1.284 g (8.2 mM) of 3-methoxy-5-methylthiopyridine and 2.87 g (24.8 mM) of pyridinium hydrochloride are heated at 150° C. for 2 hours in a reactor adapted for microwaves. A saturated aqueous solution of ammonium chloride is added to the cooled reaction medium and the pH is adjusted to neutral with 1 N hydrochloric acid solution. The precipitate formed is filtered off, the filtrate is then extracted with ether and the organic phase is dried over sodium sulfate and then concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel using a dichloromethane/methanol mixture (99/1, then 80/20; v/v) as the eluent to give the expected product with a yield of 47%.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=O)=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29].C1C=CC=CC=1.Cl>N1C=CC=CC=1>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[S:29])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(C(=O)N2CCCc3ccccc32)cc1)OCC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOP(=O)(Cc1ccc(C(=S)N2CCCc3ccccc32)cc1)OCC
Temperature: 25 °C

Procedure:
0.77 Gram (2.0 mM) of 1-(4-diethoxyphosphinoylmethylbenzoyl)-1,2,3,4-tetrahydroquinoline and 1.0 g (4.6 mM) of phosphorus pentasulfide were suspended in a mixed solvent consisting of 20 ml of anhydrous benzene and 5 ml of anhydrous pyridine This suspension was heated and refluxed for 7 hours. After the reaction mixture was cooled to room temperature, the mixture was poured into 50 ml of ice-water, and the aqueous phase was acidified with 4N hydrochloric acid and then extracted with chloroform. The chloroform solution was dried over anhydrous sodium sulfate, and concentrated. Thus obtained residue was purified by means of a silica gel column chromatography (eluted with chloroform:ethyl acetate=1:1). The crude crystals were recrystallized from benzene-n-hexane to yield 0.23 g of 1-[(4-diethoxyphosphinoylmethylphenyl)thiocarbonyl]-1,2,3,4-tetrahydroquinoline as yellowish crystals. Melting point 96°-97° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][CH:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=[O:11].C(N1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])(OCC)=O>O.C(#N)C>[C:29]1(=[O:38])[N:7]([CH:8]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:17][CH:18]=2)[CH2:9][C:10]([OH:12])=[O:11])[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCCOc1ccc(C(N)CC(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCOc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a stirred solution of sodium carbonate (1.45 g, 13.7 mmol) in 500 mL of water-acetonitrile (1:1, v/v) was added 3-amino-3-(4-propoxyphenyl)propionic acid (3.05 g, 13.7 mmol) as a solid. The mixture was warmed to 30°-40° C. to dissolve the solids. The reaction mixture was allowed to cool to room temperature and N-carboethoxyphthalimide (3.00 g, 13.7 mmol) was added and the reaction mixture was stirred for one hour at room temperature. The reaction mixture was then partially concentrated to remove the acetonitrile and the pH of the resulting solution was adjusted to approximately 3 with 4N hydrochloric acid. The resulting slurry was stirred overnight and then filtered and the solid was washed with copious amounts of water. The solid was dried in vacuo (60° C., <1 mm) to afford 3.64 g (75%) of 3-phthalimido-3-(4-propoxyphenyl)propionic acid as a white powder: mp 142.5°-143.6° C., 1H NMR(DMSO-d6, 250 MHz) δ 12.43 (br s, 1 H), 7.80-7.95 (m, 4 H), 7.34 (d, 2 H, J=9 Hz), 6.89 (d, 2 H, J=9 Hz), 5.63 (overlapping dd, 1 H), 3.88 (t, 2 H, J=7 Hz), 3.45 (dd, 1 H, J1=9 Hz, J2=16.5 Hz), 3.30 (dd, 1 H, J1=7 Hz, J2=16.5 Hz), 1.60-1.85 (m, 2 H), 0.95 (t, 3 H, J=7 Hz); 13C (DMSO-d6) δ 171.8, 167.6, 158.6, 134.7, 131.1, 130.8, 128.3, 123.2, 114.4, 68.9, 49.7, 36.0, 22.0, 10.3; Anal. Calcd. for C20H19NO5. Theoretical: C, 67.98; H, 5.42; N, 3.96. Found: C, 67.90; H, 5.40; N, 4.00.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]([C:14](=[CH2:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:9](OCC)=[O:10].O.[OH-].[Na+]>C1COCC1>[CH3:7][CH:8]([C:14](=[CH2:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:9][OH:10]
Reactant: C=C(CC(C)C)C(C)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(CC(C)C)C(C)CO
Reaction time: 3 h
Yield: 78.4 %

Procedure:
To a stirred suspension of lithium aluminium hydride (LAH, 4.63 g, 122 mmol) in THF (100 mL) was added dropwise between 3-5° C. within a period of 1 h a solution of ethyl 2,5-dimethyl-3-methylenehexanoate (22.5 g, 122 mmol) in THF (500 mL), and the resulting reaction mixture was stirred for 3 h under reflux. With cooling in an ice-bath, water (5.00 mL) was added dropwise, followed by 15% aq. NaOH solution (5.00 mL) and again water (15.0 mL). After stirring for further 30 min at room temp, the formed precipitate was filtered off by suction with the aid of a sintered funnel, and washed with Et2O (100 mL). The combined filtrates were evaporated under reduced pressure, and the resulting residue was purified by silica-gel flash chromatography (pentane/Et2O, 8:2, Rf=0.18) to provide 2,5-dimethyl-3-methylenehexan-1-ol (13.6 g, 79%) as a colourless odoriferous liquid. IR (neat): ν=3332 (s, ν O—H), 1462 (w, δa, CH3), 1366 (w, δs, CH3), 1026 (s, ν C—O), 891 (s, δ C═H) cm−1. 1H NMR (CDCl3): δ=0.90 (d, J=6.5 Hz, 6H, 5-Me2), 1.05 (d, J=7.0 Hz, 3H, 2-Me), 1.69 (br. s, 1H, OH), 1.79 (sept, J=7.0 Hz, 1H, 5-H), 1.91 (dd, J=7.0, 1.5 Hz, 2H, 4-H2), 2.32 (sext, J=6.5 Hz, 1H, 2-H), 3.45-3.59 (m, 2H, 1-H2), 4.86 (d, J=1.5 Hz, 1H, 1′-HE), 4.87 (d, J=1.5 Hz, 1H, 1′-HZ) ppm. 13C NMR (CDCl3): δ=16.4 (q, 2-Me), 22.3/22.6 (2q, 5-Me2), 26.2 (d, C-5), 41.6 (d, C-2) 44.8 (t, C-4), 65.9 (t, C-1), 110.7 (d, C-1′), 150.1 (s, C-3) ppm. MS (EI): m/z (%)=142 (5) [M+], 124 (3) [M+-CH3], 111 (28) [M+-CH3O], 83 (86) [C6H11+], 69 (100) [C5H9+]. Odour description: very pleasant and fresh green-rosy note with natural slightly agrestic-earthy aspects and “vert de lilas”-like facets of lilac, hyacinth and peony.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[C:8]([CH3:13])=[C:7]2[Cl:14].C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>C1(C)C=CC=CC=1>[Cl:14][C:7]1[C:6]2[C:11](=[C:2]([C:9]3[CH:8]=[CH:7][CH:6]=[CH:11][N:10]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:20][N:21]=2)[C:8]=1[CH3:13]
Reactant: Cc1c(Cl)nc2c(Br)cccc2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(-c3ccccn3)cccc2c1Cl

Procedure:
The chlorides were prepared according to Procedure E using 8-bromo-2,4-dichloro-3-methylquinoline (0.32 g, 1.11 mmol), 2-(tributylstannyl)pyridine (0.45 mL, 1.23 mmol) and palladium tetrakistriphenylphosphine (0.13 g, 0.11 mmol) in toluene (2.2 mL) to give 8-bromo-4-chloro-3-methyl-2-(pyridin-2-yl)quinoline and further elution gave 4-chloro-3-methyl-2,8-di(pyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=332.0 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]([S:16][CH2:17][CH2:18][CH3:19])=[C:14]([C:20](=[O:28])[NH:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:13]=[N:12]2)=[CH:6][CH:5]=1.[Li+].[OH-].O>CO>[CH:22]1([NH:21][C:20]([C:14]2[CH:13]=[N:12][N:11]([CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[CH:5][CH:6]=3)[C:15]=2[S:16][CH2:17][CH2:18][CH3:19])=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCCSc1c(C(=O)NC2CCCCC2)cnn1Cc1ccc(C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCSc1c(C(=O)NC2CCCCC2)cnn1Cc1ccc(C(=O)O)cc1
Yield: 90.7 %

Procedure:
A solution of 4-(4-Cyclohexylcarbamoyl-5-propylsulfanyl-pyrazol-1-ylmethyl)-benzoic acid methyl ester (116 mg, 0.28 mmol) (Intermediate #40) and LiOH (47 mg, 1.12 mmol) in MeOH (2 ml)/Water (1 ml) was stirred overnight at ambient temperature. The bulk of the MeOH was removed in vacuo and the resulting solution was treated with citric acid (˜10 ml) then extracted with EtOAc (2×˜15 ml). The organic layers were combined, washed with brine (˜10 ml), dried (MgSO4), filtered and evaporated to yield the title compound as a white solid (102 mg, 91%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][N:25]([CH3:29])[C:26]([NH2:28])=[O:27]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:28][C:26](=[O:27])[N:25]([CH3:29])[CH3:24])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CN(C)C(N)=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(NC(=O)N(C)C)nc3)CC2)c(C)c1
Yield: 28.7 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (188 mg) described in Preparation Example 127 and 1,1-dimethylurea (66 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (55 mg) was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[CH:13]=2)[S:8][C:9]=1[CH3:10])=[O:4].[OH-].[K+].[K]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:7]2[S:8][C:9]([CH3:10])=[C:5]([C:3]([OH:4])=[O:2])[N:6]=2)=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: COC(=O)c1nc(Nc2ccc(Cl)c(OC)c2)sc1C
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(C(=O)O)c(C)s2)ccc1Cl
Temperature: 50 °C
Yield: 77.5 %

Procedure:
A mixture of 6.0 g (19 mmol) 2-(4-chloro-3-methoxy-phenylamino)-5-methyl-thiazole-4-carboxylic acid methyl ester and 11.5 mL 5M aq. KOH in 60 mL THF was heated to 50° C. for 3 h. Upon cooling to room temperature the potassium salt of the product precipitated and was filtered off. This solid was dissolved in a mixture of water (250 mL) and acetic acid (12 mL) and the solution was extracted thrice with ethyl acetate. Organic phases were pooled washed with water and the solvent was removed. The residue was stirred with dichloromethane/n-heptane (1: 1; 30 mL) and the solid was isolated by filtration. Residual solvent was removed in vacuo to yield 4.4 g (77%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7]I)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:13][CH:12]([NH:27][C:28](=[O:50])[C@H:29]([CH2:46][CH:47]([CH3:49])[CH3:48])[C@H:30](CC=C)[C:31]([NH:33]CC2C=C(F)C=C(F)C=2)=[O:32])[C:11]1=[O:51].C([O-])(=O)CCC([O-])=O.CN1C2C=CC=CC=2C(C2C=CC=CC=2)=NC(N)C1=O>>[CH3:9][N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:13][C@H:12]([NH:27][C:28](=[O:50])[C@H:29]([CH2:46][CH:47]([CH3:49])[CH3:48])[C@H:30]([CH2:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:31]([NH2:33])=[O:32])[C:11]1=[O:51]
Reactant: C=CC[C@H](C(=O)NCc1cc(F)cc(F)c1)[C@@H](CC(C)C)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reactant: ICCC1CCCC1
Agent: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Agent: O=C([O-])CCC(=O)[O-]
Product: CC(C)C[C@@H](C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O)[C@H](CCC1CCCC1)C(N)=O

Procedure:
A procedure analogous to the preparation of Example 5 was followed. The appropriate succinate ester was prepared using the method disclosed in PCT publication WO 98/51665, using 2-(cyclopentyl)ethyl iodide for R3—X in place of allyl bromide (see Scheme 2). The anti-succinate half-ester was coupled to (S)-isomer benzodiazepine (30) using the procedures of Step 1. After Steps 2 and 3, the title compound was isolated. MS (M+H)+=475; (M+Na)+=497.2.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.[CH2:18]([O:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([CH2:36][OH:37])[C:27]=1[CH3:38])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+].O>CN(C=O)C>[CH2:18]([O:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([CH2:36][O:37][C:2]2[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([O:10][CH2:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:3]=2)[C:27]=1[CH3:38])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1c(CO)nc2ccccc2c1OCc1ccccc1
Reactant: Clc1cc(Cl)c(OCC2CCOCC2)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(COc2nc(OCC3CCOCC3)c(Cl)cc2Cl)nc2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
2,3,5-trichloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridine (214 mg) and [4-(benzyloxy)-3-methylquinolin-2-yl]methanol (222 mg) were dissolved in DMF (5 mL), and 60% sodium hydride (40 mg) was added thereto, followed by stirring at room temperature for 3 hours. Water (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (80 mL). The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 4-(benzyloxy)-2-({[3,5-dichloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-2-yl]oxy}methyl)-3-methylquinoline (250 mg).