Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[NH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)=[O:27]>>[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1)(=[O:27])[NH2:25]
Reactant: NC(=O)c1ccccc1B(O)O
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: NC(=O)c1ccccc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 16 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2-aminocarbonylphenylboronic acid (available from Combi-Blocks Inc.; 66 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-carbamoyl-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (15 mg, 8%). 1H NMR (300 MHz, DMSO-d6) δ 13.07 (br s, 1H), 8.46 (s, 1H), 8.36 (d, J=14.1 Hz, 2H), 8.04-8.18 (m, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.58 (d, J=7.2 Hz, 2H), 7.42-7.51 (m, 2H), 7.12-7.34 (m, 3H). The compound of Example 81 has the same formula as the compound of Example 113.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][C:13]([OH:15])=O)[CH:8]=2)[O:3]1.[CH:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>C1COCC1>[CH3:16][C:2]1([CH3:1])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][C:13]([NH:27][CH:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH2:18]3)=[O:15])[CH:8]=2)[O:3]1
Reactant: NC1CCCc2ccccc21
Reactant: CC1(C)C=Cc2cc(CC(=O)O)ccc2O1
Solvent: C1CCOC1
Product: CC1(C)C=Cc2cc(CC(=O)NC3CCCc4ccccc43)ccc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9.6 g 1,1-carbonyldiimidazole (=CDl) dissolved in 85 ml THF was slowly added to a solution of 11.7 g of the 2,2-dimethyl-2H-chromen-6-yl acetic acid obtained above in 100 ml THF and stirred for 30 min. at room temperature. 8.8 ml 1,2,3,4-tetrahydro-1-naphthylamine, dissolved in 30 ml THF, was dropped slowly into this receiving solution, the resulting mixture was stirred for 1 hour and left to stand overnight at room temperature. The solvent was largely evaporated at reduced pressure, and the remaining residue was stirred with a mixture of diethyl ether and isopropanol (100:1 v/v) and crystallized. The resulting crystals were removed by suction and dried at 65° C. and 20 bar. Chromatography of the diethyl ether/isopropanol washing liquid on silica gel yielded further intermediate product, which was combined with the main quantity and dried. 17.5 g 2-(2,2-dimethyl-2H-chromen-6-yl)-N-1,2,3,4-tetrahydronaphth-1-yl acetamide was obtained as colorless solid, which was used without further purification for the subsequent reaction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([OH:12])=[O:11].CCOCC>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[F:9]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(Br)c(F)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
To a suspension of 1-bromo-2,4-difluorobenzene (11.7 mL, 104 mmol) in 96 mL concentrated H2SO4 at 0° C. was added concentrated HNO3 (85 mL) dropwise maintaining the temperature below 20° C. The resulting mixture was stirred for 10 minutes at 0° C., then poured into a mixture of ether and ice water with vigorous stirring. The aqueous phase was separated and extracted with ether. The combined organic phases were washed with aqueous NaHCO3 and brine, dried and concentrated. The residue was purified using silica gel column chromatography with 15% acetone in hexanes to provide 1-bromo-2,4-difluoro-5-nitrobenzene (23 g, 96.6 mmol, 93.3% yield) as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=O)=[N:6][C:5]=1[Cl:14].O(Cl)Cl.[P+5].[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:6]([CH:12]=[N:11][CH:10]=2)[C:5]=1[Cl:14])=[O:15]
Reactant: COC(=O)c1ccc(CNC=O)nc1Cl
Agent: ClOCl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2cncn2c1Cl
Temperature: 65 °C
Yield: 86 %

Procedure:
To a suspension of 2-chloro-6-formylaminomethylnicotinic acid methyl ester (42.6 g, 0.19 mol) in toluene (400 mL) was added phosphorous (V) oxychloride (18.2 mL, 0.20 mol) and the reaction mixture heated at 65° C. for 1.5 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 mL) before treating with sodium hydroxide solution (2 M) to adjust pH˜8. The layers were separated and the aqueous layer extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4) then charcoal (˜5 g) was added and the solution mixed for 5 minutes before being filtered and concentrated in vacuo to yield the title compound as a tan solid (34.4 g, 88%) 1H NMR (CDCl3, 400 MHz) 8.52 (1H, s), 7.57 (1H, s), 7.45 (1H, d, J=9.3 Hz), 7.25 (1H, d, J=9.1 Hz), 3.97 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:21]3[CH:20]=[N:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1ccc(OC)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: COc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 2-methoxy-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:22])=[CH:27][CH:26]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1

Procedure:
N-(4-Methoxyphenyl)-2′-methyl-5′-(5methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-methoxyaniline using method I. NMR; δH [2H6]—DMSO 10.21,(1H, b), 8.05,(2H, d), 7.90,(1H, dd), 7.79,(1H, d), 7.70,(2H, d), 7.58-7.55,(3H, m), 6.93,(2H, d), 3.74,(3H, s), 2.57,(3H, s), 2.33,(3H, s). LCMS; retention time 3.40 min, MH+ 400.
Reaction SMILES: [CH2:1]([Si:4]([CH2:19][CH:20]=[CH2:21])([CH2:16][CH:17]=[CH2:18])[CH2:5][CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].C1COCC1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO>[CH2:19]([Si:4]([CH2:1][CH:2]=[CH2:3])([CH2:16][CH:17]=[CH2:18])[CH2:5][CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=1)[CH:20]=[CH2:21]
Reactant: C=CC[Si](CC=C)(CC=C)CCCc1ccc(C=O)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C=CC[Si](CC=C)(CC=C)CCCc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
Under a nitrogen atmosphere, to 4-{3-(triallylsilyl)propyl}benzaldehyde (4) (11.0 g, 36.9 mmol), THF (25 ml) and methanol (MeOH) (25 ml) were added and then cooled down to at around 0° C. with ice, and then NaBH4 (2.8 g, 73.8 mmol) was added and stirred for 3 hours. To the reacted mixture, saturated sodium bicarbonate aqueous solution was added. The obtained water layer was extracted with diethyl ether. The collected organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, obtaining a crude product. The crude product was separated and purified using silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1), obtaining 4-{3-(triallylsilyl)propyl}benzyl alcohol (38) represented by the following chemical reaction equation (yield: 9.2 g, yield (%): 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH2:13][N:12]([C:29](=[O:30])[C:28]3[CH:27]=[C:26]([O:25][CH3:24])[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: Clc1ccc(C2(CCCOC3CCCCO3)CCNC2)cc1Cl
Product: COc1cc(C(=O)N2CCC(CCCOC3CCCCO3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.1 using 4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyrrolidine (2 mmol) and 3,4,5-trimethoxy-benzoyl chloride (2 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50](/[CH:53]=[CH:54]/[CH2:55][C:56](O)=[O:57])=[CH:49][CH:48]=2)[C:43]([CH3:59])=[CH:42][C:41]=1[O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:68][C:69]([CH3:73])([CH3:72])[CH2:70][OH:71].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O.C(Cl)(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:48]=[CH:49][C:50](/[CH:53]=[CH:54]/[CH2:55][C:56]([NH:68][C:69]([CH3:73])([CH3:72])[CH2:70][OH:71])=[O:57])=[CH:51][CH:52]=2)[C:43]([CH3:59])=[CH:42][C:41]=1[O:60][CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CC(=O)O)cc1
Reactant: CC(C)(N)CO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CC(=O)NC(C)(C)CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a chloroform solution (2.2 mL) of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[(1E)-3-carboxyprop-1-en-1-yl]benzyl]-4-methylphenyl]-D-glucitol (200 mg, 0.223 mmol) were added 2-amino-2-methyl-1-propanol (40 mg, 0.446 mmol), 1-hydroxy benzotriazole (33 mg, 0.245 mmol) and WSC (60 mg, 0.312 mmol), and the mixture was stirred overnight at room temperature. To the reaction solution was added water, and the resulting mixture was extracted with chloroform. The organic layer was washed with brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=5:1 to 1:2) to obtain the title compound (120 mg, 56%) as an orange-yellow oily compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].CS[C:18](SC)=[C:19]1[C:28](=[O:29])[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH2:30][CH2:31][CH2:32][CH3:33])[C:20]1=[O:34]>C1(C)C=CC=CC=1>[CH2:30]([N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][N:23]=2)[C:28]([OH:29])=[C:19]([C:18]2[NH:1][C:2]3[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=3[S:7](=[O:8])(=[O:9])[N:10]=2)[C:20]1=[O:34])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCN1C(=O)C(=C(SC)SC)C(=O)c2cccnc21
Reactant: COCOCc1csc(N)c1S(N)(=O)=O
Solvent: Cc1ccccc1
Product: CCCCn1c(=O)c(C2=NS(=O)(=O)c3c(COCOC)csc3N2)c(O)c2cccnc21
Yield: 55.4 %

Procedure:
The product of Example 309G (110 mg, 0.43 mmol) and the product of Example 315B (140.6 mg, 0.43 mmol) were reacted in toluene (5 mL) at 100° C. for 3 hours. The reaction was concentrated under reduced pressure and the residue was purified by chromatography on silica gel using a Biotage-12 m column eluting with 1:99 methanol:dichloromethane to give the title compound as a white solid (114 mg, 54.6%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz,CDCCl3) δ ppm 1.00 (t, J=7.35 Hz, 3 H), 1.46 (m, 2 H), 1.74 (m, 2 H), 3.45 (s, 3 H), 4.56 (m, 2 H), 4.80 (s, 2 H), 4.84 (s, 2 H), 7.09 (s, 1 H), 7.26 (s, 1 H), 7.36 (dd, J=8.09, 4.41 Hz, 1 H), 8.57 (dd, J=8.09, 1.84 Hz, 1 H), 8.81 (dd, J=4.78, 1.84 Hz, 1 H), 15.06 (s, 1 H), 15.11 (s, 1 H).
Reaction SMILES: C(OC(N=NC(OCC)=O)=O)C.[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:24][CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1.O[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:24][CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[CH:28]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: OCc1ccccn1
Reactant: Nc1nc2c(s1)CCN(CC=Cc1cccc(O)c1)CC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1nc2c(s1)CCN(CC=Cc1cccc(OCc3ccccn3)c1)CC2
Temperature: 0 °C

Procedure:
A solution of 57 mg (0.33 mmol) of diethyl-azodicarboxylate in 0.15 ml of anhydrous tetrahydrofuran is added dropwise, with stirring and cooling (internal temperature 0° C.), to 100 mg (0.33 mmol) of 2-amino-6-(3-(3-hydroxy-phenyl)allyl)-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine and 36 mg (0.33 mmol) of 2-(hydroxymethyl)-pyridine and 86 mg (0.33 mmol) of triphenylphosphine in 1 ml of anhydrous tetrahydrofuran. After stirring overnight, whilst heating to ambient temperature, a further 0.33 mmol of triphenylphosphine and diethyl-azodicarboxylate are added at 0° C. and the mixture is stirred for another hour at ambient temperature. It is evaporated down in vacuo and distributed between ethyl acetate and water. The ethyl acetate phase is extracted with 2N hydrochloric acid. The aqueous hydrochloric acid phase is made alkaline with conc. ammonia and extracted with ethyl acetate; the organic phase is dried, filtered and evaporated down in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol=5:1). Yield: 13 mg (10% of theory), Melting point: 35°-40° C. (foamy). Molecular peak (m/z): Calculated: 392 Found: 392
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2cccnc2c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2cccnc2c1
Yield: 99.1 %

Procedure:
A mixture of 7-nitroquinoline (D54) (0.65 g, 3.71 mmol) and 10% palladium on charcoal (65 mg, 54% water) in methanol (20 ml) was hydrogenated at 1 atm. and ambient temperature for until complete by tlc. The catalyst was filtered off and washed with further methanol. The combined filtrated and washings were concentrated in vacuo to give the title compound as a brown solid (0.53 g). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.75 (dd, 1H), 7.98 (dd, 1H), 7.62 (d, 1H), 7.21 (d, 1H), 7.14 (dd, 1H), 6.99 (dd, 1H), 4.07 (br, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][O:26][CH3:27].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][O:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNC(=O)c1ccccc1
Yield: 44.6 %

Procedure:
Using the general method of Example 186 1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.84 g, 2.27 mmol) was reacted with benzoyl choride (260 μL, 2.27 mmol) to provide 0.48 g of N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}benzamide as a tan powder, m.p. 133.4-137.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16](N(OC)C)=[O:17])(=[O:10])=[O:9].[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:22])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[CH:16]=[O:17])(=[O:9])=[O:10]
Reactant: CON(C)C(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2ccsc2C=O)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a mixture of 3-[(4-chloro-3-methyl-1,2-oxazol-5-yl)sulfamoyl]-N-methoxy-N-methylthiophene-2-carboxamide described in Production Example 1-2 (8.0 g, 22 mmol) and tetrahydrofuran (160 mL), was added dropwise diisobutyl aluminum hydride (46 mL, 48 mmol, 1.0 M n-hexane solution) at −78° C., followed by stirring at 0° C. for 30 minutes. A saturated aqueous solution of ammonium chloride was added dropwise at 0° C. to the reaction mixture, which was then gradually allowed to warm to room temperature and stirred for 1 hour at that temperature. The reaction mixture was filtered with Celite, and water was added to the filtrate, which was then extracted with ethyl acetate. The organic layer was washed with brine, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=30:1) to give the title compound (5.1 g, 75% yield).
Reaction SMILES: Br.Br.C([NH:10][C@@H:11]1[C@@H:16]2[CH2:17][CH2:18][C@@H:13]([CH2:14][NH:15]2)[CH2:12]1)C1C=CC=CC=1.[CH:19]1([N:22]2[C:31]3[C:26](=[CH:27][C:28]([F:33])=[C:29](F)[CH:30]=3)[C:25](=[O:34])[C:24]([C:35]([OH:37])=[O:36])=[CH:23]2)[CH2:21][CH2:20]1.C1CCN2C(=NCCC2)CC1>>[NH2:10][C@@H:11]1[C@@H:16]2[CH2:17][CH2:18][C@@H:13]([CH2:14][N:15]2[C:29]2[CH:30]=[C:31]3[C:26]([C:25](=[O:34])[C:24]([C:35]([OH:37])=[O:36])=[CH:23][N:22]3[CH:19]3[CH2:21][CH2:20]3)=[CH:27][C:28]=2[F:33])[CH2:12]1
Reactant: c1ccc(CN[C@H]2C[C@H]3CC[C@@H]2NC3)cc1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Product: N[C@H]1C[C@H]2CC[C@@H]1N(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2

Procedure:
In a manner similar to that of Example 14, the title compound of Example 12 (0.80 g) was coupled to 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid in the presence of DBU, and the product was similarly subjected to catalytic hydrogenation to remove the benzyl group, yielding 0.24 g of the title compound, mp 267°-270°, [α]D20 66.3°(DMSO). NMR data was the same as for the racemic compound of Example 22.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1([NH2:18])[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[N+:8]([C:7]1[C:2]([NH:17][CH:14]2[CH2:15][CH2:16][CH:11]([NH2:18])[CH2:12][CH2:13]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: NC1CCC(N)CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC1CCC(Nc2ncccc2[N+](=O)[O-])CC1
Yield: 54.8 %

Procedure:
2-Chloro-3-nitropyridine (10 g, 63.3 mmol), cyclohexane-1,4-diamine (7.2 g, 63.3 mmol), anhydrous dimethylformamide (100 mL) and anhydrous sodium carbonate (13.4 g, 126 mmol) were combined with stirring under nitrogen. The reaction mixture was stirred at room temperature for 14 hours. It was poured into water and the resulting orange solid was filtered off and found to be N1-(3-nitropyridin-2-yl)cyclohexane-1,4-diamine (8.2 g, 34.7 mmol, 54.9% yield) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C:10]2[CH:21]=[C:22](Cl)[CH:23]=[CH:24][C:9]1=2.F[C:41](F)(F)[C:42]1C=C(C=C(C(F)(F)F)[CH:69]=1)CNC1C2C=CC3CCCC=3C=2N(C(OC(C)C)=O)CCC1>>[CH:18]([O:17][C:15]([N:11]1[C:10]2[C:21]3[CH2:41][CH2:42][CH2:69][C:22]=3[CH:23]=[CH:24][C:9]=2[CH:8]([N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:39])([F:38])[F:1])[CH:33]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:31]=2)[C:26]2[NH:30][N:29]=[N:28][N:27]=2)[CH2:14][CH2:13][CH2:12]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn[nH]2)c2ccc(Cl)cc21
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc3c(c21)CCC3
Product: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn[nH]2)c2ccc3c(c21)CCC3

Procedure:
The titled compound was prepared in a manner analogous to the procedure for the preparation of (+/−)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 46, from Step 2 to Step 3) by replacing (+/−)-isopropyl 5-(3,5-bistrifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with (+/−)-isopropyl 6-(3,5-bis-trifluoromethyl-benzylamino]-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylate (prepared above) in Example 46 Step 2. MS (ES−): 581 (M−H).