Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH2:23])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C=O)C.C(N(C(C)C)CC)(C)C.Cl[C:39]1[O:40][C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=1>CO>[O:40]1[C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=[C:39]1[NH:23][C@@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]1[NH:16][C@H:12]1[CH2:13][CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11]1
Reactant: N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: Clc1nc2ccccc2o1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=[N+]([O-])c1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3Nc3nc4ccccc4o3)C2)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
To a 1 dram vial was added (1R,2R)—N1-(1-(4-nitrophenyl)piperidin-3-yl)cyclohexane-1,2-diamine (25 mg, 0.079 mmol), DMF (1 mL), diisopropyl ethyl amine (0.069 mL, 0.393 mmol) and 2-chlorobenzo[d]oxazole (0.013 mL, 0.118 mmol). The vial was capped and the reaction was stirred at 65° C. for 1 hr. After this time, the reaction was diluted with MeOH and purified using RP prep-HPLC. Two diastereomers were separated. The desired isomer had the shorter retention time. The fractions with the desired material were concentrated to give the product (1R,2R)—N1-(benzo[d]oxazol-2-yl)-N2-((S)-1-(4-nitrophenyl)piperidin-3-yl)cyclohexane-1,2-diamine (16 mg, 0.036 mmol, 45.4% yield) as yellow solid. Anal. Calcd. for C24H29N5O3 m/z 435.5, found: 436.3 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 8.06-7.92 (m, 2 H), 7.37 (d, J=7.70 Hz, 1 H), 7.25-7.15 (m, 2 H), 7.06 (t, J=7.70 Hz, 1H), 6.65 (d, J=9.35 Hz, 2 H), 5.33-5.15 (m, 1 H), 3.67 (d, J=9.08 Hz, 1 H), 3.59 (d, J=11.28 Hz, 1 H), 3.44 (br. s., 1 H), 3.16-3.03 (m, 1 H), 2.89 (br. s., 2 H), 2.63 (br. s., 1 H), 2.40 (br. s., 1 H), 2.16 (d, J=11.28 Hz, 1 H), 2.00-1.91 (m, 1 H), 1.82 (d, J=9.63 Hz, 4 H), 1.71-1.58 (m, 3 H), 1.44 (d, J=9.35 Hz, 2 H); 13C NMR (126 MHz, CDCl3) δ ppm 162.09, 162.07, 154.71, 148.33, 126.15, 124.01, 121.2, 116.46, 112.55, 108.84, 59.37, 57.80, 53.01, 51.03, 48.07, 32.22, 31.92, 29.73, 24.84, 24.60, 22.91.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:51][C:52]([F:67])([F:66])[C:53]1[CH:65]=[CH:64][CH:63]=[CH:62][C:54]=1[O:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C=O)C.O>[O:13]=[C:11]([N:59]1[CH2:58][CH2:57][CH:56]([O:55][C:54]2[CH:62]=[CH:63][CH:64]=[CH:65][C:53]=2[C:52]([F:51])([F:66])[F:67])[CH2:61][CH2:60]1)[CH2:10][NH:9][C:7]([C:4]1[CH:3]=[CH:2][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)=[O:8]
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 46 %

Procedure:
To a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (0.09128 g, 0.00036 mol) in DMF (2 mL) was added DIPEA (0.126 g, 0.00098 mol), HOBt (0.05266 g, 0.0003901 mol) and EDCI.HCl (0.07457 g, 0.00039 mol) at ambient temperature. After 2 minutes 4-(2-trifluoromethyl-phenoxy)-piperidine trifluoroactetate (0.11 g, 0.00033 mol) was added and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with cold water and the resulting precipitate was isolated by filtration and dried to afford 0.072 g (46%) of biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LCMS: 483.18 (M+1)+, 95.73%, 1H NMR (CDCl3): δ 7.9 (d, 2H), 7.64-7.54 (m, 4H), 7.46-7.3 (m, 4H), 7.02-6.9 (q, 2H), 4.75 (s, 1H), 4.4-4.2 (dd, 2H), 4.2-4.0 (m, 2H), 3.65-3.35 (m, 4H), 2.05-1.8 (m, 4H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][C@H:10]2[C@@H:12]([C@:13]([C:18]3[CH:23]=[C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=4)(=[O:27])=[O:26])[CH:21]=[CH:20][C:19]=3[F:35])([CH:15]([F:17])[F:16])[N:14]=1)[CH2:11]2)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[O:9][C@H:10]2[C@@H:12]([C@:13]([C:18]3[CH:23]=[C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=4)(=[O:26])=[O:27])[CH:21]=[CH:20][C:19]=3[F:35])([CH:15]([F:16])[F:17])[N:14]=1)[CH2:11]2
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(NS(=O)(=O)c3ccc(Cl)cn3)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@](c2cc(NS(=O)(=O)c3ccc(Cl)cn3)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
To a solution of tert-butyl((1R,5S,6R)-5-(5-(5-chloropyridine-2-sulfonamido)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (0.061 g, 0.11 mmol) in DCM (2 mL) at room temperature was added trifluoroacetic acid (2.0 mL). The reaction mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was partitioned between saturated NaHCO3 and EtOAc. The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were washed with brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (30% to 70% EtOAc in heptane) to give the title compound (0.045 g, 0.10 mmol, 90% yield) as a white solid. MS m/z=446.9 [M+H]+. Calculated for C17H14ClF3N4O3S 446.0. 1H NMR (400 MHz, CDCl3) δ 0.80-0.90 (m, 1H), 1.33 (t, J=6.85 Hz, 1H), 1.69-1.78 (m, 2H), 3.65-3.70 (m, 1H), 5.70 (s br, 2H), 6.06 (t, J=56.10 Hz, 1H), 6.95 (dd, J=6.75, 2.64 Hz, 1H), 7.06 (dd, J=11.44, 8.71 Hz, 1H), 7.45 (ddd, J=8.56, 4.25, 2.84 Hz, 1H), 7.72 (s, 2H), 8.33 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[C:4]=1[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:19][CH:18]=1)=[O:16].B(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[C:4]=1[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:19][CH:18]=1)=[O:16]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OC)ccc2c1
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(O)ccc2c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
Dissolve (2,6-dimethoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (56.0 g, 123 mmol) in chloroform (500 mL). Cool to 0° C. Add boron trichloride (150 mL, 150 mmol, 1 M solution in dichloromethane) and stir 2 hours. Warm to room temperature and stir 1.5 hours. Add additional boron trichloride (50 mL, 50 mmol) after cooling to 0° C. Warm to room temperature and stir overnight. Carefully add ice and saturated aqueous sodium bicarbonate. Separate organic and wash aqueous three times with a 3:1 dichloromethane:isopropanol mixture. Concentrate in vacuo and dissolve in dichloromethane. Dry over sodium sulfate, decant, and concentrate in vacuo. Slurry in ether and filter, rinsing with hexanes to give 49.4 g of (2-hydroxy-6-methoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (99%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:12]([CH3:14])[CH3:13])[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH2:29])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1>>[CH3:13][N:12]([CH3:14])[C:4]1[N:3]=[C:2]([NH:29][C:19]2[CH:20]=[CH:21][C:22]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:17]([O:16][CH3:15])[CH:18]=2)[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: CN(C)c1cc(C(C)(C)O)nc(Cl)n1
Product: COc1cc(Nc2nc(N(C)C)cc(C(C)(C)O)n2)ccc1-n1cnc(C)c1

Procedure:
Using in analogous manner the procedure described in example 1e), 2-(2-chloro-6-dimethylamino-pyrimidin-4-yl)-propan-2-ol (65 mg, 0.3 mmol) was reacted with 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.3 mmol) to give the title compound was obtained as light yellow foam (24 mg, 21%). MS ISP (m/e): 383.3 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.75 (d, 1H), 7.63 (s, 1H), 7.26 (s, 1H), 7.15 (d, 1H), 6.99 (dd, 1H), 6.87 (s, 1H), 6.01 (s, 1H), 4.38 (br s, 1H), 3.86 (s, 3H), 3.16 (s, 6H), 2.30 (s, 3H), 1.51 (s, 6H).
Reaction SMILES: C(C1C=CC=CC=1C1[S:10]C=C(C2C=CC=CC=2)N=1)=O.[CH3:20][O:21][CH:22]([O:31][CH3:32])[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26].S>>[CH3:20][O:21][CH:22]([O:31][CH3:32])[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]([NH2:26])=[S:10]
Reactant: COC(OC)c1ccccc1C#N
Reactant: O=Cc1ccccc1-c1nc(-c2ccccc2)cs1
Agent: S
Product: COC(OC)c1ccccc1C(N)=S

Procedure:
A solution of 2.65 g of 2-(o-formylphenyl)-4-phenylthiazole [M.P. 99°-100°; obtainable by reacting o-dimethoxymethylbenzonitrile with H2S to give o-dimethoxymethylthiobenzamide (M.P. 100°-102°), reacting the latter with α-bromoacetophenone to give o-dimethoxymethylthiobenzoic acid imide S-phenacyl ester (oil), and cyclizing the latter to give 2-(o-dimethoxymethylphenyl)-4-phenylthiazole by boiling with methanol and subsequent hydrolysis with aqueous hydrochloric acid], 1.06 ml of 33% aqueous ammonia, 2.32 g of methyl acetoacetate and 120 ml of methanol is boiled for 18 hours and evaporated. Treating the residue with ether gives 2,6-dimethyl-3,5-dimethoxycarbonyl-4-o-(4-phenyl-2-thiazolyl)-phenyl-1,4-dihydropyridine, M.P. 145°-148° (decomposition).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@H:9]([N:13]1[CH:17]=[C:16]([CH2:18][C@@H:19]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:20]([NH2:22])=[O:21])[N:15]=[N:14]1)[CH2:8][CH2:7][CH2:6]2)=O.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[CH3:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([NH:23][C@H:19]([CH2:18][C:16]2[N:15]=[N:14][N:13]([C@H:9]3[C:10]4[C:5](=[CH:4][C:3]([CH2:1][N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[CH:12][CH:11]=4)[CH2:6][CH2:7][CH2:8]3)[CH:17]=2)[C:20]([NH2:22])=[O:21])(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCCc4cc(C=O)ccc43)nn2)C(N)=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCCc4cc(CN5CCCCC5)ccc43)nn2)C(N)=O)cc1
Temperature: 60 °C

Procedure:
A mixture of (R)-3-(1-((R)-6-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylbenzenesulfonamido)propanamide (0.21 g, 0.45 mmol) and piperidine (0.20 g, 2.2 mmol) in 5 mL 1,2-dichloroethane was heated to 60° C. for 30 min. The reaction mixture was cooled and treated with NaBH(OAc)3 and a drop of HOAc. The resulting mixture was heated to 80° C. for 16 h. The reaction mixture was cooled, quenched with H2O, and extracted with CHCl3 (3×). The combined extracts were dried over MgSO4, concentrated and purified by SiO2 (5% MeOH/CH2Cl2) to give a white solid. MS (m/z): 537.4 (m+H).
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:24])[CH:15]([NH:16][C:17](=[S:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C@H:12]2[S:11][CH2:10][C:9]=1[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:7])(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[C:6]([C:8]1[N:13]2[C:14](=[O:24])[CH:15]([NH:16][C:17](=[S:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C@H:12]2[S:11][CH2:10][C:9]=1[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)C1=C(Cc2cccnc2)CS[C@@H]2C(NC(=S)CCC(=O)O)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(=S)NC1C(=O)N2C(C(=O)O)=C(Cc3cccnc3)CS[C@H]12
Reaction time: 0.25 h

Procedure:
4-t-Butoxycarbonyl-7-carboxymethylthioacetamido-3-(3-pyridylmethyl)ceph-3-em (XLIV) (250 mg.) was dissolved in trifluoroacetic acid (3 ml.) and allowed to stand at room temperature for 15 mins. The trifluoroacetic acid was stripped off under reduced pressure and the last traces removed by additions of dry toluene and reevaporation. The residue was taken up in acetone (1 ml.) and the small amount of insoluble material discarded. The title compound (XLV) ws precipitated by careful addition of the acetone solution to dry ether (10 ml.). It was an off-white non-crystalline powder (150 mg., 54%);
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH2:20][NH:21][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[CH3:1])=[CH:15][CH:14]=1
Reactant: NCC(c1ccc(F)cc1)N1CCOCC1
Reactant: Cc1cccc(C(=O)O)c1C
Product: Cc1cccc(C(=O)NCC(c2ccc(F)cc2)N2CCOCC2)c1C

Procedure:
From 2,3-dimethylbenzoic acid and 2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[CH:8]3[CH2:19][CH:10]([C:11]4[CH:16]=[C:15]([F:17])[C:14]([Br:18])=[CH:13][C:12]=4[C:6]2=[N:5][C:4]=1[C:20]([NH2:22])=[O:21])[CH2:9]3.[F:23][C:24]1([F:30])[CH2:26][CH:25]1[C:27](O)=[O:28]>>[Br:18][C:14]1[C:15]([F:17])=[CH:16][C:11]2[CH:10]3[CH2:9][CH:8]([CH2:19]3)[N:7]3[C:3]([CH2:2][NH:1][C:27]([CH:25]4[CH2:26][C:24]4([F:30])[F:23])=[O:28])=[C:4]([C:20]([NH2:22])=[O:21])[N:5]=[C:6]3[C:12]=2[CH:13]=1
Reactant: O=C(O)C1CC1(F)F
Reactant: NCc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Product: NC(=O)c1nc2n(c1CNC(=O)C1CC1(F)F)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
3-(aminomethyl)-10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 2,2-difluorocyclopropanecarboxylic acid similarly to as described in example 2 with non-critical modifications to afford crude 10-bromo-3-((2,2-difluorocyclopropanecarboxamido)methyl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was reacted directly with 2-methyl-3-butyne-ol via General Procedure F to afford 14 mg (33%) of 3-[[(2,2-difluorocyclopropanecarbonyl)amino]methyl]-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide M+1=473.2.
Reaction SMILES: C([O:8][C:9](=[O:39])[CH:10]([N:22]1[CH:26]=[CH:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:23]1)[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])C1C=CC=CC=1>O>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][CH:10]([N:22]1[CH:26]=[CH:25][N:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:31][CH:32]=2)[CH2:23]1)[C:9]([OH:39])=[O:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CC(C(=O)OCc1ccccc1)N1C=CN(c2ccc(-c3ccccc3)cc2)C1)OCc1ccccc1
Solvent: O
Product: O=C(CC(C(=O)O)N1C=CN(c2ccc(-c3ccccc3)cc2)C1)OCc1ccccc1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A suspension of 2(RS)-(3-biphenyl-4-yl-1H-imidazol-1-yl)-succinic acid dibenzyl ester (551 mg, 1.07 mmol) in H2O (0.5 mL) was refluxed overnight. Once allowed to cool to ambient temperature, the resultant precipitate was collected and dried in vacuo to provide 436 mg (96%) of 2(RS)-(3-biphenyl-4-yl-1H-imidazol-1-yl)-succinic acid 4-benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][C:9]([CH2:11][OH:12])=[N:10][C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:15])[C:9]([CH2:11][OH:12])=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CI
Reactant: OCc1nc2ccc(Cl)nc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CO)nc2ccc(Cl)nc21

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 3.00 g of 5-chloro-2-hydroxymethyl-3H-imidazo[4,5-b]pyridine (prepared as described in Preparation 43), 0.71 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 1.1 ml of methyl iodide and 70 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 10:1 by volume as the eluent, to give 1.60 g of the title compound, melting at 204-210° C.
Reaction SMILES: [CH3:1]N(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:40])[O:32][CH:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36].CI>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH3:1])[C:31](=[O:40])[O:32][CH:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36]
Reactant: CN(C)C=O
Reactant: CCCC(CCC)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCCC(CCC)OC(=O)N(C)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (11 mg), and 1-propylbutyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (62 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of methyl iodide (77 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (43 mg, yield 68%).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[NH2:27])[CH:19]=[CH:18]3)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.[F:39][C:40]([F:46])([F:45])[S:41](O)(=[O:43])=[O:42].C(O)(=O)C>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[NH:27][S:41]([C:40]([F:46])([F:45])[F:39])(=[O:43])=[O:42])[CH:19]=[CH:18]3)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3N)ccc2c1
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3NS(=O)(=O)C(F)(F)F)ccc2c1

Procedure:
2-{6-[(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3yl)methyl]quinolin-2-yl}aniline (8.73 g, 21.4 mmol) prepared by the method disclosed in Japanese Patent Unexamined Publication No. 6-80664, triethylamine (6.0 ml, 42.8 mmol) and chloroform (87 ml) were mixed and stirred. While cooling on an ice-bath, a solution of anhydrous trifluoromethanesulfonic acid (3.6 ml, 21.4 mmol) in chloroform (36 ml) was added dropwise over 50 minutes. After stirring for 10 minutes, 2M acetic acid (123 ml) was added dropwise under ice-cooling. The solution was partitioned and the organic layer was washed twice with ion exchange water (123 ml), once with 2% aqueous hydrogencarbonate solution (123 ml) and once with ion exchange water (123 ml) to give a crude solution of N-{2-{6-[(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]quinolin-2-yl}phenyl}trifluoromethanesulfonamide in chloroform. To this solution was added ethanol (60 ml), and the mixture was heated to a bath temperature of 90-115° C. to distill away 176 ml thereof. After standing still overnight at 0° C., the precipitated crystals were collected by filtration. The crystals were washed 3 times with ethanol (10 ml) and dried under reduced pressure. Of the obtained crystals (8.48 g), 8.36 g was taken. Thereto were added ethyl acetate (425 ml) and ethanol (175 ml), and the mixture was heated to distill away 325 ml thereof. The reaction mixture was stood still at room temperature and the precipitated crystals were collected by filtration. After washing 3 times with ethanol (10 ml), the crystals were dried under reduced pressure to give 6.36 g of crystals. This recrystallization step was repeated to give 5.52 g of N-{2-{6-[(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]quinolin-2-yl}phenyl}trifluoromethanesulfonamide as yellow crystals, melting point 252.0° C.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH:27]=[CH:28][CH3:29])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH:27]=[CH:28][CH3:29])=[CH:7][CH:6]=1
Reactant: CC=CCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccc(NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC=CCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccc(N)cc1
Temperature: 25 °C

Procedure:
The mixture of 1.2 g of 4-(4-acetamidophenylmercapto)-3-(2-butenylamino)-5-sulfamoylbenzoic acid and 12 ml of 2N aqueous sodium hydroxide is refluxed for 1 hour under nitrogen. After cooling to room temperature it is filtered, the filtrate acidified with glacial acetic acid to a pH of 4-5 and the precipitate formed filtered off. It is washed with water and recrystallized from 50% aqueous ethanol, to yield the 4-(4-aminophenylmercapto)-3-(2 -butenylamino)-5-sulfamoylbenzoic acid, melting at 242°.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][N:12]2[N:15]=[C:16]([C:18]([O:20]CC)=[O:19])[CH:17]=[C:11]2[CH2:10]1)=[O:8].[OH-].[Na+].Cl>O1CCCC1.CO>[CH3:1][C:2]1[C:3]2[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][N:12]2[N:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=[C:11]2[CH2:10]1)=[O:8]
Reactant: CCOC(=O)c1cc2n(n1)CCN(C(=O)c1sc3ccccc3c1C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)N2CCn3nc(C(=O)O)cc3C2)sc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The ethyl 5-(3-methylbenzo[b]thiophene-2-carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate obtained in the previous step was dissolved in a mixture of tetrahydrofuran (1.8 mL) and methanol (0.3 mL). To the resulting solution was added 1M aqueous sodium hydroxide (0.4 mL, 0.4 mmol). The solution was stirred at room temperature for 4 hours whereupon the reaction was neutralized with the addition of 1M aqueous hydrochloric acid (0.4 mL). The solvents were evaporated under reduced pressure to afford crude Intermediate 24 as a white solid.