Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH2:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:35][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: CC(C)CN
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Agent: Cl
Product: CC(C)CNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 17.1 mg (0.23 mmol) of iso-butylamine are reacted together by general method E. 15.2 mg (26.9% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([C:13]([OH:15])=O)[C:6]=2[N:5]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:43][C:44]1[C:45]([CH3:51])=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(N(CC)CC)C>[Cl:43][C:44]1[C:45]([CH3:51])=[C:46]([NH:47][C:13]([C:12]2[C:6]3[N:5]=[C:4]([CH2:3][O:2][CH3:1])[NH:8][C:7]=3[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[O:15])[CH:48]=[CH:49][CH:50]=1
Reactant: COCc1nc2c(C(=O)O)cc([N+](=O)[O-])cc2[nH]1
Reactant: Cc1c(N)cccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1nc2c(C(=O)Nc3cccc(Cl)c3C)cc([N+](=O)[O-])cc2[nH]1
Reaction time: 18 h
Yield: 104.9 %

Procedure:
To a suspension of methyl 2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylate (Example 11, Step 3) (4.8 g) in MeOH (120 mL), were added lithium hydroxide hydrate (4.56 g) and water (54 mL). The mixture was stirred at room temperature for 16 hours. Under ice-cooling, 1N hydrochloric acid was added slowly to the reaction mixture to adjust the pH to about 2. The precipitate was collected by filtration and dried to obtain 2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylic acid (4.6 g). To the solution of 2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylic acid (4.6 g) in DMF (90 mL), HBTU (8.23 g), triethylamine (2.19 g) and 3-chloro-2-methylaniline (3.07 g) were added sequentially, and the solution was stirred for 18 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate and stirred for 1 hour. The precipitate was collected by filtration and washed sequentially with water and ethyl acetate to obtain N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxamide (7.2 g) as pale yellow powder. To the solution of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxamide (7.2 g) in MeOH-THF (1:1, 120 mL), were added 1% platinum+0.1% copper-activated carbon (Degussa type CF105 R/W) (1.4 g). The mixture was stirred under hydrogen atmosphere (3 atm) for 4 hours. The catalyst was filtered off, and the mother liquid was concentrated. The residual solid was washed with ethyl acetate to obtain 6-amino-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (5.1 g) as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.[F:28][C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:31]2[CH2:32][CH2:33][C@H:29]([F:28])[CH2:30]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: F[C@H]1CCNC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C2CCc3c2nc(Cl)nc3N2CC[C@H](F)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (135 mg, 0.477 mmol) in MeOH (4768 μL) was added DIPEA (208 μL, 1.192 mmol), then (S)-3-fluoropyrrolidine (46.7 mg, 0.524 mmol). The reaction was allowed to stir at ambient temperature for 2 h. The solvent was removed and the residue applied to Silica gel and eluted with an EtOAc/Hex gradient to afford two diasteriomers (Hp1 and Hp2). Hp1: LC-MS (M+H)+=336.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.06-7.13 (2 H, m), 6.93-7.00 (2 H, m), 5.32 (1 H, td, J=52.57, 3.17 Hz), 4.17 (1 H, dd, J=9.16, 5.49 Hz), 4.06-4.14 (1 H, m), 3.98-4.06 (1 H, m), 3.76-3.90 (2 H, m), 3.25 (1 H, ddd, J=15.11, 8.55, 6.26 Hz), 3.08-3.16 (1 H, m), 2.51-2.60 (1 H, m, J=13.20, 9.12, 9.12, 6.41 Hz), 2.32-2.42 (1 H, m), 2.00-2.17 (2 H, m). Hp2: LC-MS (M+H)+=336.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.06-7.14 (2 H, m), 6.94-7.02 (2 H, m), 5.25-5.40 (1 H, m), 3.99-4.24 (3 H, m), 3.75-3.92 (2 H, m), 3.19-3.28 (1 H, m), 3.10-3.19 (1 H, m), 2.57 (1 H, dddd, J=13.24, 8.74, 8.55, 4.58 Hz), 2.31-2.43 (1 H, m), 1.94-2.17 (2 H, m)
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27]>>[N:1]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][CH3:23])=[O:20])=[CH:21][CH:22]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1N
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: COc1ccccc1NC(=O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (20) (100 mg, 0.32 mmol) was treated with 2-methoxyaniline (30 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-20% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(2-methoxyphenyl)benzamide as a white solid. Yield: 39 mg (38%). 1H-NMR: 9.75 (s, 1H), 8.05 (d, J=8.5 Hz, 2H), 7.73 (d, J=8.5 Hz, 2H), 7.69-7.61 (m, 2H), 7.24-7.07 (m, 5H), 6.96 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 3.85-3.79 (m, 2H), 2.46 (t, J=7.0 Hz, 2H), 1.67-1.59 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][OH:9])=[O:5])[CH3:3].FC1C([O:20][C:21](=O)[C@@H:22]2[CH2:26][C@@H:25]([OH:27])[CH2:24][N:23]2C(OC(C)(C)C)=O)=C(F)C(F)=C(F)C=1F.[ClH:40]>CN(C)C=O.C(O)(C)C>[ClH:40].[OH:27][C@H:25]1[CH2:24][NH:23][C@H:22]([C:21]([NH:1][C@H:2]([C:4]([NH:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][OH:9])=[O:5])[CH3:3])=[O:20])[CH2:26]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C[C@H](N)C(=O)N[C@@H](CO)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: C[C@H](NC(=O)[C@@H]1C[C@@H](O)CN1)C(=O)N[C@@H](CO)C(=O)O
Temperature: 20 °C
Reaction time: 24 h

Procedure:
N-alanylserine (1.5 kg, 8.515 M) and Boc-trans-4-hydroxy-L-proline (3.72 kg) (prepared as described in step 2) were heated at 50° C. in dimethylformamide (15 L) for 3 hours. The solution was cooled to 20° C., treated with concentrated hydrochloric acid (7.5 L) and stirred at room temperature for 24 hours. The resulting slurry was diluted with isopropanol (30 L), stirred at room temperature for 30 minutes and then cooled to 0° C. for 1 hour. The solid was collected by filtration and washed with isopropanol (20 L). The solid was dried in vacuo at 40° C. to afford the title compound as a white crystalline solid.
Reaction SMILES: [N:1]1[C:6]2[N:7]([C:10]3([CH2:13][OH:14])[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:14][CH2:13][C:10]1([N:7]2[C:6]3[N:1]=[CH:2][N:3]=[CH:4][C:5]=3[CH:9]=[CH:8]2)[CH2:11][CH2:12]1
Reactant: C1=COCCC1
Reactant: OCC1(n2ccc3cncnc32)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: c1ncc2ccn(C3(COC4CCCCO4)CC3)c2n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a stirred solution of (1-Pyrrolo[2,3-d]pyrimidin-7-yl-cyclopropyl)-methanol (Preparation 247, 240 mg, 1.27 mmol) in THF (12 mL) was added 3,4-dihydro-2H-pyran (0.46 mL, 5.07 mmol) followed by addition of PTSA (24 mg, 0.13 mmol). The reaction mixture was stirred at 60° C. for 4 hours. The reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution (15 mL) and extracted with dichloromethane (3×25 mL). The combined organic layer was washed with brine (10 mL), dried over sodium sulphate and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of dichloromethane:methanol 100:0 to 98:2) to afford the title compound as a light brown gum in 90% yield, 320 mg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C)C=O>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1cccc(O)c1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 96.5 %

Procedure:
3-Hydroxybenzaldehyde (3 g, 24.6 mmol) and potassium carbonate (10.2 g, 73.8 mmol) were suspended in N,N-dimethylformamide (60 mL). 1-Bromobutane (3.17 mL, 29.5 mmol) was added to this suspension and stirred for 19 hours at room temperature. This mixture was partitioned into ethyl acetate and water. This organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (4.23 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C)=[C:4]([CH:12]2[CH2:14][CH2:13]2)[CH:3]=1.Cl>CCOC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH:12]2[CH2:14][CH2:13]2)[CH:3]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1C1CC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)cc1C1CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A suspension of N-(4-chloro-2-cyclopropylphenyl)acetamide (689 mg, 3.29 mmol) in 2M HCl (aq) (25 ml, 823 mmol) was stirred at 100° C. for 3 hrs and then 90° C. for 16 hrs. The resulting mixture was cooled to RT, diluted with EtOAc and water and the layers separated. The organic layer was extracted with 0.1 M HCl (aq) and the organic portion was discarded. To the combined aqueous portions was added 2M NaOH (aq) until basic and resulting mixture was extracted with EtOAc (2×). The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under vacuum to give the title compound as a dark yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1.CCN(CC)CC.[CH3:38][C:39](OC(C)=O)=[O:40].C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:10][CH2:9][C:7]1[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=1[CH2:11][N:12]([CH2:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=1)[CH:13]1[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:16][CH2:15][CH2:14]1)[CH2:2][NH:1][C:39](=[O:40])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccnc1CN(Cc1ccc(CN)cc1CO)C1CCCc2cccnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(CN(Cc2ncccc2C)C2CCCc3cccnc32)c(CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.6 %

Procedure:
To a solution of (5-aminomethyl-2-{[(3-methyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol (0.0980 g, 0.25 mmol) in CH2Cl2 (3 mL) was added Et3N (0.05 mL, 0.38 mmol), KI (0.0042 g, 0.03 mmol), and Ac2O (0.0237 mL, 0.25 mmol). After stirring at room temperature for 18 hours, saturated NaHCO3 (10 mL) was added and extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (100:1:1 CH2Cl2-MeOH—NH4OH) provided 74.0 mg (64%) of COMPOUND 422 as a white solid. 1H NMR (CDCl3) δ 1.56-1.64 (m, 2H), 1.98 (s, 4H), 2.15-2.19 (m, 2H), 2.24 (s, 3H), 2.60-2.80 (m, 2H), 3.66-3.71 (m, 2H), 3.78-3.91 (m, 2H), 4.15 (d, 2H, J=12.3 Hz), 4.33-4.37 (m, 2H), 5.75 (s, 1H), 7.00-7.11 (m, 3H), 7.21 (s, 1H), 7.32 (d, 2H, J=7.5 Hz), 7.42 (d, 2H, J=7.2 Hz), 8.36 (t, 2H, J=5.1 Hz).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH2:5](N)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N>>[CH2:5]([NH:1][C:2]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(N)=O
Reactant: NCc1ccccc1
Agent: N
Product: O=C(NCc1ccccc1)NCc1ccccc1
Yield: 599.4 %

Procedure:
Heated was a mixture of urea 5.84 g (9.72 mmol) and benzylamine 25.0 g (23.3 mmol, 2.4 equivalents) at 150° C.-155° C. for 5 hours attaching with an air cooler. During the heating, observed was the ammonia gas evolution from colorless liquid reaction mixture. By cooling, it turned solidified at around room temperature. Purified was the reaction product by recrystallization from ethanol-benzene (1:1 mixture) to give N,N′-dibenzylurea 14.0 g as white fine needles (59.9% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[C:22]([C:24]2[C:29]([I:30])=[C:28]([N:31]([CH3:35])[C:32](=[O:34])[CH3:33])[C:27]([I:36])=[C:26]([N:37]([CH3:41])[C:38](=[O:40])[CH3:39])[C:25]=2[I:42])[CH:21]=[C:20]([N+:43]([O-])=O)[C:5]=1[C:6]([C:8]1([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]1[NH2:11])[OH:9])=[O:7])([O-])=O.[H][H]>[Pd]>[NH2:43][C:20]1[CH:21]=[C:22]([C:24]2[C:25]([I:42])=[C:26]([N:37]([CH3:41])[C:38](=[O:40])[CH3:39])[C:27]([I:36])=[C:28]([N:31]([CH3:35])[C:32](=[O:34])[CH3:33])[C:29]=2[I:30])[CH:23]=[C:4]([NH2:1])[C:5]=1[C:6]([C:8]1([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]1[NH2:11])[OH:9])=[O:7]
Reactant: CC(=O)N(C)c1c(I)c(-c2cc([N+](=O)[O-])c(C(=O)C3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3N)c([N+](=O)[O-])c2)c(I)c(N(C)C(C)=O)c1I
Reactant: [H][H]
Agent: [Pd]
Product: CC(=O)N(C)c1c(I)c(-c2cc(N)c(C(=O)C3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3N)c(N)c2)c(I)c(N(C)C(C)=O)c1I

Procedure:
2,6-dinitro-4-[3′,5′-bis(N-methylacetamido)-2′,4′,6′-triiodophenyl]-benzoyl-D-glucosamine (15) is catalytically reduced by hydrogen in the presence of palladium on charcoal to yield 2,6-diamino-4-[3′,5′-bis(N-methylacetamido)-2′,4′,6′-triiodophenyl]-benzoyl-D-glucosamine (16).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24]1[N:25]([CH:30]2[CH2:33][CH2:32][CH2:31]2)[N:26]=[C:27]([CH3:29])[CH:28]=1)=[O:4].[OH-].[Li+]>CO>[CH:30]1([N:25]2[C:24]([N:6]3[CH2:7][C@H:8]([S:10]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=4[C:20]([F:21])([F:22])[F:23])(=[O:11])=[O:12])[CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])=[CH:28][C:27]([CH3:29])=[N:26]2)[CH2:31][CH2:32][CH2:33]1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1c1cc(C)nn1C1CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)O)n(C2CCC2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide avoiding methanol as a cosolvent to give the title compound as yellow foam which was used in the next step without further purification. MS (ESI): m/z=476.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[O:8][C@H:9]3[CH:19]([OH:20])[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH2:12][C@H:10]3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C)(C)C.C(O)(C)C>C(Cl)Cl>[C:1]1([C:7]2[O:8][C@H:9]3[C:19](=[O:20])[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH2:12][C@H:10]3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1c2ccccc2C[C@H]2N=C(c3ccccc3)O[C@@H]12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CC(C)(C)O
Product: O=C1c2ccccc2C[C@H]2N=C(c3ccccc3)O[C@@H]12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under argon to a solution of (±)-(3aR,9aR)-3a, 4,9,9a-tetrahydro 2-phenyl-naphth-[2,3-d]oxazol-9-ol in methylene chloride (10 ml) was added Dess Martin periodinane (640 mg) and tert-butylalcohol (56 mg). After 5 hours stirring at room temperature, isopropanol was added and the reaction mixture was filtered on a silica gel column (elution with cyclohexane: ethyl acetate, 40:1). Evaporation of solvents gave the title compound as an oil (150 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([NH:22][C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=O)[CH:19]=[N:18]2)=[CH:13][CH:12]=1>C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([N:22]3[C:26](=[O:28])[CH2:25][CH2:24][C:23]3=[O:29])[CH:19]=[N:18]2)=[CH:13][CH:12]=1
Reactant: CC1CCCN1CCCOc1ccc(-n2cc(NC(=O)CCC(=O)O)cn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC1CCCN1CCCOc1ccc(-n2cc(N3C(=O)CCC3=O)cn2)cc1
Temperature: 25 °C

Procedure:
A solution of 1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1H-pyrazol-4-ylamine obtained in the same manner as shown in Example 29-(1) (0.186 g) and succinic anhydride (0.074 g) in toluene (12 mL) was stirred under heating at reflux for 4 hours. The reaction mixture was cooled in an ice bath, and the precipitated crystal was collected by filtration and washed with toluene to give N-(1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1H-pyrazol-4-yl)succinamic acid (0.191 g) as a colorless powder. A suspension of N-(1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1H-pyrazol-4-yl)succinamic acid thus obtained (0.108 g) in acetic anhydride (5.4 mL) was stirred under heating at reflux for 30 minutes. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: hexane:ethyl acetate=1:1). The resulting solid was washed with diisopropyl ether to give the titled compound (0.044 g) as a colorless powder.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[Na].[Li]>>[C:12](#[N:13])[C:6]1[C:7](=[CH:10][CH:11]=[CH:4][CH:5]=1)[C:8]#[N:9]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: [Li]
Agent: [Na]
Product: N#Cc1ccccc1C#N

Procedure:
Phthalonitrile compound 123 was synthesized in the same manner as in Example 11, except that 4-nitrophthalonitrile was used instead of the 3-nitrophthalonitrile used in Example 11, and that operation of salt-exchange from a sodium salt into a lithium salt was further conducted.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[C:6]3=[C:7]([CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][N:5]3[C:4](=O)[CH2:3]1)[CH:8]=[CH:9][CH:10]=2>O1CCCC1>[CH3:1][C:2]1([CH3:24])[C:11]2[C:6]3=[C:7]([CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][N:5]3[CH2:4][CH2:3]1)[CH:8]=[CH:9][CH:10]=2
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)CC(C)(C)c3cccc(c32)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2CCC(C)(C)c3cccc(c32)C1
Yield: 57.7 %

Procedure:
A solution of 38 mg (0.115 mmol) tert-butyl 8,8-dimethyl-6-oxo-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate of step 1.2 in 1 mL of tetrahydrofuran was treated with 0.46 mL of 1 molar solution of borohydride-tetrahydrofuran complex in tetrahydrofuran. The mixture was stirred over night, and then quenched with water and diluted hydrochloric acid. The pH was adjusted to pH 9 by addition of aqueous sodium hydroxide solution and the mixture extracted three times with 10 mL of dichloromethane each. The solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica (eluent: 20-30% ethyl acetate in heptane) to yield 21 mg of the title compound as a clear oil.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][C:14]2=[O:17])=[CH:9][CH:8]=1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[O:17])[NH:1][C:15]=2[CH:16]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)NC(=O)CCC2
Yield: 71.1 %

Procedure:
4 g of sodium azide are added portionwise to 8.3 g of 7-methoxy-1-tetralone in 36 ml of acetic acid. Then 17 ml of concentrated sulphuric acid are added dropwise, without a rise in temperature over 40°; the solution is poured onto ice and neutralised with 2 N sodium hydroxide solution. The separating bulk of crystals is removed and recrystallised from ethyl acetate. One obtains 6.4 g of 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (m.p. 137°-138°).
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:13]>O>[NH:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:13])[NH2:3]
Reactant: NN
Reactant: Cc1cc(C#N)ccc1F
Solvent: O
Product: Cc1cc(C#N)ccc1NN
Temperature: 100 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
Hydrazine monohydrate (180 mL) was added to 4-fluoro-3-methylbenzonitrile (5.0 g), followed by stirring at 100° C. for 4 hr. Water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain compound (154a) (4.33 g, 79%).
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1.[BH4-].[Na+].C([O-])(=O)C.[NH4+]>C(O)C>[OH:10][CH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [NH4+]
Solvent: CCO
Product: O=Cc1cccc(CO)c1
Reaction time: 1 h
Yield: 46.3 %

Procedure:
To isophthalaldehyde (200 g) in absolute ethanol (3 L) at 0° C. was added NaBH4 (15.6 g). After 1 hour at O° C. the reaction mixture was poured onto 25% aqueous ammonium acetate (2 L). The ethanol was evaporated and the product was extracted with EtOAc. The resulting mixture was purified by flash chromatography (30% EtOAc/Hexane) to provide 94 g of the title product.