Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:20][O:19][C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:4][CH2:5][C:6](=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[O:2]1.[NH2:21][C@H:22]([C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])[CH3:23]>>[CH2:10]([O:9][C:7]([CH:6]([NH:21][C@H:22]([C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])[CH3:23])[CH2:5][CH2:4][C:3]1([O:19][CH2:20][CH2:1][O:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)C(=O)CCC1(c2ccccc2)OCCO1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Product: CCOC(=O)C(CCC1(c2ccccc2)OCCO1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
The process described in Example 17 was repeated using ethyl 5,5-ethylenedioxy-2-oxo-5-phenylpentanoate and L-alanyl-L-proline as starting materials. There was thus obtained as an oil N-[1-ethoxycarbonyl-4,4-ethylenedioxy-4-phenylbutyl]-L-alanyl-L-proline.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:12][CH2:11]1)[CH3:8])([CH3:4])([CH3:3])C.Cl.ClC(OC1C=[CH:31][C:30]([Cl:33])=[CH:29]C=1)=O>CO.O>[Cl:33][C:30]1[CH:31]=[CH:3][C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][C@H:10]2[CH2:11][CH2:12][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:14][CH2:15]2)[CH3:8])=[CH:4][CH:29]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CN(C[C@H]1CC[C@H](CCCCO)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: CN(C[C@H]1CC[C@H](CCCCO)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the reactions described in examples 1.5 and 1.7 trans-[4-(4-hydroxy-butyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester (example 3.2) was treated with hydrogen chloride solution in methanol/water followed by acylation with 4-chlorophenyl chloroformate giving trans-[4-(4-hydroxy-butyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 354 (MH+, 1Cl).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([Br:10])[CH:4]=1.CN(C)[CH:13]=[O:14]>C(Cl)Cl>[Br:10][C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([Br:9])[CH:6]=1)[CH:13]=[O:14]
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Mg]
Solvent: ClCCl
Product: O=Cc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
1.344 G (56 mM) of magnesium was added to a solution of 15-7 G(50 mM) of 1,3,5-tribromobenzene and the mixture was stirred at room temperature after 5 hours, most of the metal was digested. To the resulting brown Grignard solution was added 7.5 mL (0.1M) of N,N-dimethylformamide at 0° under nitrogen. The resulting mixture was stirred overnight at room temperature. Solvent was removed in vacuo at room temperature. The residue was taken up in 200 mL of ethyl acetate and washed with 6×50 mL of saturated sodium chloride solution, dried over anhydrous MgSO4. Solvent was removed to give a crude solid, which was dissolved in minimum amount of CH2Cl2 and applied on silica gel. Elution with 1:9 mixture of ether:hexane containing methylene chloride gave 45% yield of the desired aldehyde as white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([C:12]1[C:17]([Cl:18])=[N:16][C:15](Cl)=[CH:14][N:13]=1)=[O:11].[CH3:20][O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30]>CN(C=O)C>[CH3:20][O:21][C:22](=[O:31])[CH:23]([C:15]1[CH:14]=[N:13][C:12]([C:10](=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[Cl:3])=[C:17]([Cl:18])[N:16]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30]
Reactant: COC(=O)Cc1ccccc1F
Reactant: O=C(c1ccccc1Cl)c1ncc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1cnc(C(=O)c2ccccc2Cl)c(Cl)n1)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of sodium hydride (0.175 g, 7 mmol) and (2-Chloro-phenyl)-(3,5-dichloro-pyrazin-2-yl)-methanone (0.86 g, 2.99 mmol) in 5 mL DMF was added (2-Fluoro-phenyl)-acetic acid methyl ester (0.503 g, 2.99 mmol). The reaction mixture was stirred for one hour at room temperature, and then was quenched by addition of water and aqueous HCl. The aqueous mixture was extracted with methylene chloride, and the combined organic phases were dried over MgSO4, filtered, and evaporated under reduced pressure to give 1.19 g of crude [6-Chloro-5-(2-chloro-benzoyl)-pyrazin-2-yl]-(2-fluoro-phenyl)-acetic acid methyl ester. Mass Spec. M+H=419.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]([CH2:18][CH3:19])[C:3]1=[O:20].C(N(CC)CC)C.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30]>O1CCCC1>[CH:9]1([C:7]2[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[N:4]([CH2:18][CH3:19])[C:3](=[O:20])[CH:2]([NH:1][C:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)=[O:30])[N:8]=2)[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CCN1C(=O)C(N)N=C(C2CCCC2)c2ccccc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
A solution of crude 3(R,S)-amino-5-cyclopentyl-l,3-dihydro-1-ethyl-2H-1, 4-benzodiazepin-2-one [Example 5, Step 5] (0.23 g, 0.92 mmol) in dry tetrahydrofuran (15 ml) under an atmosphere of nitrogen, at 0° C., was treated with triethylamine (0.11 ml, 0.92 mmol) followed by a solution of 4-nitrophenyl chloroformate (184 mg, 0.92 mmol) in tetrahydrofuran (10 ml). After stirring at ambient temperature for 30 min the solid which precipitated was removed by filtration and the tiltrate concentrated in vacuo to afford the title compound (0.32 g, 79%) as a colourless solid. mp 136°-138° C. 1H NMR (360 MHz, CDCl3) δ 0.9 (3H, t, J=7 Hz), 1.0-2.2 (8H,m), 3.50 (1H, p, J=7 Hz), 3.70 (1H, m), 4.18-4.28 (1H, m), 5.14 (1H, d, J=8 Hz), 7.30-8.20 (8H, m), 9.12 (1H, d, J=8 Hz).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][CH:24]=O.[CH2:26]([NH2:31])[CH2:27][CH:28]([CH3:30])[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:29][CH:28]([CH3:30])[CH2:27][CH2:26][NH:31][CH2:24][CH2:23][CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:2]1=[O:1]
Reactant: O=CCCN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: CC(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)CCNCCCN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a solution of 3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propanal (0.34 g, 1.00 mmol) and isoamylamine (0.20 mL, 1.72 mmol) in 1,2-dichloroethane (20 mL) was added sodium triacetoxy borohydride (0.43 g, 1.92 mmol). The reaction mixture was stirred at ambient temperature for 18 h. The reaction was quenched with saturated sodium bicarbonate solution, and extracted with dichloromethane. The combined organic solution was washed with water, brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, the residue was subjected to column chromatography with ethyl acetate in hexanes (30% plus 1% 7 M ammonia in methanol) to afford 1′-{3-[(3-methylbutyl)amino]propyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.37 g, 91%). The compound was then converted to its hydrogen chloride salt (0.36 g) by treatment with hydrogen chloride (2 M solution in diethyl ether, 0.5 mL, 1.0 mmol): mp 98-101° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 8.79 (brs, 2H), 7.32-7.03 (m, 4H), 6.49 (s, 1H), 6.38 (s, 1H), 4.71 (ABq, 2H), 4.49-4.43 (m, 2H), 3.82-3.65 (m, 2H), 2.94-2.82 (m, 6H), 2.00-1.96 (m, 2H), 1.60-1.41 (m, 3H), 0.83 (d, J=9 Hz, 6H); MS (ES+) m/z 407.2 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[N:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1>N1C=CC=CC=1>[C:1]([NH:8][C:9]1[N:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Nc1ncc([N+](=O)[O-])cn1
Reactant: CCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ncc([N+](=O)[O-])cn1
Yield: 82.2 %

Procedure:
Valeroyl chloride (861 mg, 7.14 mmol) was added dropwise to a stirred suspension of 2-amino-5-nitropyrimidine (500 mg, 3.57 mmol) in pyridine (10 ml) and the reaction was heated at reflux for 4 hours under an inert atmosphere. The solvent was removed in vacuo and the residue stirred in 2N hydrochloric acid (100 ml) and extracted with ethyl acetate. Solvent evaporation in vacuo yielded 2-(N-pentanoyl)amino-5-nitropyrimidine (658 mg, 82% yield) as a brown solid:
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:15]([C:26](O)=[O:27])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:32]2N(O)N=[N:35][C:33]=2[CH:34]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.O>[CH:33]1([NH:35][C:26]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[C:16]=2[CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:27])[CH2:34][CH2:32]1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 188.6 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-(3-phenylpropyl)-1H-1,2,3-triazole-4-carboxylic acid (398 mg, 1.05 mmol) obtained in Example 100b), HOBt (71.8 mg, 0.526 mmol, 0.5 eq.) and cyclopropylamine (0.098 ml, 1.37 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 6 ml), WSC (247 mg, 1.26 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 12 hr. Water (20 ml) was added to the reaction mixture, and the mixture was stirred. The precipitate was collected by filtration, washed with water and dried to give the title compound as a white powder (414 mg, 0.992 mmol, 94.4%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([I:9])[C:6]([O:10][CH3:11])=[CH:5][CH:4]=1.O>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[I:9][C:7]1[C:6]([O:10][CH3:11])=[CH:5][CH:4]=[C:3]([CH:2]=[O:1])[N:8]=1
Reactant: COc1ccc(CO)nc1I
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C=O)nc1I
Yield: 44.8 %

Procedure:
175 g of manganese dioxide is added to a solution of 29 g of 6-hydroxymethyl-2-iodo-3-methoxypyridine in 600 ml of toluene, and the suspension is heated with stirring and refluxed for three hours on a water separator. The reaction mixture is filtered, the filter residue is washed with dichloromethane, the filtrate is dried on sodium sulfate and concentrated by evaporation. The crude product is chromatographed on silica gel with hexane/0-25% ethyl acetate. 12.9 g of 2-iodo-3-methoxypyridine-6-aldehyde of melting point 118°-121° C. is obtained.
Reaction SMILES: COC1C=C(NC2C3C(=C(C)C=C(S(C4C=CC=C(C(=O)NCCCCCCCC=O)C=4)(=O)=O)C=3)N=CC=2C(N)=O)C=CC=1.[OH:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][C:56]([S:59]([C:62]3[CH:63]=[C:64]4[C:69](=[C:70]([CH3:72])[CH:71]=3)[N:68]=[CH:67][C:66]([C:73]([NH2:75])=[O:74])=[C:65]4[NH:76][C:77]3[CH:82]=[CH:81][CH:80]=[C:79]([O:83][CH3:84])[CH:78]=3)(=[O:61])=[O:60])=[CH:55][CH:54]=2)=[CH:49][CH:48]=1>>[CH:46]([C:47]1[CH:48]=[CH:49][C:50]([C:53]2[CH:58]=[CH:57][C:56]([S:59]([C:62]3[CH:63]=[C:64]4[C:69](=[C:70]([CH3:72])[CH:71]=3)[N:68]=[CH:67][C:66]([C:73]([NH2:75])=[O:74])=[C:65]4[NH:76][C:77]3[CH:82]=[CH:81][CH:80]=[C:79]([O:83][CH3:84])[CH:78]=3)(=[O:60])=[O:61])=[CH:55][CH:54]=2)=[CH:51][CH:52]=1)=[O:45]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(-c5ccc(CO)cc5)cc4)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCC=O)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(-c5ccc(C=O)cc5)cc4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 112, using Intermediate 65 as a substrate. ES/MS calcd. for C31H26N3O5S+ 552.2. Found m/z=552.2 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][C:21]=1[OH:28].Cl>C(O)C.O.C(OCC)(=O)C>[CH2:7]([O:28][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:20]=1[O:19][CH2:18][CH2:17][CH2:16][F:15])[CH:24]=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1ccc(OCCCF)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCCCF)c(OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
Potassium carbonate (3.87 g, 28.0 mmol) and benzyl chloride (3.2 mL, 27.8 mmol) were added to a suspension of 4-(3-fluoropropoxy)-3-hydroxybenzaldehyde described in Production Example 33-1 (4.62 g, 23.3 mmol) in ethanol (46 mL) under nitrogen atmosphere at mom temperature, and the mixture was stirred at 90° C. for 1.5 hours. The reaction mixture was cooled to 0° C., then 2 M hydrochloric acid, ethyl acetate, and water were added for partition. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and then filtered. The solvent was evaporated and the resultant residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=9:1-3:2-1:1). The target fraction was concentrated under vacuum to obtain the title compound (6.14 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][N:16]([C:18]([O:20]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:15][CH:14]([C:30]([O:32][CH3:33])=[O:31])[CH2:13]1.[NH:34]1[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][N:16]([C:18]([N:34]2[CH2:39][CH2:38][S:37][CH2:36][CH2:35]2)=[O:20])[CH2:15][CH:14]([C:30]([O:32][CH3:33])=[O:31])[CH2:13]1
Reactant: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2F)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2F)CN(C(=O)N2CCSCC2)C1
Temperature: 150 °C

Procedure:
1.28 g (2.73 mmol) of the compound from Example 88A, 1.41 g (13.6 mmol) of thiomorpholine and 1.13 g (8.18 mmol) of potassium carbonate were added to 18 ml of DMF, and the mixture was heated in a single-mode microwave (Emrys Optimizer) at 150° C. for 40 minutes. For workup, the reaction solution was concentrated by rotary evaporation, and the residue was admixed with water. After addition of ethyl acetate and phase separation, the organic phase was washed with aqueous 1 N hydrochloric acid solution, dried (magnesium sulphate), filtered and concentrated under reduced pressure. This gave 946 mg of crude product in 72% purity (LC-MS), which was reacted without any further purification steps.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14].O>CN(C=O)C.C(Cl)Cl.CO.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][N:8]([S:22]([C:19]3[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=3)(=[O:23])=[O:24])[C:4]=2[CH:3]=1
Reactant: Brc1ccc2[nH]cnc2c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)n2cnc3ccc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Bromo-1H-benzimidazole (756 mg) was dissolved in anhydrous DMF (3 ml) and cooled in an ice bath. Sodium hydride (60% in mineral oil) (153 mg) was added in one portion. The reaction was stirred for 1 h, before addition of 4-nitrobenzenesulfonyl chloride (850 mg) in DMF (2 ml) to the reaction. The reaction was stirred for a further hour before warming to RT and addition of water (10 ml). The reaction was stirred vigorously then left at RT overnight. Ethyl acetate (ca. 10 ml) was added to the reaction mixture and was then vigorously stirred. The reaction was dissolved in DCM:methanol and passed through a 1 g SAX cartridge. The residue was purified on silica cartridge using cyclohexane:ethyl acetate with a 50-100% gradient. Fractions containing the product were combined and evaporated to dryness to afford the title compound, 401 mg.
Reaction SMILES: [CH3:1][CH:2]1[CH:14](O)[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[CH2:3]1)[CH:10]=[CH:9][CH:8]=[CH:7]3.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1>[CH3:1][C:2]1[CH2:3][C:4]2[C:5]([CH:14]=1)=[C:6]1[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7]1
Reactant: CC1Cc2ccc3ccccc3c2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1=Cc2c(ccc3ccccc23)C1
Temperature: 25 °C

Procedure:
A mixture of 2-methyl-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-ol (obtained as described above) and 1 g of p-toluenesulphonic acid in 200 mL of benzene was refluxed for 1 h. Then the reaction mixture was cooled to room temperature and treated with a saturated aqueous solution of Na2CO3. The organic phase was isolated, dried over MgSO4 and evaporated off to dryness. Yield 14.2 g (55% based on starting 2-methyl-2,3-dihydro-1H-cyclopenta[a]naphtalen-1-one).
Reaction SMILES: [NH2:1][CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C>O1CCOCC1>[N+:19]([C:18]1[C:13]([NH:1][CH2:2][N:3]2[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]2=[O:11])=[N:14][CH:15]=[CH:16][CH:17]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCCC1CC(=O)N(CN)C1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCC1CC(=O)N(CNc2ncccc2[N+](=O)[O-])C1
Yield: 52.6 %

Procedure:
A mixture of 1-(aminomethyl)-4-propylpyrrolidin-2-one x76 (1 eq, 17.09 mmol, 2.67 g), 2-chloro-3-nitropyridine (1 eq, 17.09 mmol, 2.709 g) and triethylamine (1.1 eq, 18.8 mmol, 1.902 g, 2.62 ml) in dioxane (20 ml) is refluxed 48 h. After cooling, the crude mixture is filtrated and the dioxane is distilled under vacuum. The residue is purified by preparative chromatography to afford 2.5 g of 1-{[(3-nitropyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one x77.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:30])[CH2:27][CH2:28][NH2:29])[CH2:22][CH2:21]2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)=[CH:6][CH:5]=1.[CH3:32][C:33]1[C:38]([C:39]([OH:41])=O)=[C:37]([CH3:42])[N:36]=[CH:35][N:34]=1>>[C:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][N:10]([CH:20]1[CH2:21][CH2:22][N:23]([CH:26]([CH3:30])[CH2:27][CH2:28][NH:29][C:39]([C:38]2[C:33]([CH3:32])=[N:34][CH:35]=[N:36][C:37]=2[CH3:42])=[O:41])[CH2:24][CH2:25]1)[C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=1)#[N:19]
Reactant: COC(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCN)CC2)cc1
Reactant: Cc1ncnc(C)c1C(=O)O
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1
Yield: 67.7 %

Procedure:
Using general procedure E with 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-benzoic acid methyl ester (see EXAMPLE 107) (300 mg, 0.71 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (119 mg, 0.78 mmol) followed by general procedure K with the resulting ester afforded 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid as a white solid (260 mg, 74%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CCO>[OH:20][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: OC1(c2ccccn2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: OC1(c2ccccn2)CCNCC1
Reaction time: 36 h
Yield: 93.9 %

Procedure:
A mixture of N-benzyl-4-hydroxy-4-(2-pyridyl)piperidine (1.2 g, 4.48 mmol), 20% Pd—C (0.2 g) and EtOH (100 mL) was stirred at H2 (150 psi ) for 36 h. The catalyst was removed by filtration and washed with more ethanol. Solvent was evaporated to give pure 4-hydroxy-4-(2-pyridyl)piperidine (0.75 g, 94%).
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:5])[OH:4])[CH3:2].[CH3:27][C:28]([CH3:35])([CH3:34])[C:29](=[O:33])[S:30][CH2:31]Cl>>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:4])[O:5][CH2:31][S:30][C:29](=[O:33])[C:28]([CH3:35])([CH3:34])[CH3:27])[CH3:2]
Reactant: CC(C)(C)C(=O)SCCl
Reactant: CCP(=O)(O)c1cc(Oc2ncc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Product: CCP(=O)(OCSC(=O)C(C)(C)C)c1cc(Oc2ncc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
In the same way, P-ethyl-2-nitro-5-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenylphosphinic acid is reacted with S-(chloromethyl) 2,2-dimethylpropanothioate to give 2,2-dimethylpropionylthiomethyl P-ethyl-2-nitro-5-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenylphosphinate.
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[CH:13]=[C:12]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2].[OH-].[Na+]>CO>[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][O:16][C:14]1[CH:15]=[C:10]([N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:6][C:7]([OH:9])=[O:8])[CH:11]=[C:12]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:13]=1)([OH:23])=[O:22]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCC(=O)OC)cc(N(CC(=O)O)CC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCC(=O)O)cc(N(CC(=O)O)CC(=O)O)c1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
A solution of 2.0 g (3.3 mmol) of N-(carboxymethyl)-N-[3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenyl]glycine and 2.8 ml (16.5 mmol) of 6N NaOH in 100 ml of methanol was stirred at reflux under argon for 16 hours. After cooling to room temperature, the precipitated sodium salt was removed by filtration, dissolved in 300 ml of water and the mixture was acidified with 4 ml of 6N HCl. The product was extracted with ethyl acetate and the dried extract was concentrated at reduced pressure to a solid which was recrystallized from acetone-hexane to give 1.8 g (92% yield, mp 126°-128°) of N-[3-(4-carboxybutoxy)-5-(octadecyloxy)phenyl]-N-(carboxymethyl)glycine.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: O=C1NCCCn2c1cc1cc(F)cc(Br)c12
Reactant: OB(O)c1ccc(F)c(F)c1
Product: O=C1NCCCn2c1cc1cc(F)cc(-c3ccc(F)c(F)c3)c12

Procedure:
The title compound, light yellow solid (79 mg, 96%), MS (ISP) m/z=331.1 [(M+H)+], mp 230.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-fluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 2) (74.3 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).