Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([N:16]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:19][CH2:18]3)[S:14][CH:15]=2)=[CH:7][CH:6]=1.Cl>>[ClH:1].[ClH:1].[ClH:1].[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([N:16]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][CH2:18]3)[S:14][CH:15]=2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCN(c1nc(-c2ccc(C=NN)cc2)cs1)C1CCN(CC(=O)OCC)CC1
Agent: Cl
Product: NN=Cc1ccc(-c2csc(N(CCC(=O)O)C3CCN(CC(=O)O)CC3)n2)cc1
Yield: 80 %

Procedure:
700 mg of ethyl 3-[N-{4-[4-(aminoiminomethyl)phenyl]-1,3-thiazol-2-yl}-N-(1-ethoxycarbonylmethyl-piperid-4-yl)amino]propionate hydrochloride (EXAMPLE 2) are added to 25 ml of 6N hydrochloric acid and the reaction mixture is heated under reflux for 5 hours. The mixture is evaporated to dryness and the residue is crystallized from acetone to give white crystals which melt at 215° C.; yield: 80%.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[H-].[Na+].Cl[C:29]1[N:30]([CH2:37][C@:38]2([CH3:41])[CH2:40][O:39]2)[CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[N:33]=1>CN(C=O)C>[CH3:40][C@@:38]1([CH2:41][O:21][C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:11][CH2:10][CH:9]([O:8][C:7]4[CH:22]=[CH:23][C:4]([O:3][C:2]([F:1])([F:24])[F:25])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)[O:39][C:29]2=[N:33][C:32]([N+:34]([O-:36])=[O:35])=[CH:31][N:30]2[CH2:37]1
Reactant: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COc2ccc(N3CCC(Oc4ccc(OC(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 54.6 %

Procedure:
4-[4-(4-Trifluoromethoxyphenoxy)piperidin-1-yl]phenol (17.4 g, 49.0 mmol) was dissolved in DMF (150 ml). To the solution, sodium hydride (2.15 g, 53.8 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 80° C. To the solution, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (14.9 g, 68.6 mmol) was added with cooling on ice-bath, and the solution was stirred for further 20 minutes at 80° C. To the reaction mixture, ice-water was added, and the mixture was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) and then crystallized from methylene chloride/ethyl acetate to afford (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (14.3 g, yield 55%) as a light yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([C:14](OC)=O)[C:9]1=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:27][C:28]([NH:30][C@H:31]([C:41]([OH:43])=O)[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:41](=[O:43])[C@H:31]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[NH:30][C:28]([O:27][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:29])[C@@H:10]([CH2:14][C:6]([O:5][CH3:1])=[O:19])[C:9]1=[O:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: COC(=O)[C@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)OC(C)(C)C)CCN1C(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 117.1 %

Procedure:
To a mixture of 28.8 g of (S)-3-methoxycarbonyl-2-oxopiperazine-1-acetic acid t butyl ester, 23.0 g of N-benzyloxycarbonyl-O-methyl-L-tyrosine and 202 ml of methylene chloride, 15.3 g of 1-(3-dimethylaminopropyl)-3-ehtylcarbodiimide was added. The mixture was stirred for 2 hours and concentrated under reduced pressure. The residue was disolved in ethyl acetate. The solution was washed with a 5% aqueous solution of potassium hydrogensulfate and a saturated sodium hydrogen carbonate. The organic layer was concentrated under reduced pressure to give 37.0 g of crude (S)-4-(N-benzyloxycarbonyl-O-methyl-L-tyrosyl)-3-methoxycarbonylmethyl-2-oxopiperazine-1-acetic acid t butyl ester. This product was dissolved in 74.0 ml of methylene chloride, to which was added 74.0 ml of trifluoroacetic acid. The mixture was stirred for one hour at room temperature. The reaction solution was concentrated under reduced pressure. The residue was subjected to azeotropy with toluene several times to afford 39.12 g of the title compound as a colorless oily product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:21]2[S:22][CH:23]=[C:24]([C:26](Cl)=[O:27])[N:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26]([C:24]1[N:25]=[C:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[S:22][CH:23]=1)=[O:27]
Reactant: O=C(Cl)c1csc(-c2ccccc2)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1csc(-c2ccccc2)n1
Yield: 65.8 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0441 g, 0.187 mmol), 2-phenylthiazole-4-carbonyl chloride (0.044 g; 0.187 mmol), and triethylamine (0.066 mL; 0.467 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 3 to 30% of ethyl acetate in dichloromethane gave 0.047 g (66%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-phenylthiazole-4-carboxamide as a solid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li].[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][N:25]=3)[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.IC>C1COCC1.CCCCCCC.C1COCC1.O>[CH3:1][C:19]1[N:18]([S:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:17])=[O:16])[C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][N:25]=2
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Reactant: CC(C)NC(C)C
Agent: [Li]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4.8 ml of a 2M solution of lithium diisopropylamine in THF/heptane are added dropwise over the course of 60 min. to a solution of 1 g of 1-(benzenesulfonyl)-7-azaindole in 20 ml of THF at −70° C. under an N2 atmosphere. The mixture is allowed to warm to 20° over the course of 50 minutes. The suspension is cooled to −70°, and a solution of 1.1, g of iodomethane in 20 ml of THF is added dropwise over the course of 20 minutes. The mixture is stirred at −70° for one hour and subsequently at room temperature for 14 h. The mixture is diluted with water and extracted with dichloromethane. The extract is dried over sodium sulfate, filtered, the solvent is removed and crystallised from cyclohexane, giving 0.68 g of 2-methyl-1-(benzenesulfonyl)-7-azaindole, M˜272.32 g/mol, M+H found 273, NMR corresponds.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@:13]2(CO)[C@@H:11]([CH2:12]2)[N:10]1[C:17](=[O:31])[CH2:18][N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[C:21]([C:28](=[O:30])[CH3:29])=[CH:20]1)=[O:8].[C:36]([O:40]C(N1[C@H](C(=O)N[C@@H](C2C=CC=C(Cl)C=2F)CO)C[C@@H]2[C@H]1C2)=O)(C)(C)C.ClCl.CCOC(C)=O>>[Cl:1][C:2]1[C:3]([F:35])=[C:4]([C@H:5]([NH:6][C:7]([C@@H:9]2[CH2:14][C@@H:13]3[C@@H:11]([CH2:12]3)[N:10]2[C:17](=[O:31])[CH2:18][N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28](=[O:30])[CH3:29])=[CH:20]2)=[O:8])[CH2:36][OH:40])[CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)N[C@H](CO)c1cccc(Cl)c1F
Reactant: CC(=O)c1cn(CC(=O)N2[C@H](C(=O)NCc3cccc(Cl)c3F)C[C@@]3(CO)C[C@@H]23)c2ncccc12
Agent: ClCl
Solvent: CCOC(C)=O
Product: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)N[C@H](CO)c2cccc(Cl)c2F)c2ncccc12

Procedure:
The title compound was prepared in 2 steps according to the procedure described for the preparation of Example 610 (1R,3S,5S)-2-[2-(3-acetyl-pyrrolo[2,3-b]pyridin-1-yl)-acetyl]-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide from (1R,3S,5R)-3-[(S)-1-(3-chloro-2-fluoro-phenyl)-2-hydroxy-ethylcarbamoyl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (prepared as described in Scheme B9). White powder. TLC, Rf (CH2/Cl2/EtOAc 9:1)=0.70; MS (UPLC/MS): 499.3/501.3 [M+H]+, 543.2/545.3 [M+HCOO]−; tR (HPLC conditions a): 3.02 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].Cl[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=1.O>C1COCC1>[O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=2)[CH2:3][CH2:2]1
Reactant: OC1CCOCC1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 35.4 %

Procedure:
Oxan-4-ol (0.302 g, 2.96 mmol) was dissolved in THF (5 mL) and cooled to 0 C under nitrogen. Potassium tert-butoxide (0.332 g, 2.96 mmol) was added and the mixture stirred for 5 min. Ethyl 6-chloronicotinate (0.500 g, 2.69 mmol) was added, the mixture was warmed to room temperature and stirred for 3 h. Water (5 mL) was added and the mixture extracted with EtOAc (2×10 mL). The organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with a gradient of 5-20% EtOAc in heptane to afford the title compound as a colourless oil (0.239 g, 35%). 1H NMR (250 MHZ, CDCl3) δ ppm 8.80 (1H, dd), 8.14 (1H, m), 6.73 (1H, dd), 5.25 (1H, m), 4.39 (2H, dq), 3.96 (2H, m), 3.60 (2H, m), 2.05 (2H, m), 1.81 (2H, m) and 1.40 (3H, dt).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](I)=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCOCC1>[Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1nc(Cl)[nH]c1I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [BH4-]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1c[nH]c(Cl)n1
Yield: 72.6 %

Procedure:
2-Chloro-5-iodo-4-nitroimidazole (273 mg) was suspended in 1,4-dioxane (5 ml), then tetra-n-butyl ammonium borohydride (515 mg) was added, the reaction mixture was heated and refluxed for 10 hours. Then diluted hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was treated with concentrated hydrochloric acid, the separated matters were collected by filtration. The filtrate was extracted with ethyl acetate, the separated matter obtained from the organic layer was combined together with the previously obtained solid matter and purified by use of a silica gel column chromatography (eluent: n-hexane/ethylacetate=3/1 to 2/1), there was obtained 2-chloro-4-nitroimidazole (107 mg, yield: 72.5%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([Cl:30])[CH:24]=1.C(N(CC)C(C)C)(C)C>ClCCl.O1CCCC1.CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([NH:27][C:26]1[CH:28]=[CH:29][C:23]([O:22][C:21]([F:20])([F:31])[F:32])=[CH:24][C:25]=1[Cl:30])=[O:10])#[N:2]
Reactant: COc1ccc(C#N)cc1C(=O)O
Reactant: Nc1ccc(OC(F)(F)F)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1C(=O)Nc1ccc(OC(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 2.7 h
Yield: 89.7 %

Procedure:
5-Cyano-2-methoxybenzoic acid (0.73 g) obtained in step A, and 16 μL of N,N-dimethylformamide were dissolved in 18 mL of dichloromethane, and the solution was cooled to 0° C. To this solution, 0.54 mL of oxalyl chloride was added little by little, and the mixture was stirred for 2.7 hours at room temperature. The reaction mixture was distilled under reduced pressure, and dried to obtain a light yellow solid. This solid was added, with the use of 10 mL of tetrahydrofuran, to a solution of 0.95 g of 4-trifluoromethoxy-2-chloroaniline and 2.1 mL of N,N-diisopropylethylamine dissolved in 20 mL of tetrahydrofuran. The mixture was stirred overnight at room temperature, and then tetrahydrofuran was distilled off under reduced pressure. The resulting solid was purified by silica gel column chromatography using methylene chloride as an elution solvent, thereby obtaining 1.37 g (90%) of 5-cyano-N-(4-trifluoromethoxy-2-chlorophenyl)-2-methoxybenzamide.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:22]2[C:10](=[C:11]([CH3:25])[C:12]3[N:13]([CH3:24])[C:14]4[CH:15]=[CH:16][C:17]([OH:23])=[CH:18][C:19]=4[C:20]=3[CH:21]=2)[CH:9]=[CH:8][N:7]=1)=O)C.[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31]>>[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:4]([C:6]1[C:22]2[C:10](=[C:11]([CH3:25])[C:12]3[N:13]([CH3:24])[C:14]4[CH:15]=[CH:16][C:17]([OH:23])=[CH:18][C:19]=4[C:20]=3[CH:21]=2)[CH:9]=[CH:8][N:7]=1)=[O:3]
Reactant: CCOC(=O)c1nccc2c(C)c3c(cc12)c1cc(O)ccc1n3C
Reactant: NCCCCN
Product: Cc1c2ccnc(C(=O)NCCCCN)c2cc2c3cc(O)ccc3n(C)c12

Procedure:
0.47 g (1.407 mmol) of the ester obtained in Step A of Example 11 are dissolved in 9 ml of 1,4-diaminobutane under an argon atmosphere. The mixture is heated at 130° for 3 hours.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25](=[O:34])[N:26]([CH3:33])[C:27](=[O:32])[N:28]([CH3:31])[C:29]=2[CH3:30])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1[C:13]([CH2:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:16])=[O:7].[OH-].[Na+]>C(O)C>[Cl:16][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14][CH3:15])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:35])=[O:2])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:25](=[O:34])[N:26]([CH3:33])[C:27](=[O:32])[N:28]([CH3:31])[C:29]=2[CH3:30])=[CH:22][CH:23]=1)=[O:7]
Reactant: CCc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
To a suspension of N-[(2-chloro-6-ethylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester (0.33 mmol, 164 mg) in ethanol (2 mL) was added aqueous 1.0 N sodium hydroxide (0.7 mL) at room temperature. The mixture was stirred for 3 h at room temperature. The ethanol was removed under reduced pressure and the residue was diluted with water (30 mL). The aqueous solution was washed with diethyl ether (30 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted into ethyl acetate (2×35 mL). The combined organic extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate afforded 138 mg (87% yield) of N-[(2-chloro-6-ethylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine as a white solid: mp 187-190° C. ES-HRMS m/e calcd for C25H26ClN3O5 (M+Na) 506.1459, found 506.1455.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[NH:14]([CH2:16]C(O)=O)[CH3:15]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:9])[CH2:15][N:14]([CH3:16])[C:7](=[O:8])[C:6]=2[CH:13]=1
Reactant: CNCC(=O)O
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Solvent: CS(C)=O
Product: CN1CC(=O)Nc2ccc(Cl)cc2C1=O
Temperature: 150 °C

Procedure:
A mixture of 5-chloroisatoic anhydride 401 (20 g, 101 mmol) and sarcosine (9.02 g, 101 mmol) in DMSO (160 mL) was heated at 150° C. for 5 hr, cooled to room temperature and poured into ice water (750 mL) to furnish a light brown precipitate. This solid was collected by filtration, washed with water (3×200 mL) and dried. The benzodiazepine 402 was obtained as a light brown solid (19 g, 84% yield). This material was used directly in the next experiment.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:42])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:42])[C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=3)[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: CCCCCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Product: CCCCCCCCc1ccc(C(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)cc1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.078 g, 0.282 mmol) was reacted with N-(2-azidoethyl)-4-octylbenzamide (0.085 g, 0.282 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-octylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.64 (s, 2H), δ 7.47 (s, 1H), δ 7.21 (s, 1H), δ 7.09 (s, 2H), δ 6.47 (bs, 3H), δ 4.48 (s, 2H), δ 3.84 (s, 2H), δ 2.53 (s, 4H), δ 2.28 (t, J=15.9 Hz, 2H), δ 1.51 (bs, 6H), δ 1.18 (bs, 10H), 0.77 (t, J=6.6 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 180.7, 180.2, 168.3, 147.4, 142.4, 139.2, 131.4, 128.8, 127.4, 107.4, 49.6, 40.2, 36.1, 32.1, 31.4, 29.9, 29.6, 29.5, 28.8, 28.2, 28.1, 25.4, 22.9, 14.3 ppm; HRMS (ESI) calcd for C32H49N7O3 (M+) 579.3896. found 579.3890, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-octylbenzamide hydrochloride (0.097 g, 67% yield). 1H NMR (400 MHz, CD3OD) δ 7.65 (s, 2H), δ 7.23 (s, 3H), δ 6.45 (s, 1H), δ 3.97 (s, 4H), δ 2.60 (s, 4H), δ 2.47 (s, 2H), δ 1.57 (m, 6H), δ 1.27 (bm, 12H), δ 0.83 (t, J=6.4 Hz, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 183.5, 172.0, 169.3, 161.8, 153.9, 147.4, 131.2, 128.5, 127.7, 127.3, 119.1, 108.8, 104.7, 94.6, 63.4, 38.7, 35.6, 31.8, 31.3, 29.3, 29.2, 29.1, 28.1, 27.7, 27.1, 24.2, 22.5, 13.3, 12.6 ppm; HRMS (ESI) calcd for C27H41N7O (M+) 479.3372. found 479.3378.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][C:14]([O:16]CC)=O)=[CH:7][CH:6]=1)[CH3:2]>C1(C(C2C=CC=CC=2)=O)C=CC=CC=1.C(OCC)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][C:12]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:13][C:14]2=[O:16])=[O:25])[CH3:2]
Reactant: CCOC(=O)CC(=Nc1ccc(C(=O)OCC)cc1)c1ccccc1
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1ccc2[nH]c(-c3ccccc3)cc(=O)c2c1
Temperature: 250 °C

Procedure:
4-Amino-benzoic acid ethyl ester (66 g, 0.4 mol) and 3-oxo-3-phenyl-propionic acid ethyl ester (0.4 mol, 1 eq.) were dissolved in 500 mL cyclohexane and refluxed for 2 days using a Dean-Stark trap. The solution was filtered, the solvent evaporated and the residue recrystallized to give 4-(2-ethoxycarbonyl-1-phenyl-ethylideneamino)-benzoic acid ethyl ester (Compound 481a) MS: 340.18 (M+H+). 4-(2-Ethoxycarbonyl-1-phenyl-ethylideneamino)-benzoic acid ethyl ester was dissolved in diphenyl-methanone (250 mL) and heated to 250° C. for 4 hr. The resulting solution was diluted with diethyl ether and filtered to give 48.6 g of the title intermediate as a white crystalline solid.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[OH-].[Na+].Cl.[N:16]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[C@@H:18]([NH:24][C:25]([C:27]1[O:28][C:29]3[CH:35]=[CH:34][C:33](Br)=[CH:32][C:30]=3[CH:31]=1)=[O:26])[CH2:17]2>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:16]12[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23]1)[C@@H:18]([NH:24][C:25]([C:27]1[O:28][C:29]3[CH:35]=[CH:34][C:33]([C:6]4[CH:7]=[CH:8][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][CH:5]=4)=[CH:32][C:30]=3[CH:31]=1)=[O:26])[CH2:17]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(Br)ccc2o1
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2ccc3oc(C(=O)N[C@H]4CN5CCC4CC5)cc3c2)cc1
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
120 mg (0.73 mmol) of 4-(dimethylamino)phenylboronic acid and 1.46 ml of 1N sodium hydroxide solution are added to a mixture of 170 mg (0.49 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzofuran-2-carboxamide (Example 3A) and 35 mg (0.05 mmol) of PdCl2(dppf) in 2 ml of DMF. The reaction mixture is heated at 85° C. overnight. The solvent is removed under reduced pressure. Addition of a mixture of 1N sodium hydroxide solution and ethyl acetate to the residue is followed by extraction of the aqueous phase once more with ethyl acetate. The combined organic phases are washed twice with each of 1N sodium hydroxide solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated in a rotary evaporator under reduced pressure. The crude product is taken up in methanol and shaken together with acidic ion exchanger (Dowex® WX2-200) for about 20 min. The loaded ion exchanger is washed three times with 30 ml of methanol each time, then with DMF, again with methanol, with dichloromethane, again with methanol, with water and finally with methanol again. The product is eluted with methanol/triethylamine 95:5. The solvent is removed in a rotary evaporator under reduced pressure. 138 mg (73% of theory) of the title compound are isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:25][O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH2:25][O:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)([OH:23])=[O:22]
Reactant: COC(=O)CCCCCNC(=O)C(COc1cccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(O)CCCCCNC(=O)C(COc1cccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Yield: 125.9 %

Procedure:
The procedure described in Example 115 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(5-methoxycarbonylpentyl)-3-(pyridin-3-yloxy)propanamide (46.6 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(5-carboxypentyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride (30.7 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[Cl:18][C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:17][C:2]([F:1])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:19]([Cl:18])=[O:21])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1ccc(N2CCNCC2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Cl)N1CCN(c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 300.8 %

Procedure:
A mixture of 1-(4-trifluoromethoxyphenyl)piperazine (1.0 g, 4.1 mmol), triphosgene (0.42 g, 1.4 mmol), and pyridine (0.66 ml, 8.2 mmol) in toluene (20 ml) was stirred at 100° C. for 4.5 hours. To which ethyl acetate was added, and the mixture was washed with water, dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 4-(4-trifluoromethoxyphenyl)piperazine-1-carbonylchloride (1.3 g, quantitative) as a brown oil.