Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:19]=2)[NH:16][C:15]([C:24]2[S:25][CH:26]([CH2:29][C:30]([OH:32])=O)[CH2:27][N:28]=2)=[CH:14]3)=[CH:6][CH:5]=1.Cl.C(N=C=N[CH2:39][CH2:40][CH2:41][N:42](C)C)C.ON1C2C=CC=CC=2N=N1.C1(N)CC1>O.CN(C)C=O>[CH:41]1([NH:42][C:30](=[O:32])[CH2:29][CH:26]2[S:25][C:24]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[CH:12][C:11]([O:10][C:7]3[CH:8]=[N:9][C:4]([CH2:3][O:2][CH3:1])=[CH:5][CH:6]=3)=[CH:19][C:18]=4[O:20][CH:21]([CH3:23])[CH3:22])=[N:28][CH2:27]2)[CH2:39][CH2:40]1
Reactant: COCc1ccc(Oc2cc(OC(C)C)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCc1ccc(Oc2cc(OC(C)C)c3[nH]c(C4=NCC(CC(=O)NC5CC5)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.2 %

Procedure:
A mixture of {2-[5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg), 1-hydroxybenzotriazole (130 mg), cyclopropylamine (75 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (170 mg, 52%) as pale yellow prisms. MS 495 (MH+). mp 100-101° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15](I)[CH:14]=2)=[C:7]([Br:21])[CH:6]=1.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]3[O:19][C:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:30][C:15]=3[CH:14]=2)=[C:7]([Br:21])[CH:6]=1
Reactant: C#Cc1ccccc1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(O)c(I)c2)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1cc(Br)c(Oc2ccc3oc(-c4ccccc4)cc3c2)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
Methyl[3,5-dibromo-4-(4-hydroxy-3-iodophenoxy)phenyl]acetate (730 mg, 1.3 mmol), phenylacetylen (210 mg, 2.1 mmol) and bis(triphenylphosphine)palladium (II) chloride (82 mg, 0.12 mmol), copper (I) iodide (32 mg, 0.17 mmol) and triethylamine (11 mL) was stirred at reflux. After 2 hours, dichloromethane (2 mL) was added to the reaction mixture, followed by further heating for 16 hours. The reaction mixture was allowed to cool down to room temperature, dissolved in dichloromethane and washed once with a saturated solution of aqueous ammonium chloride. The organic phase was dried over sodium sulphate and concentrated. The residue was purified on column (silica gel, gradient elution from chloroform/heptane 1:2, to chloroform/methanol 5:1), to give 600 mg (86%) of methyl[3,5-dibromo-4-(2-phenyl-5-benzofuranyloxy)phenyl]acetate as a pale yellow solid mass. 1H-NMR (300 MHz, DMSO-d6): δ 7.87 (d, J=7.4 Hz, 2H), 7.76 (s, 2H), 7.61 (d, J=9.2 Hz, 1H), 7.53 (t, 3H), 7.42 (d, J=7.1 Hz, 1H), 7.35 (s, 1H), 6.90 (s, 1H), 3.82 (s, 2H), 3.67 (s, 3H).
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14](=[O:25])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[Cl:23][C:19]1[C:18]([F:24])=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][NH:15][C:14]([C@@H:13]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[NH:8]1)=[O:25].[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)NCc1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cccc(Cl)c1F)[C@@H]1C[C@H]2C[C@H]2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1R,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (6.35 g, 17.22 mmol) in CH2Cl2 (60 mL) was added TFA (13.18 mL, 172 mmol) and the solution was stirred at RT for 3 h. The crude reaction mixture was concentrated under vacuum, Et2O was added and the white precipitate was filtered off to give the desired compound as a TFA salt. MS (LC/MS): 287.0 [M+H]+, 285.1 [M−H]−; tR (HPLC conditions f) 1.27 min.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[O:33]1[CH2:37][CH2:36][CH:35]([C:38](Cl)=[O:39])[CH2:34]1>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:38]([CH:35]3[CH2:36][CH2:37][O:33][CH2:34]3)=[O:39])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C1CCOC1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C3CCOC3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, tetrahydrofuran-3-carbonyl chloride (26 mg, 197 μmol, 3 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Reprosil C18 column, 250×30 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (21.1 mg, 62% of theory).
Reaction SMILES: C[N:2]([C:4]([C:26](=O)[CH2:27]C)=[CH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:3].O.[CH3:31][NH:32]N>CO>[CH2:26]([C:4]1[N:2]([CH3:3])[N:32]=[CH:31][C:5]=1[S:6]([C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)(=[O:7])=[O:8])[CH3:27]
Reactant: CCC(=O)C(=CS(=O)(=O)c1ccc(OS(=O)(=O)c2ccc(C)cc2)cc1)N(C)C
Reactant: CNN
Solvent: O
Solvent: CO
Product: CCc1c(S(=O)(=O)c2ccc(O)cc2)cnn1C
Temperature: 25 °C
Yield: 43.2 %

Procedure:
A mixture composed of 4.3 g (0.01 mole) of 1-(N,N-dimethylamino)-1propionyl 2-(4-tosyloxybenzenesulfonyl)ethene is heated at reflux for 20 hours in 25 ml of methanol and 10 ml of water in the presence of 2.35 g (0.05 mole) of methylhydrazine. The mixture is allowed to cool to room temperature and then cooled in ice for 1 h. It is evaporated to dryness and 4.85 g of residue are thus obtained which are recrystallized from 250 ml of water and decolorized with 0.8 g of active charcoal. The product is filtered off and allowed to crystallize for 2 hours in ice. It is recrystallized again from 50 ml of dichloroethene. In this manner, 1.15 g of 5-ethyl 4-(4-hydroxybenzenesulfonyl)1-methyl pyrazole is obtained which represents a yield of 43.2%. M.p.: 188.5°-190° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:32])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[CH:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClS([N:37]=[C:38]=O)(=O)=O.CN(C)C=O.Cl>ClCCl>[Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:32])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[C:38]#[N:37])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2)c1Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2C#N)c1Cl)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]pyrrole (1.20 g) in anhydrous dichloromethane (12 ml) was added a solution of chlorosulfonyl isocyanate (0.28 ml) in anhydrous dichloromethane (2.8 ml) dropwise in a dry ice-carbon tetrachloride bath. The mixture was stirred at the same temperature for 30 minutes and then at ambient temperature for additional 1 hour. Anhydrous dimethylformamide (0.4 ml) was added to this mixture dropwise in a dry ice-carbon tetrachloride bath. After stirring at the same temperature for 30 minutes and at ambient temperature for additional 1 hour, the reaction mixture was treated with 4N-hydrochloric acid under ice-water cooling for 30 minutes. The organic layer was isolated and the aqueous layer was extracted with chloroform twice. The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluted with n-hexane-ethyl acetate to give 1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]-2-cyanopyrrole (930 mg) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH:7]([C:12]([O:14]C)=[O:13])[C:8]([O:10]C)=[O:9])=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([C:8]([OH:10])=[O:9])[C:12]([OH:14])=[O:13])=[CH:16][CH:17]=1
Reactant: COC(=O)C(Cc1ccc(Br)cc1)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(Cc1ccc(Br)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A mixture of dimethyl 2-(4-bromobenzyl)malonate (22 g, 73.33 mmol, 1.00 equiv) and potassium hydroxide (12.3 g, 219.64 mmol, 3.00 equiv) in ethanol (140 mL) and water (140 mL) was stirred at 60° C. overnight. The resulting solution was diluted with 300 mL of ice and water then extracted with 1×500 mL of ethyl acetate. The organic layer was washed with 2×150 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 18.2 g (91%) of 2-(4-bromobenzyl)malonic acid as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>CN(C)C=O.ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
A solution of 2-benzyloxyphenol (6.01 g, 30 mmol) in anhydrous N,N-dimethylformamide (25 mL) was treated with anhydrous potassium carbonate (7.6 g, 55 mmol), then with 4-fluoronitrobenzene (3.53 g, 25 mmol), and heated to 90° C. for 5 h under nitrogen. The solution was cooled to room temperature, diluted with dichloromethane (50 mL), and treated with DOWEX® 550A OH anion exchange resin (10 g) which had been washed dry with methanol. The mixture was stirred for 3 h, filtered, and the filtrate concentrated in vacuo (exhaustively at end to remove DMF). The residue was chromatographed on silica gel (eluted with 2:1 hexane/ethyl acetate) to afford 4-(2-benzyloxyphenoxy)nitrobenzene (6.40 g, 66%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:13](OC)[C:14](=[O:17])NC)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][Mg]Br.CCOCC>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14](=[O:17])[CH3:20])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(=O)C(OC)N(CC(=O)O)C(=O)OC(C)(C)C
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)CN(CC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of N-[(tert-butoxy)carbonyl]-N-[(methoxy)-(methyl)carbamoylmethyl]glycine (1.0 g, 3.6 mmol; Helvetica Chimica Acta 2000, 83 1825), in anhydrous THF (30 mL) under an atmosphere of nitrogen, a solution of methyl magnesium bromide in ether (2.6 mL, 3M, 7.8 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, cooled back to 0° C., quenched with aqueous HCl, and diluted with ether. The organic extract was washed with brine (pH adjusted to ˜4-5 with addition of aqueous sodium hydroxide), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([N:27]1[CH2:31][CH2:30][C@H:29]([F:32])[CH2:28]1)=[O:26])[C@H:10]([C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[Pt](=O)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([N:27]1[CH2:31][CH2:30][C@H:29]([F:32])[CH2:28]1)=[O:26])[C@H:10]([CH:12]1[CH2:24][CH2:23][CH:15]([C:16]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])[CH2:14][CH2:13]1)[CH3:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: CCCCOC(=O)c1ccc([C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N2CC[C@H](F)C2)cc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCCCOC(=O)C1CCC([C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N2CC[C@H](F)C2)CC1

Procedure:
To a solution of the material prepared in Step A (2.8 g, 6.1 mmol) in acetic acid (100 mL) was added solid platinum(IV) oxide (0.75 g). The mixture was placed under 3 atm of hydrogen gas at ambient temperature for 36 h. The mixture was filtered through Celite, and the resulting solution was concentrated in vacuo affording the title compound as a 2:1 mixture of cis and trans cyclohexyl diastereomers, which was used without further purification.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]([C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:35]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C:37](O)=[O:38].ON1C(=O)CCC1=O.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH:35]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C:37]([NH:12][C@H:13]([C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])=[O:22])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:38]
Reactant: N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 4 °C
Yield: 65.5 %

Procedure:
A mixture of p-toluenesulfonic acid salt of Phe-Gly-OBzl (3.06 g), Boc-Gly-OH (1.10 g), N-hydroxysuccinimide (941 mg), N-methylmorpholine (0.725 ml), and N,N-dimethylformamide (40 ml) was cooled to 4° C., and added with N,N′-dicyclohexylcarbodiimide (1.56 g). The mixture was allowed to react overnight at room temperature with stirring, and then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=98:2 solution) to give Boc-Gly-Phe-Gly-OBzl (1.93 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[N+:15]([CH3:18])([O-])=O.[OH-].[Na+].C(O)(=O)C>C(O)C>[OH:7][CH:6]([C:5]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:18][NH2:15]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(C(O)CN)cc(OC)c1OC
Temperature: 0 °C

Procedure:
A solution of 3,4,5-trimethoxybenzaldehyde (10 g, 51 mmol) and nitromethane (10 mL) in ethanol at 0° C. was treated with 10% sodium hydroxide (21.4 mL, 53.5 mmol), stirred for 45 sesonds, treated with 2% acetic acid (162 mL), stirred for 1 hour in the ice bath, and filtered. The solid was washed with water and dried under vacuum to provide 9.0 g of the desired product as an off-white solid.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=O)(C)(C)C.Cl>CCOC(C)=O.CO>[CH:20]1([C:18]([NH:17][CH2:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][NH2:8])=[CH:15][CH:14]=2)=[O:19])[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)C2CC2)cc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: NCc1ccc(CNC(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
Dissolve N-(tert-butoxycarbonyl)-4-[(cyclopropanecarbonyl-amino)-methyl]-benzylamine (529 mg, 1.74 mmol) in EtOAc (20 mL) and MeOH (15 mL). Bubble hydrogen chloride through the solution for 15 min, and stir the mixture overnight at room temperature. Concentrate the mixture in vacuo and dissolve the resulting solid in water. Adjust the pH to 9-11 with 20% aqueous K2CO3 (w/w %) and extract three times with chloroform/iso-propanol (3:1). Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (40 g, pre-packed cartridge) eluting with DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) (1:0 over 5 min, 19:1 over 5 min, 9:1 over 5 min, 4:1 over 5 min, 1:1 over 10 min, 1:3; 50 mL/min) to obtain the desired intermediate (275 mg, 77%). MS (APCI+) m/z: 188 (M-NH3+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1I)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[N:7]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[Cl:20])[CH2:15][CH:16]1[CH2:18][CH2:17]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N(CC1CC1)c1cnccc1I
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CC1CC1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from cyclopropylmethyl-(4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Light yellow oil (85%). MS (ESI): m/z=359.152 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9](O)(=O)[CH2:10][OH:11]>C(OCC)(=O)C>[OH:11][CH2:10][C:9]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: O=C(O)CO
Reactant: Nc1ccccc1S
Solvent: CCOC(C)=O
Product: OCc1nc2ccccc2s1
Yield: 69.5 %

Procedure:
60 g of 2-aminothiophenol and 36.6 g of glycolic acid were heated at 130° C. in a sealed tube for 12 h. The reaction product was dissolved in ethyl acetate and dried over sodium sulfate and the solvent was concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give 55 g of the titled compound in the form of white crystals.
Reaction SMILES: C1COCC1.C([O:14][CH2:15][C:16]1([CH3:26])[O:25][CH2:24][C:19]2([O:23][CH2:22][CH2:21][O:20]2)[CH2:18][O:17]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[CH3:26][C:16]1([CH2:15][OH:14])[O:17][CH2:18][C:19]2([O:20][CH2:21][CH2:22][O:23]2)[CH2:24][O:25]1
Reactant: CC1(COC(=O)c2ccccc2)OCC2(CO1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(CO)OCC2(CO1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a THF (10 ml) and methanol (5 ml) solution of the (8-methyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)methyl benzoate (1.92 g, 6.52 mmol) obtained in the step (5b), a 1N aqueous sodium hydroxide solution (10 ml, 10 mmol) was added and stirred at room temperature for one hour. The reaction mixture was extracted with dichloromethane (50 ml) four times, dried over anhydrous sodium sulfate, and then, concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate=1/1-0/1 gradient) and desired fractions were concentrated to obtain the title compound (1.12 g, 90.0% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[O:22]1[CH2:25][C:24](=[O:26])[CH2:23]1>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([C:24]4([OH:26])[CH2:25][O:22][CH2:23]4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: O=C1COC1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Product: COC(=O)c1nc2n(c1C1(O)COC1)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (0.3 g) was reacted with oxetan-3-one similar to as described in example 8 with non-critical modifications to produce methyl 10-bromo-9-fluoro-3-(3-hydroxyoxetan-3-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. This crude intermediate was reacted via General Procedure L to provide 10-bromo-9-fluoro-3-(3-hydroxyoxetan-3-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was reacted as a crude with 2-Methyl-3-butyne-ol via General Procedure F to afford 23 mg (51.1%) 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-(3-hydroxyoxetan-3-yl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][NH2:5].[C:6]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7]1>CO>[SH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:13])[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: NCCCS
Reactant: O=C1CCCC(=O)O1
Solvent: CO
Product: O=C(O)CCCC(=O)NCCCS
Temperature: 25 °C
Yield: 126.7 %

Procedure:
To a solution of 6.84 g (0.075 mole) of 3-mercapto propyl amine (homocysteamine) in 20 cm3 of methanol, maintained under an inert atmosphere and stirred at ambient temperature, there are added, by portions, 8.56 g (0.075 mole) of glutaric anhydride while maintaining the temperature of the reaction mixture lower than 40° C. After stirring for 6 hours 30 minutes the reaction is complete. The solution is evaporated to dryness under reduced pressure. The product is then dried under a vacuum at a temperature lower than 60° C. and 19.5 g of N-(3-mercapto propyl) glutaramic acid are obtained in the form of a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][C:5]=1[F:13])(=[O:3])[CH3:2].C(O)(=O)C.[Br:18]Br>CO>[Br:18][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][C:5]=1[F:13])=[O:3]
Reactant: CC(=O)c1ccc(B(O)O)cc1F
Reactant: BrBr
Solvent: CO
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(B(O)O)cc1F
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
An oven-dried, 500-milliliter, 3-necked, round-bottomed flask was charged with 5 grams (27.4 millimole) of 4-acetyl-3-fluorophenyl boronic acid and 25 milliliters of methanol under a nitrogen atmosphere. The solution was cooled to 0° C. using an ice bath. To this solution was added 0.2 milliliters (0.55 equivalents) of glacial acetic acid. In a 100 milliliters Erlenmeyer flask was taken 1.27 milliliters (3.95 grams, 24 millimole, 0.9 equivalents) of elemental bromine dissolved in 4 milliliters of cold methanol. The bromine solution was added dropwise to the above solution at 0° C. using an addition funnel. With the addition of Br2, the solution slowly turned light orange and finally to dark orange when addition was complete. After about 5-6 hours, the progress of the reaction was monitored by NMR. Depending on the progress of reaction, another 10-20 mole % of bromine was added after cooling the solution to 0° C. Total reaction time was approximately 24 hours.