Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])P(OC)(OC)=O.CC1(C)[O:26][C:25](=O)[CH:24]=[C:23]([CH3:28])O1.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:4]1[C:23]([CH3:28])=[CH:24][C:25](=[O:26])[N:11]1[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:19]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: COC(=O)C1C(C)=CC(=O)N1C(=O)OC(C)(C)C
Temperature: 23 °C
Yield: 86.2 %

Procedure:
A solution of tert-butoxycarbonylamino-(dimethoxy-phosphoryl)-acetic acid methyl ester (20.0 g, 67 mmol, 1 equiv), 2,2,6-trimethyl-[1,3]dioxin-4-one (43.96 ml, 47.8 g, 336 mmol, 5.0 equiv), and 2,6-lutidine (11.71 ml, 10.77 g, 101 mmol, 1.5 equiv) in toluene (200 ml) was heated at reflux for 16 h. The reaction mixture was allowed to cool to 23° C. and was concentrated. The residue was purified by flash column chromatography (5% ethyl acetate-dichloromethane initially, grading to 8% ethyl acetate-dichloromethane) to give 3-methyl-5-oxo-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (14.74 g, 86%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:30][OH:31])[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:34]I.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:30][O:31][CH3:34])[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2noc(-c3cc4c(CO)nccc4o3)n2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1nccc2oc(-c3nc(COC4CCN(C(=O)OC(C)(C)C)CC4)no3)cc12
Reaction time: 1.5 h

Procedure:
To a stirred solution of 4-[5-(4-hydroxymethylfuro[3,2-c]pyridine-2-yl)-[1,2,4]oxadiazole-3-ylmethoxy]piperidine-1-carboxylic acid tert-butyl ester (Example 24, 50 mg, 116 μmol) in THF was added sodium hydride (60% dispersion in mineral oil, 6 mg, 150 μmol). After effervescence had ceased, MeI (10 μL, 161 μmol) was added. After 90 min, the mixture was poured into H2O and extracted with EtOAc. The organic layer was separated, washed with brine, dried and concentrated. Purification via column chromatography afforded the title compound: RT=3.54 min; m/z (ES+)=445.1 [M+H]+.
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20](Br)=[O:21].[CH3:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>>[CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[CH2:19][C:20]([NH:27][CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=1[CH3:23])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1CN
Reactant: c1ccc(CC2NCCc3ccccc32)cc1
Reactant: O=C(Br)CBr
Product: Cc1ccccc1CNC(=O)CN1CCc2ccccc2C1Cc1ccccc1

Procedure:
prepared by reaction of 1-Benzyl-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methylbenzylamine
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.[NH2:31][OH:32]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[N:31][OH:32])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2ccc(C=O)cc2)cc1
Reactant: NO
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2ccc(C=NO)cc2)cc1

Procedure:
This compound was prepared from 4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-carbaldehyde, and hydroxylamine in substantially the same manner, as described in Example 1 step a, and was obtained as an off-white solid; MS m/e 422 (M+);
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[CH3:5][CH:6]([CH3:12])[CH2:7][CH2:8][C:9](=[O:11])[CH3:10].[CH2:13]=O.Cl.[OH-].[Na+]>CO.C(Cl)Cl>[CH3:2][N:3]([CH2:13][CH:8]([CH2:7][CH:6]([CH3:12])[CH3:5])[C:9](=[O:11])[CH3:10])[CH3:4]
Reactant: C=O
Reactant: CNC
Reactant: CC(=O)CCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)C(CC(C)C)CN(C)C
Temperature: 80 °C
Yield: 15.9 %

Procedure:
Dimethylamine HCl (90 g, 1.1 mol), 5-methyl-2-hexanone (450 mL, 3.3 mol), and paraformaldehyde (50 g, 1.7 mol) were suspended in MeOH (80 mL) and concentrated HCl (200 μL) was added. The reaction mixture was heated to 80° C. for 12 hours. The mixture was allowed to cool to room temperature and 10% NaOH was added until basic. The entire mixture was extracted with Et2O (100 mL, 2×). The organic layer was dried over MgSO4 and concentrated. The crude reaction mixture was columned via flash column chromatography (0.5:9.5 MeOH:CH2Cl2) to give 30 g (175 mmol) of 3-dimethylaminomethyl-5-methyl-hexan-2-one 1a in a 16% yield.
Reaction SMILES: CC(C)([O-])C.[K+].[N+]([O-])(O)=O.[CH3:11][C:12]1[CH:16]=[C:15]([CH3:17])[N:14]([C:18](=[NH:20])[NH2:19])[N:13]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]=[S:23]>CS(C)=O>[CH3:11][C:12]1[CH:16]=[C:15]([CH3:17])[N:14]([C:18]([NH:19][C:22]([NH:21][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[S:23])=[NH:20])[N:13]=1
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: CC(C)(C)OC(=O)NCCN=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O=[N+]([O-])O
Product: Cc1cc(C)n(C(=N)NC(=S)NCCNC(=O)OC(C)(C)C)n1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
554.7 mg (4.94 mmol) of potassium tert-butoxide are dissolved in 12 ml of DMSO while cooling slightly in ice, and then 596.8 mg (2.96 mmol) of 3,5-dimethyl-1H-pyrazole-1-carboximidamide nitrate are added. A clear solution is produced after stirring for about 5 minutes. Then 500 mg (2.47 mmol) of tert-butyl (2-isothiocyanatoethyl)carbamate are added, and the icebath is removed. The mixture is heated at 60° C. for a further 3 h and the solution obtained in this way is employed for the further subsequent reactions.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O[N:18]1C2C=CC=CC=2N=N1.O.N>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([NH2:18])=[O:15])[CH2:11][S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Reactant: On1nnc2ccccc21
Agent: N
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CSC[C@H]1C(N)=O
Yield: 71 %

Procedure:
(4R)-3-(tert-Butyloxycarbonyl)thiazolidine-4-carboxylic acid (12.5 g, 54.1 mmol) was dissolved in CH2Cl2/DMF (9:1, 150 ml). To this solution at 0° C. was added 1-hydroxybenzotriazole hydrate (14.6 g, 108 mmol) and water-soluble carbodiimide (13.0 g, 65 mmol). After 1 h at 0° C. ammonia (35%, 50 ml) was added. After 18 h at 0° C. to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (500 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant: 2% methanol, 98% chloroform) to give a colourless oil identified as the title compound (8.9 g, 38.4 mmol, 71%).
Reaction SMILES: [CH3:1][CH:2]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:16]([N:8]([CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCBr
Reactant: CCCCCC(C)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(C)N(CCCC)c1ccccc1
Yield: 44 %

Procedure:
A mixture of N-(1-methylhexyl)aniline (76 parts), 1-bromobutane (66 parts), anhydrous potassium carbonate (65 parts) and DMF (150 parts) was stirred while heating under reflux for 41 hours. An additional quantity of 1-bromobutane (44 parts) was added and the mixture stirred while heating under reflux for a further 19 hours. The cooled mixture was poured into water (400 parts) and the organic phase separated. The aqueous phase was extracted with toluene, the organic phases and toluene extract were combined and washed with water (2×100 parts) before evaporating to leave N-butyl-N-(1-methylhexyl)aniline (72.8 parts, 44%) which was purified by vacuum distillation to give N-butyl-N-(1-methylhexyl)aniline b.pt 73°-80° C., 2.6 mm Hg.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1.[BH4-].[Na+]>CC(C)=O>[C:2]1([CH2:1][N:9]2[CH2:10][CH:11]=[C:12]([CH2:15][CH2:16][OH:17])[CH2:13][CH2:14]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1ccncc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Product: OCCC1=CCN(Cc2ccccc2)CC1
Yield: 18.5 %

Procedure:
Benzyl bromide (4.4 mL, 41 mmol) was added to a solution of 4-pyridineethanol (5 g, 41 mmol) in acetone (100 mL) and the mixture was heated under reflux for 16 hours. The mixture was cooled and the solid was collected, washed with acetone (50 mL) and diethyl ether (2×50 mL) then dissolved in methanol (100 mL) and treated with sodium borohydride (6.2 g 164 mmol). The mixture was heated under reflux for 16 hours, cooled, and the solvent was evaporated under reduced pressure. Ethyl acetate (200 mL) and aqueous sodium hydrogen carbonate (10%, 150 mL) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×100 mL), the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (92:8:1), to give the title compound as a colorless oil (1.65 g, 18%). m/z (ES+) 218 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14](=O)[CH2:13][CH2:12][N:11]([CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.C(O)(=O)C([O-])=O.N1CCCCC1=O.[NH2:30][OH:31]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14](=[N:30][OH:31])[CH2:13][CH2:12][N:11]([CH3:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(C2CN(C)CCC2=O)cc1
Agent: O=C([O-])C(=O)O
Agent: O=C1CCCCN1
Product: COc1ccc(C2CN(C)CCC2=NO)cc1

Procedure:
Cis-8-methoxy-2-methyl-6-phenyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine is obtained by addition of 3-amino-2-p-methoxyphenylpropionic acid ethyl ester to acrylic acid ethyl ester, reductive methylation of 2-p-methoxyphenyl-3,3'-iminodipropionic acid diethyl ester (M.P. of the hydrogen oxalate 152°) with formaldehyde to obtain 2-p-methoxymethyl-N-methyl-3,3'-iminodipropionic acid diethyl ester, reaction of the latter compound to obtain 3-carbethoxy-5-(p-methoxyphenyl)-1-methyl-4-piperidone (M.P. of the hydrochloride 180°-182°), which is converted by hydrolysis and subsequent decarboxylation into 3-p-methoxyphenyl-1-methyl-4-piperidone (M.P. of the hydrogen oxalate 137°-138°). The resulting piperidone is reacted with hydroxylamine to obtain 3-p-methoxyphenyl-1-methyl-4-piperidone oxime (M.P. 121°-122°), the oxime is hydrogenated with Raney nickel to obtain 4-amino-3-p-methoxyphenyl-1-methyl-piperidine (mixture of the two diastereoisomers), the amino compound is treated with benzoyl chloride, cis-4-benzoylamino-3-p-methoxyphenyl-1-methylpiperidine (M.P. 164°-165°) is isolated from the reaction mixture, and the latter amide is cyclized with phosphorus oxychloride to obtain the desired benzonaphthyridine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[N:5][C:4]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:3]1.[Cl-].[CH3:16][C:17]1[N:22]2[N:23]=[C:24]([CH2:26][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:25]=[C:21]2[C:20]([CH3:46])=[N:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:16][C:17]1[N:22]2[N:23]=[C:24](/[CH:26]=[CH:7]/[C:6]3[N:2]([CH3:1])[N:3]=[C:4]([N:9]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]4)[N:5]=3)[N:25]=[C:21]2[C:20]([CH3:46])=[N:19][CH:18]=1
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: Cn1nc(N2CCCCC2)nc1C=O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ncc(C)n2nc(/C=C/c3nc(N4CCCCC4)nn3C)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.6 %

Procedure:
A mixture of 1-methyl-3-(piperidin-1-yl)-1H-1,2,4-triazole-5-carbaldehyde (60 mg, 309 μmol, Eq: 1.00), ((5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphonium chloride (142 mg, 309 μmol, Eq: 1.00) and DBU (51.7 mg, 51.2 μl, 340 μmol, Eq: 1.1) in tetrahydrofuran (15 ml) was stirred for 18 hours at 25° C. under argon. The crude material was applied on silica gel and purified by flash chromatography over a 20 g silica gel column using ethyl acetate/methanol 0-7% as eluent affording 5,8-dimethyl-2-[(E)-2-(2-methyl-5-piperidin-1-yl-2H-[1,2,4]triazol-3-yl)-vinyl]-[1,2,4]triazolo[1,5-a]pyrazine (56 mg, 53.6%) as a yellow solid. MS: m/z=339.5 (M+H+), MP: 186-188° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.N1CCC[C@H:18]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[CH:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[N:8](/[CH:34]=[C:35](/[C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)\[CH3:18])[C:9]=2[CH:10]=1
Reactant: CN1CCc2[nH]c3cc(Cl)c(Cl)cc3c2C1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Fc1ccc(C=CBr)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)c(Cl)cc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
7,8-Dichloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (900 mg, 3.54 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (66 mg, 0.354 mmol), L-proline (81 mg, 0.69 mmol) and potassium phosphate (1.5 g, 7.08 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(2-Bromovinyl)-4-fluorobenzene (900 mg, 4.23 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 80° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-10% MeOH-DCM. The product was further purified by HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH:8]=O.[CH2:11]([NH:13][NH2:14])[CH3:12]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1/[CH:8]=[N:14]/[NH:13][CH2:11][CH3:12]
Reactant: O=Cc1c(Br)cncc1Br
Reactant: CCNN
Product: CCN/N=C/c1c(Br)cncc1Br
Temperature: 100 °C
Yield: 100 %

Procedure:
In analogy to GP 1, 2.65 g of 3,5-dibromo-pyridine-4-carbaldehyde (10 mmol, 1 eq; commercially available or prepared as described in U.S. Pat. No. 6,232,320 or WO2005110410) were dissolved in 32 mL 1-propyl alkohol, treated with 2.25 g N-ethyl hydrazine (oxalate salt; 15 mmol, 1.5 eq.) and heated to 100° C. for 30 min (employing a Biotage Initiator® microwave oven in batch mode). The reaction mixture was concentrated, the residue partitioned between conc. aq. sodium bicarbonate solution and ethyl acetate, the aqueous layer reextracted with ethyl acetate, the combined organic layers dried and concentrated in vacuo to yield 3.08 g of the desired product (10 mmol, quantitative yield), which was used in the subsequent cyclization without further purification steps.
Reaction SMILES: [Br:1]Br.C(N)(C)(C)C.[C:8]([CH:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([OH:20])[C:14]=2[CH2:13][CH:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:11]1)#[N:9]>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:1][C:18]1[CH:17]=[CH:16][C:15]2[CH:10]([C:8]#[N:9])[O:11][CH:12]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][C:14]=2[C:19]=1[OH:20].[Br:1][C:18]1[CH:17]=[CH:16][C:15]2[C@H:10]([C:8]#[N:9])[O:11][C@H:12]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][C:14]=2[C:19]=1[OH:20]
Reactant: N#CC1OC(c2ccccc2)Cc2c(O)cccc21
Reactant: BrBr
Solvent: CC(C)(C)N
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: N#CC1OC(c2ccccc2)Cc2c1ccc(Br)c2O
Product: N#C[C@@H]1O[C@H](c2ccccc2)Cc2c1ccc(Br)c2O
Temperature: -78 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
Bromine (0.11 mL, 2.1 mmol) was added to a solution of 0.91 mL (8.7 mmol) of t-butylamine in 15 mL of toluene at 31 30° C. The resultant mixture was stirred at -30° C. for 10 minutes, cooled to -78° C. and then treated with a solution of 1.09 g (4.3 mmol) of 1-cyano-3,4-dihydro -5-hydroxy-3-phenyl-1H-2-benzopyran, from Step 3, in 15 mL of methylene chloride. The reaction mixture was stirred at -78° C. for 3 h, allowed to slowly warm to ambient temperature over a 3 h period and then partitioned between ethyl acetate and water. The organic extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel eluted with 1% ethyl acetate in hexane to give 0.32 g (24% yield) of [1 R, 3 R]-6-bromo-1-cyano-3,4-dihydro-5-hydroxy-3-phenyl-1H-2-benzopyran and 0.26 g (20% yield) of [1R,3S] 6-bromo-1-cyano-3,4-dihydro-5-hydroxy-3-phenyl-1H-2-benzopyran.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:17])[C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([CH3:13])[C:6]=2[C:14]=1[O:15][CH3:16].[C:18]([O:22][C:23](=[O:45])[C@@H:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH:25]([CH3:27])[CH3:26])([CH3:21])([CH3:20])[CH3:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:18]([O:22][C:23](=[O:45])[C@@H:24]([NH:28][S:29]([C:32]1[CH:33]=[CH:34][C:35]([C:38]2[CH:39]=[CH:40][C:41]([NH:44][C:10]([C:8]3[O:9][C:5]4[C:4]([Cl:17])=[CH:3][C:2]([Cl:1])=[C:14]([O:15][CH3:16])[C:6]=4[C:7]=3[CH3:13])=[O:12])=[CH:42][CH:43]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH:25]([CH3:27])[CH3:26])([CH3:20])([CH3:21])[CH3:19]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Reactant: COc1c(Cl)cc(Cl)c2oc(C(=O)O)c(C)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Cl)cc(Cl)c2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.2 %

Procedure:
To 80 mg of 5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 120 mg of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester, 154 mg of BOP, 50 mg of N,N-diisopropylethylamine and 4 mL of DMF. The mixture was stirred at room temperature for 48 h. The mixture was washed with brine and was extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removal of the solvent in vacuo and purification of the residue by column chromatography on silica gel gave 110 mg (60% yield) of (S)-2-{4′-[(5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid tert-butyl ester as an off-white solid.
Reaction SMILES: [CH2:1]([N:4]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[N:5]1)[CH:2]=[CH2:3].[CH3:23][O:24][CH:25]([O:34][CH3:35])[CH2:26][NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH2:1]([N:4]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([N:27]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:26][CH:25]([O:34][CH3:35])[O:24][CH3:23])=[O:19])=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1nnc(-c2cccc(CCOCCC(=O)O)c2)n1
Reactant: COC(CNC1CCCCC1)OC
Product: C=CCn1nnc(-c2cccc(CCOCCC(=O)N(CC(OC)OC)C3CCCCC3)c2)n1

Procedure:
The subtitled compound (450 mg) was prepared from 3-(3-(2-allyl-2H-tetrazol-5-yl)phenethoxy)propanoic acid [Example 7, Step ii)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 14, Step iii). 1H NMR (300 MHz, CD3OD) δ 8.04-7.92 (m, 2H), 7.49-7.36 (m, 2H), 6.29-6.11 (m, 1H), 5.47-5.30 (m, 4H), 4.56 and 4.39 (2×t, J=5.3 Hz, 1H), 4.09-3.94 (m, 1H), 3.81-3.67 (m, 4H), 3.372 and 3.368 (2×s, 6H), 3.34 and 3.29 (d, J=5.3 Hz, 2H), 3.00-2.91 (m, 2H), 2.72-2.64 (m, 2H), 1.84-1.02 (m, 10H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[NH:11][NH2:12].N1C=CC=CC=1>C(OCC)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([N:11]([NH2:12])[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:8])=[O:7]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=S(=O)(Cl)CCCCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N(N)S(=O)(=O)CCCCCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 17.1 %

Procedure:
A solution of 40 g of 4-chloro-1-butanesulphonyl chloride in 400 ml of diethyl ether was added dropwise to a solution of 30.4 g of tert-butyl carbazate and 17 ml of pyridine in 400 ml of diethyl ether at room temperature. The mixture was stirred at room temperature for 72 hours and then washed with water. The separated organic phase was dried over anhydrous magnesium sulphate. The oily residue obtained after evaporation of the solvent was purified by flash column chromatography on silica gel using hexane/ethyl acetate (8:2, increasing to 6:4) for the elution. 10.25 g of tert-butyl 2-[(4-chlorobutyl)sulphonyl]carbazate were obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:13])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH3:11])=[O:4].[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.C(O)(=O)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:13][Br:14])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH3:11])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cc(Cl)nc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1c(C)cc(Cl)nc1CBr

Procedure:
To a solution of 710 mg, (3.6 mmol) 6-chloro-2,4-dimethyl-pyridine-3-carboxylic acid methylester in CCl4 (16 ml) were added 688 mg (3.90 mmol) N-bromosuccinimide, 59 mg (0.36 mmol) AIBN and 210 μl (3.72 mmol) acetic acid. The reaction mixture was irradiated with a 200 W Wolfram lamp at 60° C. for 24 h. The mixture was then filtered through celite, washed with CCl4 and concentrated in vacuo. After CC (hexane/EtOAc 97:3) of the residue a mixture of 6-chloro-2,4-dimethyl-pyridine-3-carboxylic acid methylester, 4-(bromomethyl)-6-chloro-2-methyl-pyridine-3-carboxylic acid methylester and 2-(bromomethyl)-6-chloro-4-methyl-pyridine-3-carboxylic acid methylester was obtained. This mixture was dissolved in dioxane (10 ml) and added at 0° C. to a solution prepared by dissolving 594 mg (25.8 mmol) sodium in MeOH (11 ml) at 0° C. This reaction mixture was stirred at RT for 3 h. Then the reaction solution was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. After CC (hexane/EtOAc 97:3) of the residue again a mixture of 6-chloro-4-(methoxymethyl)-2-methyl-pyridine-3-carboxylic acid methylester and 6-chloro-2-(methoxymethyl)-4-methyl-pyridine-3-carboxylic acid methylester was obtained. This material was dissolved in NMP (7.8 ml) and 860 μl (9.85 mmol) morpholine and 1.36 g (9.85 mmol) K2CO3 were added followed by heating at 100° C. for 5 h. Then the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 9:1) provided 90 mg (0.32 mmol, 9%) 2-(methoxymethyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid methylester.