Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]3[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:12]=3[C:13]([OH:15])=O)[CH2:8]2)=[CH:4][CH:3]=1.Cl.[NH2:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1>>[F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:8][N:9]([C:11]3[N:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][C:12]=3[C:13]([NH:27][C:28]3([C:31]4[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=4)[CH2:30][CH2:29]3)=[O:15])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ccc(F)cc2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4ccc(F)cc4)C3)CC2)cc1
Yield: 60 %

Procedure:
The title compound (D173) (80 mg) was prepared according to the experimental procedure described in Description 146 starting from 2-(3-(4-fluorophenoxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinic acid (D122) (90 mg, 0.252 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (57.51 mg, 0.252 mmol).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[ClH:22]>CO>[ClH:22].[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:3]([N:2]([CH3:21])[CH3:1])=[O:20]
Reactant: CN(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-tert-butyloxycarbonyl-(S)-phenylalanine dimethylamide (Preparation 7, 24.8 g, 84 mmol) in methanol (50 mL) was added a solution of hydrochloric acid (4N, in dioxane, 40 mL) and the mixture stirred at rt for 3 h. The resulting solution was concentrated in vacuo then dissolved in water (300 mL). The aqueous solution was washed with ethyl acetate (3×100 mL) and concentrated again. Successive recrystallisations with methanol (200 mL) and a mixture of methanol and (1:1, 200 mL) gave the title compound as colourless crystals. δH (D2O) 2.75, 2.90 (6H, 2×s), 3.18 (2H, m), 4.72 (1H, t), 7.28-7.45 (5H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:10]=3[S:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][O:18][C:15]1[CH:16]=[CH:17][C:9]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[C:12]([CH3:13])[S:11][C:10]=2[CH:14]=1
Reactant: BrCCCCBr
Reactant: Cc1sc2cc(O)ccc2c1-c1ccc(Br)cc1
Product: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1

Procedure:
In analogy to example 27.1, 3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophen-6-ol and 1,4-dibromobutane were converted to yield 6-(4-bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene as colorless oil, MS: 452 (M, 2Br).
Reaction SMILES: Cl.Cl.[C:3]1([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17](=[NH:20])OC)[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][NH:27][C:28]1[C:29](N)=[CH:30][CH:31]=[CH:32][CH:33]=1>C(O)(=O)C>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][N:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:20]=[C:17]1[CH2:16][CH:13]1[CH2:12][CH2:11][N:10]([CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:15][CH2:14]1
Reactant: COC(=N)CC1CCN(Cc2ccccc2)CC1
Reactant: Nc1ccccc1NCc1ccco1
Agent: Cl
Solvent: CC(=O)O
Product: c1ccc(CN2CCC(Cc3nc4ccccc4n3Cc3ccco3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 27.3 parts of O-methyl 1-(phenylmethyl)-4-piperidineethanimidate dihydrochloride, 14 parts of N-(2-furanylmethyl)-1,2-benzenediamine and 250 parts of acetic acid was stirred overnight at room temperature. The reaction mixture was evaporated and water was added to the residue. The whole was alkalized with sodium carbonate and extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from 1,1'-oxybisethane. The product was filtered off and dried, yielding 15.5 parts (57%) of 1-(2-furanylmethyl)-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole; mp. 124.8° C. (3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.CON(C)[C:18](=[O:22])[CH2:19][O:20][CH3:21]>CCOCC>[Cl:9][C:4]1[CH:3]=[C:2]([C:18](=[O:22])[CH2:19][O:20][CH3:21])[CH:7]=[CH:6][C:5]=1[Cl:8]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: COCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: CCOCC
Product: COCC(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of 4-bromo-1,2-dichlorobenzene (2.04 g, 9.01 mmol) and ether (5 mL) cooled to −78° C. was added as a steady stream n-BuLi (3.61 ml, 9.01 mmol) and the reaction was stirred for 10 min then cannulated into a solution of N,2-dimethoxy-N-methylacetamide (1.0 g, 7.51 mmol) and ether (10 mL) which was stirred for an additional 20 min. The reaction was quenched with water and extracted with EtOAc. The organic fractions were dried, filtered and concentrated. The crude product which was purified by SiO2 chromatography eluting with hexane/EtOAc (9:1) to afford 1.30 g (79.0%) of 1-(3,4-dichlorophenyl)-2-methoxyethanone as a white solid (192).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:15])[C:12]=1[O:13][CH3:14])[CH:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[NH:8][CH2:7][CH2:6]2.[CH2:25]=O.[BH4-].[Na+]>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:15])[C:12]=1[O:13][CH3:14])[CH:9]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[N:8]([CH3:25])[CH2:7][CH2:6]2
Reactant: C=O
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)c(O)c32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(CC2c3c(cc(OC)c(OC)c3O)CCN2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
6,7-Dimethoxy-1-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-8-ol (2.55 g, 7.74 mmol) obtained in Example 1-2 was dissolved in 100 ml of chloroform-methanol (1:1), 35% formalin (3.6 ml, 45.3 mmol) was added and the mixture was stirred at room temperature for 2 hours. Sodium borohydride (3.40 g, 89.8 mmol) was added under ice cooling and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, 200 ml of water was added to the resultantresidue, and the mixture was neutralized with 1N hydrochloric acid and thenextracted with chloroform (100 ml×3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol) to give 2.09 g (yield: 79%) of the captioned compound as pale yellow powder. Melting point: 112°-114° C. FAB-MS (m/z, (C20H25NO4 +H)+ ): 344 1H-NMR (300MHz, CDCl3, δ ppm): 2.35 (3H, s), 2.35-2.45 (1H, m), 2.73-2.87 (2H, m), 2.98 (1H, dd, J=3.2Hz, 14.2Hz), 3.20-3.32 (1H, m), 3.78(3H, s), 3.83 (3H, s), 3.88 (3H, s), 3.95 (1H, d, J=3.2Hz, 8.8Hz), 6.20 (1H, s), 6.80 (1H, d, J=8.8Hz), 7.18 (1H, d, J=8.8Hz)
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:12]1([CH2:15][OH:16])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:3]([O:16][CH2:15][CH:12]2[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: OCC1CC1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Product: O=C(O)c1cnc(OCC2CC2)c(Cl)c1
Yield: 98 %

Procedure:
The title compound is prepared in 98% yield (4.65 g, white solid) from 5,6-dichloronicotinic acid (4.00 g, 20.8 mmol) and cyclopropylmethanol (2.25 g, 31.3 mmol) in a similar manner to Step-1 of Amine-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:31][C:30]2[CH:29]=[CH:28][C:27]([S:24]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)(=[O:26])=[O:25])=[CH:34][CH:33]=2)=[C:6]1[CH3:15]
Reactant: O=Cc1ccc(S(=O)(=O)c2ccc(F)cc2)cc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2ccc(S(=O)(=O)c3ccc(F)cc3)cc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and 4-(4-fluorobenzenesulfonyl)benzaldehyde.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[NH:11][C:10](=[O:12])[C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[NH:4][CH2:3]1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([N:4]1[CH2:3][C:2]([CH3:13])([CH3:1])[NH:11][C:10](=[O:12])[C:5]21[CH2:9][CH2:8][CH2:7][CH2:6]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)CNC2(CCCC2)C(=O)N1
Reactant: BrCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)CN(Cc2ccccc2)C2(CCCC2)C(=O)N1
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 6.72 g of 8,8-dimethyl-6,9-diaza-spiro[4.5]decan-10-one in 35 ml of DMF were added 4.8 ml of benzyl bromide and 6.9 ml of Hünig's base. The reaction was stirred at r.t overnight. The precipitated product was isolated by suction and washed with DMF and EtOAc. The filtrate was concentrated and the resulting residue was dissolved in EtOAc, washed with water, dried over Na2SO4, filtered and concentrated to yield a second fraction of the product. 9.62 g (96%) of the title compound were obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([O:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])[CH:4]=1.[OH:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:15][C:14]1[O:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:11][C:10]=1[CH2:9][O:8][C:5]1[CH:4]=[C:3]([CH2:2][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:26]=[CH:27][CH:28]=2)[O:7][N:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCc2cc(OCc3nc(-c4ccccc4)oc3C)no2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
A mixture of 5-chloromethyl-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)isoxazole (457 mg), methyl 2-(3-hydroxyphenyl)acetate (249 mg), anhydrous potassium carbonate (415 mg) and N,N-dimethylformamide (10 mL) was stirred at 60° C. for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-[3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethoxy]phenyl]acetate as a colorless oil (604 mg, 93%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[CH2:19][OH:20])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:21]>CCO.O1CCOCC1>[ClH:21].[ClH:21].[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[CH2:19][OH:20])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@@H]2CO)CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: OC[C@H]1CCCN1C1CCNCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A solution of 8.80 g (30.9 mmol) of 4-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester in 200 ml of EtOH was treated at RT with 15.5 ml (62.0 mmol) of hydrochloric acid in 1,4-dioxane (4 molar) and the mixture was heated up to 100° C. After two hours, the solvents were evaporated and the residue was re-crystallized from MeOH/MeCN and Et2O to give 6.53 g (82%) of the title compound as off-white solid. MS: 185.1 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[K].[CH:13](=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]>O>[N+:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[O:16][C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[CH:13]=[O:21])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: O=Cc1ccccc1O
Agent: [K]
Solvent: O
Product: O=Cc1ccccc1Oc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
Briefly, 200 parts of 2,5-dichloro-nitrobenzene were heated to 160° C. and stirred, and 160 parts of the potassium salt of salicylaldehyde was added over a period of 30 minutes. After the addition was complete, an exothermic reaction took place, and the temperature rose to about 195° C. Heating was discontinued until the reaction subsided, and the mixture was heated for 1 hour at 150° C. The mixture was cooled, ice and water were added, and it was extracted with ether. The ether layer was filtered to remove insoluble material, and the resultant solution was dried over sodium sulfate. The ether solvent was evaporated, and the residual oil was recrystallized from a mixture of hexane and benzene to give 2-(2-nitro-4-chloro-phenoxy)benzaldehyde melting at about 100°-101° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[CH3:26])=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[CH3:26])=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Reactant: OB(O)c1cccc(Cl)c1Cl
Product: CCOC(=O)/C=C(\C)c1ccc(-c2cccc(Cl)c2Cl)cc1
Yield: 72.5 %

Procedure:
(E)-Ethyl 3-(2′,3′-Dichloro-biphenyl-4-yl)-but-2-enoate (1.07 g, 73% yield) was prepared from 2,3-dichlorophenylboronic acid (1.26 g, 6.60 mmol) and (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (1.0 g, 4.40 mmol) by a procedure analogous to that described in example 52a.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](B(O)O)=[CH:5][N:4]=1.Br[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:15]2[CH:16]=[C:17]([NH2:18])[CH:19]=[CH:20][CH:21]=2)=[CH:5][N:4]=1
Reactant: Nc1cccc(Br)c1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ncc(-c2cccc(N)c2)c(OC)n1
Temperature: 25 °C
Yield: 55 %

Procedure:
2,4-dimethoxypyrimidine-5-boronic acid (0.160 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in DME (3 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.610 mL, 1.22 mmol) and Pd(PPh3)4 (0.02 g, 0.017 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (10-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.074 g in 55% yield.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1.O[C@H]1CC(=O)C(CCC[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=O)=C1>>[O:33]1[CH2:34][CH2:28][CH2:29][CH2:30][CH:31]1[O:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1
Reactant: COC(=O)CCCCCCC1=C[C@@H](O)CC1=O
Reactant: COC(=O)CCCCCCC1=CC(O)CC1=O
Product: COC(=O)CCCCCCC1=CC(OC2CCCCO2)CC1=O

Procedure:
When an equivalent quantity of methyl 7-(3(RS)-hydroxy-5-oxocyclopent-1-en--yl)heptanoate is substituted for the methyl 7-(3(S)-hydroxy-5-oxocyclopent-1-en-1-yl)-heptanoate and the procedure detailed in Part A substantially repeated, there is obtained methyl 7-(3(RS)-tetrahydropyran-2-yloxy-5-oxocyclopent-1-en-1-yl)heptanoate.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[C:9](=O)[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)([CH2:11][CH2:12][CH3:13])[CH2:7][CH2:6][CH2:5]1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([NH:45][C:46]([NH2:48])=[NH:47])[CH:36]=[CH:37][C:38]=1[N:39]1[CH:43]=[C:42]([CH3:44])[N:41]=[CH:40]1>>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([NH:45][C:46]2[N:48]=[CH:3][C:4]3[CH2:5][CH2:6][CH2:7][C:8]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)([CH2:11][CH2:12][CH3:13])[C:9]=3[N:47]=2)[CH:36]=[CH:37][C:38]=1[N:39]1[CH:43]=[C:42]([CH3:44])[N:41]=[CH:40]1
Reactant: CCCC1(c2cccc(OC)c2)CCCC(=CN(C)C)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: CCCC1(c2cccc(OC)c2)CCCc2cnc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc21

Procedure:
The title compound was prepared from 6-[1-dimethylamino-methylidene]-2-(3-methoxy-phenyl)-2-propyl-cyclohexanone (101 mg, 0.33 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (124 mg, 0.33 mmol) using in analogous manner the procedure described in example 45b). Obtained as white solid (24 mg, 15%). MS ISP (m/e): 484.5 [(M+H)+]. mp 166-168° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].[NH2:20][C@@H:21]([CH2:25][OH:26])[CH:22]([CH3:24])[CH3:23].C(O)(=O)C.C([BH3-])#N>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH2:14][NH:20][C@H:21]([CH:22]([CH3:24])[CH3:23])[CH2:25][OH:26])[CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: O=Cc1cccc(-c2ccc(F)c(C(F)(F)F)c2)n1
Reactant: CC(C)[C@@H](N)CO
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)[C@H](CO)NCc1cccc(-c2ccc(F)c(C(F)(F)F)c2)n1
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a solution of Example 267A (0.500 g, 1.86 mmol) in methanol (20 mL) at ambient temperature was added D-valinol (0.20 mL, 1.9 mmol) and acetic acid (0.40 mL, 7.4 mmol) followed by MP-cyanoborohydride (2.49 mmol/g; 1.0 g). After 2 hours, the mixture was filtered, concentrated and the residue partitioned between ether and 1M NaOH. The organic extract was concentrated and purified by chromatography to provide 390 mg (59%) of the title compound. MS (DCI+) m/z 270 (M+H); 1H NMR (500 MHz, CDCl3) δ 8.28 (dd, J=6.8, 2.0 Hz, 1H), 8.24-8.15 (m, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.34-7.25 (m, 2H), 4.04 (q, J=14.5 Hz, 2H), 3.70 (dd, J=10.9, 4.0 Hz, 1H), 3.49 (dd, J=10.8, 6.9 Hz, 1H), 2.53 (td, J=6.7, 4.1 Hz, 1H), 1.97-1.85 (m, 1H), 1.04 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:43])[N:14]([CH2:18][C:19]([N:21]([CH2:29][CH2:30][O:31][NH:32][C:33]([NH2:42])=[N:34]C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[O:20])[CH:15]=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(Cl)Cl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:43])[N:14]([CH2:18][C:19]([NH:21][CH2:29][CH2:30][O:31][NH:32][C:33]([NH2:42])=[NH:34])=[O:20])[CH:15]=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N=C(N)NOCCN(C(=O)Cn1cccc(NS(=O)(=O)Cc2ccccc2)c1=O)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NOCCNC(=O)Cn1cccc(NS(=O)(=O)Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 3-benzylsulfonylamino-1-{[N,N′-di(tert-butoxycarbonyl)] [(2-guanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone (155 mg, 0.25 mmol), as prepared in the preceding step, and trifluoroacetic acid (2 mL) in methylene chloride (3 mL) was stirred at room temperature for 2 h. After evaporation of the solvent in vacuo, the residue was purified by Waters Sep-Pak (10 g, 10% methanol in methylene chloride) to give the title compound as a colorless foam (160 mg, 92%). 1H-NMR (300 MHz, DMSO c6) δ 11.00 (s, 1H), 8.66 (s, 1H), 8.45 (t, J=5.3 Hz, 1H), 7.72 (br s, 4H), 7.40 (d, J=6.9 Hz, 1H), 7.33 (m, 5H), 7.19 (d, J=7.0 Hz, 1H), 6.19 (d, J=7.0 Hz, 1H), 4.62 (s, 2H), 4.55 (s, 2H), 3.83 (t, J=5.1 Hz, 2H), 3.39 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H22N6O5S: 423.1 (M+H), 445.1 (M+Na); Found: 423.3, 445.0.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][C:17]4[CH:18]=[CH:19][C:20]5[N:21]([C:23]([CH:26]=[O:27])=[CH:24][N:25]=5)[CH:22]=4)=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1.O.[BH4-].[Na+]>CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][C:17]4[CH:18]=[CH:19][C:20]5[N:21]([C:23]([CH2:26][OH:27])=[CH:24][N:25]=5)[CH:22]=4)=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(C=O)n5c4)n3n2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(CO)n5c4)n3n2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-[6-(1-Methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-imidazo[1,2-a]pyridine-3-carbaldehyde (Example 297, 50 mg, 0.140 mmol) was dissolved in MeOH (3 mL) and water (1 mL) then NaBH4 (2.6 mg, 0.070 mmol) was added. The RM was stirred at rt for 30 min. It was quenched with water and EtOAc. The precipitate formed was filtered off. The filtrate was concentrated then was triturated with MeOH. The salt was filtered off. The filtrate was concentrated and then triturated again with Et2O, The precipitate was filtered off and it was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in DCM) to afford after evaporation of the solvent the title compound as a yellow solid (tR 0.6 min (conditions 2), MH+=360).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36](O)=[O:37])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:22]([CH3:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1.[O:43]=[S:44]1(=[O:56])[CH2:49][CH2:48][CH:47]([N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:46][CH2:45]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:22]([CH3:35])[CH:21]=3)[C:36]([N:53]3[CH2:54][CH2:55][N:50]([CH:47]4[CH2:46][CH2:45][S:44](=[O:43])(=[O:56])[CH2:49][CH2:48]4)[CH2:51][CH2:52]3)=[O:37])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1
Reactant: O=S1(=O)CCC(N2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCS(=O)(=O)CC3)CC2)cc(C)c1OCc1ccccc1

Procedure:
Prepared analogously to Example 1i from 150 mg (0.26 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1g) and 57 mg (0.26 mmol) 1-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-piperazine.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]3[N:18]=[N:17][NH:16][N:15]=3)=[CH:12][C:11]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:10]([Cl:23])[CH:9]=2)[S:4][CH:5]=1.Cl[CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[CH2:27]([O:26][CH2:25][N:15]1[C:14]([C:13]2[C:8]([NH:7][CH2:6][C:3]3[S:4][CH:5]=[CH:1][CH:2]=3)=[CH:9][C:10]([Cl:23])=[C:11]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:12]=2)=[N:18][N:17]=[N:16]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCOCc1ccccc1
Reactant: NS(=O)(=O)c1cc(-c2nn[nH]n2)c(NCc2cccs2)cc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cc(-c2nnnn2COCc2ccccc2)c(NCc2cccs2)cc1Cl

Procedure:
Azosemide can be reacted with benzyl chloromethyl ether, triethylamine and sodium iodide in DMF to yield 5-[1-(benzyloxymethyl)-1H-tetrazol-5-yl]-2-chloro-4-[(2-thienylmethyl)amino]benzenesulfonamide.