Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:12]([O:19][C@H:20]1[C@H:26]2[CH2:27][CH2:28][NH:29][C@@H:21]1[CH:22]([O:25]2)[O:23][CH3:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>CCOCC>[CH2:12]([O:19][C@H:20]1[C@H:26]2[CH2:27][CH2:28][N:29]([C:2]([O:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:3])[C@@H:21]1[CH:22]([O:25]2)[O:23][CH3:24])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC1O[C@@H]2CCN[C@H]1[C@H]2OCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: COC1O[C@@H]2CCN(C(=O)OCc3ccccc3)[C@H]1[C@H]2OCc1ccccc1

Procedure:
Benzyl chloroformate (1.30 ml, 9.17 mmol) was added to a solution of methyl 3-O-benzyl-2,6-imino-2,5,6-trideoxy-D-lyxo-hexofuranoside epimers (22αβ) (α:β 1:2) (1.52 g, 6.11 mmol), in a stirred 3:2 mixture of ether and saturated sodium bicarbonate (60 ml). After 18 hours the ether layer was removed and the aqueous phase extracted further with ether (3×50 ml). The combined ether extracts were dried, filtered and evaporated. Purification by flash chromatography afforded both the methyl 3-O-Benzyl-N-benzyloxycarbonyl-2,6-imino-2,5,6-trideoxy-D-lyxo-hexofuranoside anomers as clear oils.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:10][CH:11]=[CH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:7][CH2:8][CH3:9]>ClCCl>[CH2:6]([O:10][CH:11]=[C:12]([Cl:4])[C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])[CH2:7][CH2:8][CH3:9]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCOC=CC(=O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC=C(Cl)C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h
Yield: 92.1 %

Procedure:
28.0 g (0.22 mole) of sulphuryl chloride in 60 ml of dichloromethane are added dropwise with stirring to 39.0 g (0.2 mole) of 4-n-butoxy-1,1,1-trifluoro-but-3-en-2-one in 200 ml of dichloromethane at 0° C. After stirring for 4 hours at 0° C., the solvent and unreacted sulphuryl chloride are distilled off and the residue is distilled slowly under reduced pressure. 42.5 g of pale yellow 4-n-butoxy-3-chloro-1,1,1-trifluorobut-3-en-2-one of boiling point 105°-106° C./12 mbar, nD20 =1.4484 are obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.CC(O)=O>CO.[OH-].[OH-].[Pd+2]>[N:23]1[CH:24]=[CH:25][C:20]([N:17]2[CH2:16][CH2:15][N:14]([C:11]3([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH2:19][CH2:18]2)=[CH:21][CH:22]=1
Reactant: CC(=O)NCC1(N2CCN(c3ccncc3)CC2)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)NCC1(N2CCN(c3ccncc3)CC2)CCNCC1
Reaction time: 16 h
Yield: 5 %

Procedure:
A degassed solution containing N-((1-benzyl-4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-4-yl)methyl)acetamide AM14 (1.96 mmol), AcOH (0.3 ml) and Pd(OH)2 in methanol was hydrogenated for 16 h to yield N-((4-(4-(pyridin-4-yl)-piperazin-1-yl)piperidin-4-yl)methyl)acetamide AM2, which was obtained after passage through a celite pad and solvent removed under reduced pressure. N-((4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-4-yl)methyl)acetamide AM2 was re-dissolved in dichloromethane and added to a solution containing 2-(2-(N-cyclopropyl-4-methoxy-2,6-dimethylphenylsulfonamido)ethoxy)acetic acid AC7 (0.8 equiv.), EDCI (1.5 equiv.), HOBT (1 equiv.) and DIPEA (4 equiv.) in dichloromethane at 0° C. The reaction mixture was warmed to room temperature and stirred for 16 h. The mixture was diluted with dichloromethane and was given aq. NH4Cl and aq. NaHCO3 washes. The organic layer was dried over sodium sulfate and the solvent removed. The crude product was purified by alumina column chromatography. Yield: 5%. MS, Rt=2.5 min, m/z=657.5 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:8]([C:20]([NH2:22])=O)=[C:7]2[CH2:23][CH2:24][CH2:25][O:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.FC(F)(F)C(O)=O>O1CCCC1.ClCCl.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:8]([C:20]#[N:22])=[C:7]2[CH2:23][CH2:24][CH2:25][O:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(Cn2c(C(N)=O)c(CCCOc3cccc4ccccc34)c3cccc(Br)c32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cn2c(C#N)c(CCCOc3cccc4ccccc34)c3cccc(Br)c32)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of EXAMPLE 581B (545 mg) in tetrahydrofuran (5 mL) and dichloromethane (1 ml) was added triethylamine (1 ml) followed by trifluoroacetic acid (1 ml) dropwise. After the addition, the mixture was stirred for 3 hours at 0° C. The mixture was diluted with ethyl acetate (200 mL) and water (80 mL). The aqueous layer was extracted with ether. The combined organic extracts were washed with water (×3), brine and dried over Na2SO4. After filtration, concentration of the solvent gave Example 581C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[N:21]1[CH:26]=[C:25]([C:27](O)=[O:28])[CH:24]=[N:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:25]3[CH:26]=[N:21][CH:22]=[N:23][CH:24]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1cncnc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1cncnc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-pyrimidinecarboxylic acid as starting materials, MS (LC/MS): 409.0 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8](OCC)=[O:9])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([CH:8]=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1=CCN(C)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CC=C(C=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.9 %

Procedure:
To a solution prepared by dissolving 1.7 g of ethyl 1-methyl-1,2,3,6-tetrahydro-4-pyridinecarboxylate in 20 mL of tetrahydrofuran, 773 mg of lithium aluminum hydride was added, and the mixture was stirred for 1 hour at room temperature. The reaction solution was cooled to 0° C., and then sodium sulfate decahydrate was slowly added until there are no bubbles, and stirred overnight at room temperature. The insolubles were filtered and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 40 mL of chloroform, then 2 g of manganese dioxide was added thereto, and the mixture was stirred overnight at room temperature. The insolubles were filtered through celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0-90/10), to obtain 212 mg of 1-methyl-1,2,3,6-tetrahydropyridine-4-carboaldehyde [34-1] (hereinafter, referred to as the compound [34-1]).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]2[CH2:14][CH2:15][C@:10]([CH2:16][CH2:17][O:18]CC3C=CC=CC=3)([CH:11]=[CH:12]2)[O:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:12][CH2:11][C:10]([CH2:16][CH2:17][OH:18])([CH2:15][CH2:14]2)[O:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1O[C@@]2(CCOCc3ccccc3)C=C[C@@H]1CC2
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1OC2(CCO)CCC1CC2
Reaction time: 6 h

Procedure:
1 g Pd—C is placed into an round-bottom flask under an argon atmosphere and covered with ethanol. A solution of (1S,4S)-1-(2-benzyloxy-ethyl)-2-oxa-3-aza-bicyclo[2.2.2]oct-5-ene-3-carboxylic acid tert-butyl ester (10) (2 g, 5.8 mmol) in 58 ml of ethanol is added and the mixture is hydrogenated at rt for 6 h. Then the mixture is filtrated over celite and evaporated under reduced pressure. The product was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][C:14]([F:17])([F:16])[F:15])[C:7]([OH:9])=[O:8])([O-])=O>CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][C:14]([F:15])([F:16])[F:17])[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Solvent: CO
Product: Nc1cc(C(=O)O)ccc1OC(F)(F)F
Yield: 97.7 %

Procedure:
A solution of 3-nitro-4-trifluoromethoxybenzoic acid (3 g) in methanol (240 ml) was hydrogenated at 50° C. and 50 bar using H-cube apparatus. The methanol solution was evaporated giving the title compound as a white solid (2.58 g).
Reaction SMILES: [OH-].[Na+].Cl[C:4]([O:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:15]([O:19][C:20](=[O:41])[CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][NH2:40])([CH3:18])([CH3:17])[CH3:16]>O.C(OCC)(=O)C>[C:15]([O:19][C:20](=[O:41])[CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][NH:40][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C(Cl)OC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOCCNC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 487.8 %

Procedure:
Sodium hydroxide (2.0 mL of a 3M in water, 6.0 mmol) and benzoyl chloroformate (0.52 mL, 0.36 mmol) were added in portions to compound 5 (0.90 g, 2.3 mmol) in ethyl acetate (10 mL) and the resulting mixture was stirred overnight. The reaction mixture was concentrated in vacuo, water (20 mL) was added, and the slurry was extracted with CH2Cl2 (3×100 mL), and the combined organic solutions were washed with saturated aq. NaHCO3 (20 mL) and brine (20 mL), and dried over anhydrous MgSO4. The solution was concentrated in vacuo and the residue was loaded onto a silica gel gravity column (100 g) and eluted with CH2Cl2:MeOH 100:1 to 10:1 (v/v) to afford compound 6 as a colorless oil (0.93 g, 76%).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH2:32]([O:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:9][CH:10]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:27][CH:26]=1)[CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCC(Oc1ccc(O)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Reactant: CCCCCBr
Product: CCCCCCC(Oc1ccc(OCCCCC)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 92 starting from 3-{4-[1-(4-hydroxy-phenoxy)-heptyl]-benzoylamino}-propionic acid methyl ester and 1-bromo-pentane. MS: 468.2 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.O=[C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]([C:34]([OH:36])=[O:35])[CH2:26]1.C(O)(=O)C.C([O-])(=O)C.[Na+]>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:25]2\[CH2:26][CH:27]([C:34]([OH:36])=[O:35])[C:28]3[C:33]\2=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:22][CH:23]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Reactant: O=C1CC(C(=O)O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C2\CC(C(=O)O)c3ccccc32)cc1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (500 mg), 3-oxo-1-indancarboxylic acid (284 mg), acetic acid (0.276 ml), sodium acetate (264 mg) and ethanol (20 ml) was heated to reflux for 18 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-1-indancarboxylic acid (522 mg, yield 69%) as colorless crystals. m.p. 148-149° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21]([OH:23])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.[C:43]1([NH:49][CH2:50][CH2:51][O:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[C:7]([O:11][C:12](=[O:13])[N:14]([CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:21](=[O:23])[N:49]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:50][CH2:51][O:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=2)[CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:28]1[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=1)([CH3:9])([CH3:10])[CH3:8]
Reactant: c1ccc(NCCOc2ccccn2)cc1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCOc2ccccn2)c2ccccc2)c1)c1ccncc1
Reaction time: 0.17 h
Yield: 40.1 %

Procedure:
2M Oxalyl chloride in dichloromethane (0.16 ml) and dry DMF (0.008 ml) were added to a stirred suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.115 g) in dry dichloromethane (1.5 ml) under nitrogen. After 10 min, DIPEA (0.18 ml) was added followed after a further 40 min by phenyl-2-(pyridin-2-yloxy)-ethylamine (0.059 g) and DMAP (0.008 g). After 7 days the solvent was evaporated and the residue was purified by flash chromatography, eluting with dichloromethane:methanol (98:2 v/v), to give the title compound as a pale yellow oil (0.065 g).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[C:10]([OH:20])=[C:11](C(OC)=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[C:10](=[O:20])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(O)C2CCC(C1)N2Cc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C1CCC2CCC1N2Cc1ccccc1
Temperature: 120 °C
Yield: 73.5 %

Procedure:
To a solution of methyl 8-benzyl-2-hydroxy-8-azabicyclo[3.2.1]oct-2-ene-3-carboxylate (68 mg, 0.249 mmol) in pyridine (2.5 ml) was added NaI (746 mg, 4.98 mmol). The reaction mixture was then reflux at 120° C. for 7.5 hr. The reaction mixture was concentrated and placed under vacuum. The residue was then partitioned between EtOAc and water. The aqueous phase was separated and extracted with EtOAc. All organic phases were combined, washed with saturated aqueous Na2S2O3 solution, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-40% EtOAc/Hex to give the product 8-benzyl-8-azabicyclo[3.2.1]octan-2-one (39.4 mg, 0.183 mmol) as a syrup. Anal. Calcd. for C14H17NO m/z 215.1, found: 216.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.35-7.21 (5 H, m), 3.68 (2 H, s), 3.36 (2 H, d, J=5.5 Hz), 2.45-2.28 (2 H, m), 2.27-2.16 (3 H, m), 1.81-1.70 (3 H, m).
Reaction SMILES: C([NH:8][OH:9])(OC(C)(C)C)=O.[H-].[Na+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.Cl>C(OCC)C>[NH2:8][O:9][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)NO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(CON)cc1
Reaction time: 8 h
Yield: 39 %

Procedure:
A solution was made of Boc hydroxylamine (2.0 g, 17.1 mmol) in dry TBF (60 ml). Sodium hydride (1.1 g of a 60% suspension in paraffin oil, 25.7 mmol) was then added and the suspension stirred. A catalytic amount of KI was then added to the reaction prior to the cautious addition of 4-methoxybenzyl chloride (3.2 g, 20.4 mmol). The reaction was then allowed to stir overnight before removal of solvent in vacuo. The residue was taken up with diethyl ether (100 ml) and HCl gas bubbled in for 20 minutes, causing the start of precipitation of the product. The flask was stoppered and left to stand overnight. The product was then filtered off as a off-white wax (39–52% yield according to varying batches).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[C:14](/[N+:11]([O-:13])=[O:12])\[CH3:15]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: C/C(=C\c1ccc(Cl)cc1Cl)[N+](=O)[O-]
Temperature: 90 °C
Yield: 54.7 %

Procedure:
In a sulfonation flask 2,4-dichloro-benzaldehyde (77 g, 0.44 mol), nitroethane (216 ml, 3.04 mol) and ammonium acetate (81.4 g, 1.06 mol) were added to glacial acetic acid (600 ml). The resulting solution was heated to 90° C. for three hours. After removal of the solvent ice-water (400 ml) was added. The solid product was collected by filtration, washed with water and recrystallized from ethanol. 55.9 g (55% of theory) of 2,4-dichloro-1-((E)-2-nitro-propenyl)-benzene was obtained in the form of a yellow solid (m.p. 79-81° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)=[O:11]
Reactant: Nc1ccc2ccccc2n1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc2ccccc2n1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-aminoquinoline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([NH2:17])=[O:16])=[N:8][C:7]=3[C:6]=2[CH:18]=1.[CH3:20][C:21]([OH:25])([C:23]#[CH:24])[CH3:22]>CS(C)=O.C(N(CC)CC)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:3]1[C:2]([C:24]#[C:23][C:21]([OH:25])([CH3:22])[CH3:20])=[CH:18][C:6]2[C:7]3[N:8]=[C:9]([C:15]([NH2:17])=[O:16])[S:10][C:11]=3[CH2:12][CH2:13][O:14][C:5]=2[CH:4]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCc1sc(C(N)=O)nc1-2

Procedure:
The title compound was prepared according to a procedure similar to that described in Procedure G. Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed a suspension of 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (300 mg, 0.87 mmol, 1.00 equiv), 2-methylbut-3-yn-2-ol (260 mg, 3.09 mmol, 3.50 equiv) and Pd(PPh3)2Cl2 (60 mg, 0.09 mmol, 0.10 equiv) in DMSO (1 mL) and triethylamine (1 mL). The final reaction mixture was irradiated with microwave radiation for 1 h at 70° C. The resulting solution was diluted with 20 mL of water. The solids were collected by filtration and washed with 20 mL of ethyl acetate. This resulted in 0.24 g (79%) of 8-Fluoro-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as a off-white solid. LC-MS (ES, m/z): 347[M+H]+; 1H-NMR: (300 MHz, DMSO-d6, ppm) δ 8.652 (d, 1H), 8.460 (s, 1H), 7.860 (s, 1H), 7.007 (d, 1H), 5.497 (s, 1H), 4.391 (t, 2H), 3.414 (t, 2H), 1.491 (s, 6H).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH:11]=O>CO.[Pd].O>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH:5][CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: COC(C=O)OC
Reactant: CC(C)(C)CCN
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC(CNCCC(C)(C)C)OC
Reaction time: 3 h

Procedure:
A solution of 3,3-dimethylbutan-1-amine (1.33 mL) and 2,2-dimethoxyacetaldehyde (1.5 mL) in MeOH (10 mL) was added to palladium on carbon (0.316 g) in water (0.5 mL) at 25° C. The mixture of was hydrogenated under 5 bar at 25° C. for 3 h. The reaction mixture was filtered and concentrated in vacuo to afford N-(2,2-dimethoxyethyl)-3,3-dimethylbutan-1-amine (1.85 g) as a liquid. 1H NMR (300 MHz, CDCl3) δ 4.47 (t, J=5.6 Hz, 1H), 3.40 (s, 6H), 2.75 (d, J=5.8 Hz, 2H), 2.65-2.57 (m, 2H), 1.45-1.35 (m, 2H), 0.90 (s, 9H)
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][NH:13][C@H:14]1[CH2:33][N:18]2[C:19]3[C:24]([C:25]([CH2:26][C:27]([O:29]CCC)=[O:28])=[C:17]2[CH2:16][CH2:15]1)=[CH:23][CH:22]=[CH:21][CH:20]=3>>[CH3:12][N:13]([C:9](=[O:10])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:14]1[CH2:33][N:18]2[C:19]3[C:24]([C:25]([CH2:26][C:27]([OH:29])=[O:28])=[C:17]2[CH2:16][CH2:15]1)=[CH:23][CH:22]=[CH:21][CH:20]=3
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(Cl)COc1ccccc1
Product: CN(C(=O)COc1ccccc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from phenoxyacetyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 393.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[S:24](=[O:26])(=[O:25])[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:22](=[O:35])[CH2:21]3)=[CH:16][CH:15]=2)[CH:13]=1.Br[C:53]1[CH:58]=[CH:57][C:56]([Br:59])=[CH:55][N:54]=1>>[Br:59][C:56]1[CH:57]=[CH:58][C:53]([C:40]2[CH:39]=[CH:38][C:37]([CH2:36][C:11]3[N:12]([C:14]4[CH:19]=[CH:18][C:17]([N:20]5[S:24](=[O:25])(=[O:26])[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[C:22](=[O:35])[CH2:21]5)=[CH:16][CH:15]=4)[CH:13]=[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[N:10]=3)=[CH:42][CH:41]=2)=[N:54][CH:55]=1
Reactant: CC1(C)OB(c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)N(COCC[Si](C)(C)C)S4(=O)=O)cc3)cc2)OC1(C)C
Reactant: Brc1ccc(Br)nc1
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cn4)cc3)cc2)S1(=O)=O

Procedure:
5-(4-{4-(2,4-Dichloro-phenyl)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-imidazol-1-yl}-phenyl)-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (154 mg, 0.2 mmol) was treated as described in general procedure G using 2,5-dibromopyridine (95 mg, 0.4 mmol) to give 5-{-4-[2-[4-(5-bromo-pyridin-2-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one, which was again treated as described in general procedure G using cyclohexen-1-ylboronic acid (51 mg, 0.4 mmol) to give 5-{-4-[2-[4-(5-cyclohex-1-enyl-pyridin-2-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.