Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.N1CCCCC1>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:5]#[C:4][CH2:3][CH2:2][C:1]([OH:7])=[O:6])=[CH:10][CH:11]=1)#[N:14]
Reactant: N#Cc1ccc(Br)cc1
Reactant: C#CCCC(=O)O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C#CCCC(=O)O)cc1
Temperature: 80 °C

Procedure:
A solution of 4-pentynoic acid (2.15 g, 22 mmol), 4-bromobenzonitrile (3.64 g, 20 mmol), and piperidine (40 mL) was degassed by bubbling nitrogen through the solution for 5 min. prior to the addition of tetrakis(triphenylphosphine) palladium(0) (240 mg, 0.2 mmol). The reaction vial was sealed and warmed to 80° C. for 1.5 hours. After cooling to 23° C., the reaction mixture was diluted with ethyl acetate (200 mL), filtered, and concentrated in vacuo. The residue was diluted with ethyl acetate (300 mL), washed with 5% HCl (2×100 mL), washed with water (1×100 mL), and extracted with 3% sodium carbonate (2×200 mL). The basic aqueous layer was treated with decolorizing carbon, filtered, and acidified to pH=2. The resultant solid was filtered, washed with water, dried, and purified by flash chromatography (gradient ethyl acetate:methylene chloride:acetic acid 1:9:0.005) and fractional recrystallization (methylene chloride-ether) to afford 5-(p-cyanophenyl)-4-pentynoic acid as a white solid: m.p. 149°-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([C:11]([OH:13])=O)[CH2:5]2.[NH2:14][C:15]([CH3:19])([CH3:18])[CH2:16]O>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([C:11]1[O:13][CH2:16][C:15]([CH3:19])([CH3:18])[N:14]=1)[CH2:5]2
Reactant: CC(C)(N)CO
Reactant: O=C(O)C1Cc2ccc(Br)cc2C1
Solvent: Cc1ccccc1C
Product: CC1(C)COC(C2Cc3ccc(Br)cc3C2)=N1
Yield: 63 %

Procedure:
3.9 g of 5-bromo-2-indancarboxylic acid and 2 g of 2-amino-2-methyl-1-propanol were added to 100 ml of xylene. The mixture was heated under reflux for 24 hours while removing the water produced. The reaction mixture was concentrated in vacuo and 20 ml of water was added to the residue. The mixture was extracted with chloroform. The extract was washed with wa-ter, dried and then concentrated in vacuo. The residue was purified by silica gel column chromatography to give 3 g of 2-(5-bromoindan-2-yl)-4,4-dimethyloxazoline as an oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:17][CH:16]3[N:18](CC4C=CC=CC=4)[CH:12]([CH2:13][O:14][CH2:15]3)[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C>[C:1]1([S:7]([N:10]2[CH2:11][CH:12]3[NH:18][CH:16]([CH2:15][O:14][CH2:13]3)[CH2:17]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=S(=O)(c1ccccc1)N1CC2COCC(C1)N2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=S(=O)(c1ccccc1)N1CC2COCC(C1)N2
Temperature: 23 °C

Procedure:
A mixture of 7-benzenesulfonyl-9-benzyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (CAS 335620-96-7) (2.074 g, 5.66 mmol) and 10% palladium on carbon (780 mg, 10 mol %) in ethanol (130 mL) was hydrogenated at atmospheric hydrogen pressure at 50° C. for 1.5 days. Cooled to 23° C., filtered the catalyst off, washed with ethanol, the solvent was removed in vacuum to the title compound as a light yellow solid (1.253 g, 83%), MS (ISP) m/e=269.2 [(M+H)+].
Reaction SMILES: [C:1]1([C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[Br:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.CO.C[O-].[Na+].CN(C=O)C>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1.O>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][CH2:4][C:5]1[N:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:1]([OH:3])=[O:2]
Reactant: Oc1cccc(Br)c1
Reactant: O=C1OCc2ncccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: O=C(O)c1cccnc1COc1cccc(Br)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
[step 1] 4-Azaphthalide (15.0 g, 111.0 mmol) and 3-bromophenol (21.0 g, 121.4 mmol) were suspended in xylene (450 mL), and 28% sodium methoxide methanol solution (31.5 mL, 166.5 mmol) was added dropwise at 140° C. After stirring at 140° C. for 1 hr, DMF (10 mL) was added and the mixture was further stirred for 3 hr. Water and toluene were added to the reaction mixture, and the mixture was partitioned. The aqueous layer was neutralized with hydrochloric acid and the precipitated solid was collected by filtration to give 2-(3-bromophenoxymethyl)nicotinic acid (16.75 g, 49%). [step 2] 2-(3-Bromophenoxymethyl)nicotinic acid (10.0 g, 32.5 mmol) obtained in step 1 and polyphosphoric acid (70 g) were stirred at 170° C. for 3 hr. The reaction mixture was added to ice, and the mixture was neutralized with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give 8-bromo-5-oxo-5,11-dihydrobenzooxepino[3,4-b]pyridine (2.52 g, 27%). [step 3] Using 8-bromo-5-oxo-5,11-dihydrobenzooxepino[3,4-b]pyridine (3.70 g, 12.8 mmol) obtained in step 2 and in the same manner as in Reference Example B10, step 2, (Z)-2-(8-hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)propiononitrile (0.086 g, 2%) and (E)-2-(8-hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)propiononitrile (0.224 g, 6%) were obtained. [step 4] Using (Z)-2-(8-hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)propiononitrile (0.084 g, 0.30 mmol) obtained in step 3 and in the same manner as in Reference Example B2, the title compound (0.056 g, 63%) was obtained.
Reaction SMILES: [OH:1][C:2]([C:5]1[NH:9][N:8]=[C:7]([C:10]([O:12]CC)=[O:11])[CH:6]=1)([CH3:4])[CH3:3].[OH-].[Na+].Cl>C(O)C.C1COCC1>[OH:1][C:2]([C:5]1[NH:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)O)[nH]n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(O)c1cc(C(=O)O)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
Ethyl 5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxylate (1.609 mmol, 0.319 g) was dissolved in ethanol (1 ml) and THF (4 ml). 2 M NaOH (8.05 mmol, 4.02 ml) was added and the resulting mixture was stirred overnight at RT. The reaction mixture was carefully neutralized with HCl and evaporated. The residue was dissolved in a small amount of ethanol and the salts were removed by filtration. The filtrate was evaporated. 0.227 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.39 (s, 6H), 4.72 (bs, 1H), 6.24 (s, 1H), 12.20 (bs, 1H).
Reaction SMILES: Cl[C:2]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:5]([C:6]([N:8]([CH:22]([CH3:24])[CH3:23])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[O:7])=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH2:34]([NH2:36])[CH3:35]>C(O)C>[CH2:34]([NH:36][C:2]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:5]([C:6]([N:8]([CH:22]([CH3:24])[CH3:23])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[O:7])=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1)[CH3:35]
Reactant: CC(C)N(C(=O)c1cc([N+](=O)[O-])c(Cl)cc1C(F)(F)F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CCN
Solvent: CCO
Product: CCNc1cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (3R)-3-[[4-chloro-5-nitro-2-(trifluoromethyl)benzoyl](isopropyl)-amino]piperidine-1-carboxylate (930 mg) in ethanol (6 ml) was added ethylamine (2M methanol solution, 10 ml), and the mixture was stirred at 80° C. for 2 hours. The mixture was cooled, and the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (610 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1.O>C1(C)C=CC=CC=1>[CH:20]1([N:25]2[C@@H:7]3[C@@H:8]([C:9]4[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=4[CH2:5][CH2:6]3)[CH2:13][C:14]2=[O:16])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCC1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1C1CCCC1
Reaction time: 10 h
Yield: 46 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 3.0 ml (0.0305 mol) of cyclopentylamine were added thereto and the mixture was boiled for 40 hours on a water separator. After concentration the residue was hydrogenated with 1.2 g of Raney-nickel in 500 ml of ethanol at 120° and 140 bar for 10 hours. The product was chromatographed over silica gel with cyclohexane/ether 1:1. There were obtained 2.0 g (46%) of rac-cis-3-cyclopentyl-1,3,3a,4,5,9b-hexahydro-6-methoxy-2H-benzo[e]indol-2-one as white crystals with m.p. 84°-88°.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[F:59][C:60]([F:72])([F:71])[O:61]C1C=CC(C(Cl)=O)=CC=1>>[CH3:32][CH:31]([CH3:33])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][C:5]([O:61][C:60]([F:72])([F:71])[F:59])=[CH:6][CH:7]=4)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC(F)(F)F)cc4)cc3)cc2C1=O
Yield: 84 %

Procedure:
The compound of example 157 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-trifluoromethoxy benzoyl chloride.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12](Cl)[C:11]=2[C:10]([I:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][OH:20].C[O-].[Na+].O>CO>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([O:20][CH3:19])[C:11]=2[C:10]([I:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: Clc1nccc2c1c(I)nn2Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1nccc2c1c(I)nn2Cc1ccccc1

Procedure:
To a mixture of 1-benzyl-4-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (3.7 g) in methanol (40 mL) was added sodium methoxide methanol solution (1.5 M, 27 mL) at room temperature, and the reaction mixture was refluxed overnight. The reaction mixture was added to water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was washed with petroleum ether to give the title compound (3.6 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N+:10]([O-])=[CH:11]2)=[CH:6][CH:5]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[CH:13]=2)[CH:8]=[CH:9][N:10]=1
Reactant: COc1ccc2cc[n+]([O-])cc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Product: COc1ccc2ccnc(Cl)c2c1
Temperature: 90 °C

Procedure:
7-Methoxy-isoquinoline-N-oxide hydrochloride (38.2 g) was added in portions to phosphoryl chloride (275 mL) and the mixture heated at 90° C. for 6 h. Excess of phosphoryl chloride was removed in vacuo. The remaining white solid was washed with water, filtered and dried in vacuo. Yield: 28.3 g (81%) m.p. 77-78° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[C:14]([CH3:24])=[N:15][N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:17]=1)[CH:6]=[O:7].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[C:14]([CH3:24])=[N:15][N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:17]=1
Reactant: COc1cc(C=O)ccc1OCc1cn(-c2ccccn2)nc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1OCc1cn(-c2ccccn2)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a solution of 3-methoxy-4-[(3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)methoxy]benzaldehyde (1.30 g) in tetrahydrofuran (30 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.15 g) at room temperature. After stirring at room temperature for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give {3-methoxy-4-[(3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)methoxy]phenyl}methanol as colorless crystals (0.90 g, yield 69%) from a fraction eluted with ethyl acetate-hexane (3:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 135-136° C.
Reaction SMILES: [OH:1][C:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][CH:31]=1)[O:13][CH2:14][C:15]1[CH:16]=[C:17]([C:25](OC)=[O:26])[C:18](=[CH:23][CH:24]=1)[C:19](OC)=[O:20])[CH3:9].[BH4-].[Li+]>>[OH:26][CH2:25][C:17]1[CH:16]=[C:15]([CH:24]=[CH:23][C:18]=1[CH2:19][OH:20])[CH2:14][O:13][C:12]1[CH:11]=[C:10]([CH:8]([CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([CH3:33])([OH:1])[CH3:32])[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(COc2cccc(C(C)CCCCCC(C)(C)O)c2)cc1C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Product: CC(CCCCCC(C)(C)O)c1cccc(OCc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 53(e), by reacting 97 mg (0.21 mmol) of dimethyl 4-[3-(7-hydroxy-1,7-dimethyloctyl)phenoxymethyl]phthalate (prepared from the previous product in a manner similar to Example 64(d) with 14 mg (0.63 mmol) of lithium borohydride, a colourless oil is obtained (m=83 mg; Y=99%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=2[F:13])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Cc1ccc(B(O)O)c(F)c1
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)nc(-c2ccc(C)cc2F)c1
Temperature: 80 °C
Reaction time: 42 h
Yield: 42.1 %

Procedure:
To a solution of methyl 2,6-dichloroisonicotinate (3.34 g, 16.2 mmol) in toluene (100 mL) were added (2-fluoro-4-methylphenyl)boronic acid (1.4 g, 9.09 mmol), (tetrakistriphenylphosphine)palladium (0) (0.94 g, 0.81 mmol) and sodium carbonate (2.0 M in water; 8.1 g, 16.2 mmol). The mixture was degassed with nitrogen (3×) and heated to 80° C. After 42 h, the mixture was cooled to ambient temperature and saturated NaHCO3 was added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by reverse phase chromatography (C-18, 85% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (1.07 g). MS 280.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:12][C:13](=O)[CH3:14])[C:9](=O)C)=[C:4]([O:16][CH3:17])[CH:3]=1.C([O-])(=O)C.[NH4+:22].[OH-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:13]([CH3:14])[N:22]=[CH:9]2)=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: [NH4+]
Reactant: COc1cc(Br)ccc1N(CC(C)=O)C(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc(Br)ccc1-n1cnc(C)c1
Temperature: 120 °C
Yield: 93.2 %

Procedure:
A mixture of N-(4-bromo-2-methoxyphenyl)-N-(2-oxopropyl)acetamide (23.4 g), ammonium acetate (31.5 g), and acetic acid (49 g) was agitated under heating at 120° C. for 30 minutes. After the reaction solution was neutralized with sodium hydroxide under ice-cooling, the reaction solution was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system), and 19.4 g of the title compound was obtained.
Reaction SMILES: C([O:5][C:6](=[O:33])[C@H:7]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:8][C:9](=[O:25])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:24])[CH:16]([CH3:23])[CH2:17][S:18][C:19](=[O:22])[CH2:20][CH3:21])(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:19]([S:18][CH2:17][CH:16]([CH3:23])[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([NH:8][C@H:7]([C:6]([OH:33])=[O:5])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:25])=[O:24])(=[O:22])[CH2:20][CH3:21]
Reactant: CCC(=O)SCC(C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)SCC(C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 1 h

Procedure:
The 1-(3-propanoylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine tert-butyl ester obtained was dissolved in a mixture of anisole (10 ml) and trifluoroacetic acid (20 ml). The solution was allowed to stand at room temperature for one hour and concentrated to dryness under reduced pressure. The residue was chromatographed on silica gel with chloroform-methanol (98:2) to give 1-(3-propanoylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine. The diastereomeric mixture thus obtained was dissolved in a proper amount of diethyl ether. The solution was seeded with crystals of the title compound and stored in a refrigerator. The precipitated crystals were collected and recrystallized repeatedly from diethyl ether/petroleum ether to give the title compound, m.p. 107°-114° C. [α]D20 =-81.1° (c=1.00, ethanol)
Reaction SMILES: [N:1]#[N:2].C(OC([N:10]([CH2:25][CH3:26])[C@@H:11]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:14])[CH3:12])=O)(C)(C)C>C(OCC)(=O)C.Cl>[N:1]#[N:2].[CH2:25]([NH:10][C@@H:11]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:14])[CH3:12])[CH3:26]
Reactant: CCN(C(=O)OC(C)(C)C)[C@H](C)C(=O)NCCCc1ccccc1
Agent: Cl
Agent: N#N
Solvent: CCOC(C)=O
Product: CCN[C@H](C)C(=O)NCCCc1ccccc1
Yield: 103.9 %

Procedure:
A solution of N2 -(tert-butyloxycarbonyl)-N2 -ethyl-N-(3-phenylpropyl)-D-alaninamide (4.28 g.) in hydrogen chloride-ethyl acetate (3.9N, 35 ml.) was stirred for twenty minutes at room temperature, then concentrated. The residue was stripped of volatiles under vacuum (0.1 mm.) at room temperature, affording N2 -ethyl-N-(3-phenylpropyl)-D-alaninamide (3.22 g.).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13]CC1C=CC=CC=1)=[O:5])[CH3:2]>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)COCCCCCOCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)COCCCCCO

Procedure:
58 g (0.21 mol) of benzyl 5-ethoxycarbonylmethoxypentyl ether am dissolved in 580 ml of tetrahydrofuran and the solution is hydrogenate under normal pressure at room temperature by addition of 5.8 g of 10% Pd/C as catalyst. Upon cessation of hydrogenation, the catalyst is removed by filtration and the filtrate is concentrated by evaporation. Distillation of the residue gives 5-ethoxycarbonylmethoxypentanol as a colourless liquid of b.p. 107°-111° C./2.10-2 torr.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:22])[N:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18](Br)=[CH:19][N:20]=2)[N:17]=1)[CH3:7])([CH3:3])[CH3:2].Cl.[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClCCl.N#N>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:1]([O:4][C:5](=[O:22])[N:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:29]3[CH:30]=[CH:31][C:26]([CH2:25][NH2:24])=[CH:27][CH:28]=3)=[CH:19][N:20]=2)[N:17]=1)[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N(C)CCCNc1ccc2ncc(Br)n2n1
Reactant: NCc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)OC(=O)N(C)CCCNc1ccc2ncc(-c3ccc(CN)cc3)n2n1
Temperature: 85 °C

Procedure:
To a mixture of [3-(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-propyl]-methyl-carbamic acid isopropyl ester (601.4 mg, 1.6 mmol), (4-(aminomethyl)phenyl)boronic acid hydrochloride [75705-21-4] (366.3 mg, 2.0 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (1.1 g, 4.9 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), complex with dichloromethane [95464-05-4] (138.7 mg, 0.2 mmol) contained in a 50 mL round bottomed flask was added a solution of 30% (v/v) water in 1,2-dimethoxyethane (12 mL) and a magnetic stir bar. The reaction pot was fitted to a reflux condenser, lowered into an ambient temperature oil bath, and the system taken through 10 evacuation/N2 blanket cycles while being rapidly stirred. The rapidly stirred, N2 blanketed, reaction was heated to an oil bath temperature of 85° C. for 17 h then cooled and partitioned between brine (pH adjusted to 10 with 3N aqueous sodium hydroxide) and ethyl acetate. The phase separated extract was dried (MgSO4) purified by preparative RP-HPLC. Purified chromatography fractions were combined and partitioned between aqueous saturated sodium bicarbonate and ethyl acetate. The organic extract dried (CaSO4) and evaporated to provide {3-[3-(4-aminomethyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-propyl}-methyl-carbamic acid isopropyl ester as 19.4 mg of clear yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.12 (br. s., 2H) 1.17-1.28 (m, 4H) 1.84-1.98 (m, 2H) 2.90 (s, 2H) 3.10-3.21 (m, 1H) 3.32-3.43 (m, 3H) 3.88 (s, 2H) 4.78-4.87 (m, 4H) 6.69 (d, J=9.60 Hz, 1H) 7.45 (d, J=8.34 Hz, 2H) 7.61 (d, J=9.60 Hz, 1H) 7.69-7.75 (m, 1H) 8.12 (dd, J=8.21, 2.65 Hz, 2H). 13C NMR (100 MHz, METHANOL-d4) δ ppm 22.58, 37.39, 40.24, 46.39, 70.29, 110.81, 114.20, 125.95, 126.19, 127.75, 127.85, 128.87, 129.41, 129.65, 129.73, 130.34, 138.67, 141.99, 155.32. LRMS (ESI) m/z 397.3 [(M+H)]+, calc'd for C21H28N6O2: 396.50.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:17][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=1
Reactant: NCc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCc1cccc(F)c1
Temperature: 80 °C

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitrobenzene (500 mg, 2.273 mmol) and 3-fluorobenzylamine (370 mg, 2.95 mmol) in N,N-dimethylformamide (7 mL) was treated with potassium carbonate (1.00 g, 7.24 mmol) and heated at 80° C. for 1 hour. The mixture was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude title compound which was used without further purification.