Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:3][C:4](=[O:13])[O:5]CC1C=CC=CC=1.[CH2:32]([S:39](Cl)(=[O:41])=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)(=O)C.C(Cl)Cl>[C:33]1([CH2:32][S:39]([NH:1][C@H:2]([C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:15])[CH2:3][C:4](=[O:13])[OH:5])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)NCCc1ccccc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)C[C@H](NS(=O)(=O)Cc1ccccc1)C(=O)NCCc1ccccc1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
The keto amide (8) (109 mg, 0.24 mmol) was dissolved in ethyl acetate (5 mL) and cooled in an ice bath. Dry HCl gas was bubbled through until the solution was saturated and then the solution was stirred at r.t. until the starting material had been consumed as indicated by tlc (˜30 min). The solvent was removed under reduced pressure. The residue (22) was dissolved in dry CH2Cl2 (5 mL) and triethylamine (61 mg, 84 μL) added. The solution was then added dropwise to a solution of benzyl sulfonyl chloride (46 mg, 0.24 mmol) in dry CH2Cl2 (5 mL) cooled in an ice bath. The resulting solution was allowed to stir at r.t. for 16 h. It was washed with 1M HCl, 5% sodium bicarbonate solution and saturated brine, then dried (MgSO4) and the solvent removed under reduced pressure to yield the product as a white solid (51 mg, 42%): mp 128-130° C. 1H NMR (CDCl3) δ2.61 & 2.99 (ABX, 2H, β-CH2), 2.86 (t, 2H, CH2Ph), 3.57 (m, 2H, NH—CH2), 4.74 (m, 1H, α-CH), 5.14 (2×s, 4H, benzyl CH2's), 6.53 & 6.74 (m, 2H, NH's), 7.29 (m, 15H, aromatic CH's); FABMS m/e 509 (M++1).
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]3[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:6]3=[N:5][C:4]=2[CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[CH3:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]3[CH:12]=[C:13]([C:16]4[NH:20][N:19]=[N:18][N:17]=4)[CH:14]=[CH:15][C:6]3=[N:5][C:4]=2[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2nc3ccc(C#N)cn3c(=O)c2s1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cc2nc3ccc(-c4nnn[nH]4)cn3c(=O)c2s1
Temperature: 100 °C
Yield: 80.9 %

Procedure:
A mixture of 0.21 g (0.00087 mol) of 2-methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carbonitrile (Example 45), 0.2 g (0.0031 mol) of sodium azide and 0.166 g (0.0031 mol) of ammonium chloride in 50 ml of dimethylformamide is stirred and heated to 100° C. for twenty-four hours. The reaction mixture is cooled, poured into 900 ml of ice water and acidified with concentrated hydrochloric acid. The resulting precipitate is filtered to give 0.2 g of 2-methyl-7-(1H-tetrazol-5-yl)-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidin-10-one; mp 321°-325° C. (dec) after recrystallization from pyridine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][C:4]3[CH:3]=[C:2]([F:1])[CH:10]=[CH:9][C:5]=3[C:6](=[O:8])[C:14]=2[CH:15]=1
Reactant: O=C(O)c1ccc(F)cc1COc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C1c2ccc(F)cc2COc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
To 15 g of 4-fluoro-2-[(4-fluorophenyoxy)methyl]benzoic acid is added 60 g of thionyl chloride and the mixture is refluxed with heating for 1 hour. After cooling the reaction mixture to room temperature, dry toluene is added and the solvent is distilled off under reduced pressure. The residue is added with dichloromethane and the mixture is cooled to 0° C. and added with 15 g of powdery anhydrous aluminum chloride, which is stirred for 15 minutes. The reaction mixture is added with ice-water and extracted with toluene. After the extract is successively washed with water and a saturated saline solution and dried over magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is subjected to silica-gel chromatography and eluted with toluene to give 9.1 g of 2,8-difluoro-6,11-dihydrodibenz[b,e]oxepin-11-one (oil). Mass spectrum m/z: 246(M+).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[O:24])[CH2:19][CH2:18]1>>[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[CH2:18][CH2:19][N:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([N:4]3[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]3(=[O:8])=[O:7])=[CH:27][CH:26]=2)=[O:24])[CH2:21][CH2:22]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3)CC2)c(C)c1
Yield: 25.7 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (202 mg) described in Preparation Example 4 and [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (420 mg) described in Preparation Example 108 and by the reaction and treatment in the same manner as in Example 1, the title compound (110 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[C:10]#[C:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[C:27]([O:29][CH3:30])=[O:28].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=2[C:10]#[C:11][C:12]2[CH:17]=[N:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[CH:22][C:21]=1[O:20][CH3:19]
Reactant: COC(=O)c1ccc(B(O)O)cc1OC
Reactant: CCc1nccc(Cl)c1C#Cc1ccc(N)nc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nccc(-c2ccc(C(=O)OC)c(OC)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 1.5 g (5.0 mmol) 5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-ylamine (A-30) using 1.6 g (7.4 mmol) 3-methoxy-4-methoxycarbonylphenyl boronic acid, 135 mg (0.15 mmol) Pd2(dba)3, 354 mg (0.74 mmol) X-Phos and 2.2 g (9.4 mmol) K3PO4 in 20 mL dioxane. The reaction mixture is stirred under reflux over night. The solvent is removed under reduced pressure before water is added and the formed precipitate is collected by filtration. The product is purified by chromatography on silica gel using a DCM/MeOH-gradient. Yield: 1.07 g (56%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>CCN(CC)CC.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.[Cu]I>[CH3:11][Si:12]([CH3:14])([CH3:13])[C:15]#[C:16][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc([N+](=O)[O-])c1
Reaction time: 12 h
Yield: 94 %

Procedure:
A mixture of 3-iodonitrobenzene (2.0 g, 8.0 mmol), bis(triphenylphosphine)palladium(II) chloride (0.30 g, 0.40 mmol) and copper(I) iodide (0.080 g, 0.40 mmol) in 25 mL of Et3N was degassed by freeze/pump/thaw technique (three times). Trimethylsilylacetylene (1.0 g, 10 mmol) was added and the mixture was stirred for 12 hours. The reaction mixture was filtered through a celite pad and the pad was rinsed with CH2Cl2. The filtrate was washed with sat. NH4Cl (aq.) and brine and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (Hexane, then EtOAc;Hexanes =1:30) to afford trimethyl((3-nitrophenyl)ethynyl)silane (1.65 g, 94%): 1H-NMR (300 MHz, CDCl3) δ 8.32 (dd, J=1.8, 1.8 Hz, 1H), 8.17 (ddd, J=8.4, 2.1, 0.9 Hz, 1H), 7.76 (ddd, J=7.5, 1.2, 1.2 Hz, 1H), 7.49 (dd, J=8.1, 8.1 Hz, 1H), 0.28 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:13][CH3:14])=[C:7]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1)C.[OH-].[Li+]>C1COCC1.O>[CH2:15]([N:11]([CH2:12][CH2:13][CH3:14])[C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:24])=[O:3])=[CH:6][C:7]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17]
Reactant: CCCN(CC(C)C)c1ccc(C(=O)OCC)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CC(C)C)c1ccc(C(=O)O)cc1NS(C)(=O)=O
Temperature: 70 °C

Procedure:
To a solution of ethyl-4-[isobutyl(propyl)amino]-3-[(methylsulfonyl)amino]benzoate (7 g, 0.0196 mol) in THF (70 mL) was added lithium hydroxide (4.12 g, 0.098 mol) and water (70 mL). The reaction mixture was heated at 70° C. for 5 h. The reaction mixture was diluted with water (30 mL), washed with diethyl ether (50 mL). The aqueous layer was acidified with 1M HCl until pH=2, extracted with EtOAc (2×75 mL), washed with brine, dried over sodium sulphate and evaporated to afford the title compound as an off white solid (5.6 g, 86%). 1H NMR: (DMSO-d6, 400 MHz), δ 12.78 (s, 1H), 8.39 (s, 1H), 7.87 (s, 1H), 7.65 (m, 1H), 7.28 (m, 1H), 3.09 (s, 3H), 2.97 (m, 2H) 2.84 (m, 2H), 1.67 (m, 1H), 1.41 (m, 2H), 0.84 (m, 9H). LC/MS (Method A): 329.0 (M+H)+. HPLC (Method B) Rt 4.53 min (purity: 99.12%).
Reaction SMILES: [NH2:1][CH:2](/[CH:6]=[CH:7]/[CH2:8][PH2:9])[C:3]([OH:5])=[O:4].Cl>>[CH2:3]([O:4][C:3](=[O:5])[CH:2]([NH2:1])/[CH:6]=[CH:7]/[CH2:8][PH2:9])[CH2:2][CH2:6][CH3:7]
Reactant: NC(/C=C/CP)C(=O)O
Agent: Cl
Product: CCCCOC(=O)C(N)/C=C/CP

Procedure:
1.0 g of E-2-amino-5-phosphino-3-pentenoic acid is suspended in 20 ml ofn-butanol and the suspension is saturated with hydrogen chloride gas for 3 hours at 60°. After concentration, the residue is dissolved in 15 ml of n-butanol, 10 ml of propylene oxide are added and the precipitate isfiltered off. Recrystallisation from water/acetone 1:1 yields E-2-amino-5-phosphino-3-pentenoic acid butyl ester, m.p. 160°-161°.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[CH:34][C:33]([O:36][C@H:37]([CH2:42][CH3:43])[C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]>>[Cl:14][C:15]1[CH:35]=[CH:34][C:33]([O:36][C@H:37]([CH2:42][CH3:43])[C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](=[O:28])[NH:13][C@H:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=3)[CH3:12])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: CC[C@@H](Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1)C(=O)OC
Agent: Cl
Product: CC[C@@H](Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1)C(=O)OC

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(2-chloro-5-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:44])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:19][CH2:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])(=[O:18])=[O:17])[C:5](=[O:29])[N:4]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[C:32]([C:39](F)(F)F)[CH:31]=2)[C:3]1=[O:43].CC1(C)C(=O)N(C2C=CC([NH:58][S:59](N)(=[O:61])=[O:60])=C(C)C=2)C(=O)N1CCCCCCCCCS(CCCC(F)(F)C(F)(F)F)=O>>[CH3:44][C:2]1([CH3:1])[C:3](=[O:43])[N:4]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][S:59]([NH2:58])(=[O:61])=[O:60])=[C:32]([CH3:39])[CH:31]=2)[C:5](=[O:29])[N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:19][CH2:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:24])[F:25])(=[O:18])=[O:17]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F
Reactant: Cc1cc(N2C(=O)N(CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1NS(N)(=O)=O
Product: Cc1cc(N2C(=O)N(CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1NS(N)(=O)=O

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 3, the compound of Example 31 replacing the compound of Example 2. A colourless oil is obtained.
Reaction SMILES: C(OC([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33]([N:35]2[CH2:40][CH2:39][CH:38]([C:41]([OH:43])=[O:42])[CH2:37][CH2:36]2)=[O:34])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:44].O1CCOCC1>O1CCOCC1>[ClH:44].[C:11]1([C@H:9]([NH:8][CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:25][N:24]([C:33]([N:35]3[CH2:40][CH2:39][CH:38]([C:41]([OH:43])=[O:42])[CH2:37][CH2:36]3)=[O:34])[CH2:23]2)[CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)N2CCC(C(=O)O)CC2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NC[C@H]1CN(C(=O)N2CCC(C(=O)O)CC2)C[C@@H]1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 3.0 ml ethanol solution of 105 mg of ethyl 1-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}piperidine-4-carboxylate was mixed at room temperature with 1.0 ml of 1 M sodium hydroxide aqueous solution and stirred overnight at room temperature. The reaction solution was concentrated under a reduced pressure, acidified by adding 1 M hydrochloric acid and then extracted with chloroform and dried with anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography to obtain 86 mg of 1-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}piperidine-4-carboxylic acid as a white amorphous substance. A 2.0 ml 1,4-dioxane solution of 86 mg of 1-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}piperidine-4-carboxylic acid was mixed at room temperature with 1.0 ml of 4 M hydrogen chloride/1,4-dioxane and stirred overnight at room temperature. The reaction solution was concentrated and crystallized with 1,4-dioxane-diisopropyl ether to obtain 80 mg of 1-{[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}piperidine-4-carboxylic acid hydrochloride as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si](C(C)(C)C)(C)C)[CH:6]=[CH:5]2.C([Li])CCC.C(=O)=O.[CH2:28]([O:35][CH:36]1[CH2:41][CH2:40][C:39](=[O:42])[CH:38]([CH2:43][N:44]([CH3:46])[CH3:45])[CH2:37]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1.CCCCCC.O>[CH2:28]([O:35][CH:36]1[CH2:41][CH2:40][C:39]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]3)([OH:42])[CH:38]([CH2:43][N:44]([CH3:46])[CH3:45])[CH2:37]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN(C)CC1CC(OCc2ccccc2)CCC1=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CN(C)CC1CC(OCc2ccccc2)CCC1(O)c1ccc2cc(O)ccc2c1
Temperature: 0 °C
Yield: 70.9 %

Procedure:
3.87 g (6-bromonaphthalen-2-yloxy)-tert.-butyldimethylsilane were dissolved in 19 ml THF p.a., 6.0 ml 1.6 M butyl lithium solution in hexane added dropwise with dry ice cooling, briefly stirred, then a solution of 2.00 g 4-benzyloxy-2-dimethylaminomethylcyclohexanone in 20 ml THF p.a. added dropwise and stirred for 1 hour while slowly heating. For working up, 4 ml water were added to the ice bath, the organic phase separated, the aqueous phase extracted twice with diethyl ether, the combined organic phases dried by sodium sulphate, filtered and concentrated. The crude product obtained (5.00 g) was chromatographed with ethyl acetate/methanol (V/V=1:1) on silica gel. 2.20 g 6-(4-benzyloxy-2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-naphthalen-2-ol were obtained and converted into the corresponding hydrochloride (1.33 g) in the same way as in AAV 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13](I)=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].C([Mg]Br)(C)C.CN(C1C=CC=CN=1)[CH:23]=[O:24].Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([CH:23]=[O:24])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(I)ccc2s1
Reactant: CN(C=O)c1ccccn1
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(C=O)ccc2s1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
To a solution of 5-iodo -benzo[b]thiophene-2-carboxylic acid ethyl ester (14.09 g, 42.42 mmol) at −40° C. was slowly added a solution of isopropylmagnesium bromide (0.7 M in THF, 85 mL, 59.5 mmol). The mixture was allowed to stir at −40° C. for 2 h and N-methyl-N-pyridin-2-yl-formamide (7.65 mL, 63.9 mmol) was added slowly. After warming to rt, the mixture was allowed to stir for additional 2.5 h. To the mixture was carefully added 250 mL of 1N HCl. After stirring for 10 min, the reaction mixture was diluted with CH2Cl2 (800 mL). The organic layer was separated, washed with 200 mL of saturated NaHCO3 and dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was recrystallized from MeOH to give 5-formyl-benzo[b]thiophene-2-carboxylic acid ethyl ester as a yellow solid. 1H NMR (CDCl3, 200 MHz) δ 10.12 (s, 1H), 8.37 (s, 1H), 8.18 (s, 1H), 8.08-7.90 (m, 2H), 4.44 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.4 Hz, 3H). MS (EI): cal'd 235.0 (MH+), exp 235.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[C:4]([OH:19])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(OCCCC)(=O)C>[N:26]1([C:32]([O:19][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=2[O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Reactant: O=C(Cl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOC(C)=O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1OC(=O)N1CCOCC1
Yield: 99.2 %

Procedure:
To 6.50 g (23.5 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol were added 39 g of butyl acetate and 3.57 g (25.9 mmol) of potassium carbonate, and the resultant mixture was stirred at 50° C. To the mixture was added dropwise 3.87 g (25.9 mmol) of morpholinecarbonyl chloride over one hour. The reaction mixture was subjected to reaction at 50° C. for 6 hours. After completion of the reaction, the resultant opaque mixture was subjected to filtration, and washed with butyl acetate, and then the resultant organic phase was quantitatively determined by an HPLC internal standard analysis method, which showed that 9.09 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl morpholine-4-carboxylate (yield: 99%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH:23][CH2:24][CH2:25][CH:26]=[CH2:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[CH2:16]([N:23]([CH2:24][CH2:25][CH:26]=[CH2:27])[C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH:14]=[CH2:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CCCNCc1ccccc1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: C=CCCN(Cc1ccccc1)C(=O)[C@H](CC=C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.5 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (400 mg, 1.86 mmol), N-benzylbut-3-en-1-amine (449 mg, 2.79 mmol) in DMF (5 mL) was added EDC (410 mg, 2.14 mmol), HOBt (370 mg, 2.42 mmol) and followed by TEA (0.259 mL, 1.858 mmol). The reaction was stirred at rt for 3 days. The reaction was diluted with EtOAc and washed with water (2×), 1 M aqueous KHSO4 (2×), saturated aqueous NaHCO3 (2×) and saturated aqueous NaCl. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-60% EtOAc/Hex to give (S)-tert-butyl 1-(benzyl(but-3-enyl)amino)-1-oxopent-4-en-2-ylcarbamate (270 mg, 0.753 mmol, 40.5% yield). Anal. Calcd. for C21H30N2O3 m/z 358.4. found: 359.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.43-7.13 (m, 5H), 5.85-5.62 (m, 2H), 5.40-5.27 (m, 1H), 5.19-4.97 (m, 3H), 4.87 and 4.37 (d, J=14.9 Hz, 1H), 4.76-4.51 (m, 2H), 3.59-3.22 (m, 3H), 2.39 (ddq, J=25.6, 21.3, 7.1 Hz, 4H), 1.44 and 1.42 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Na+].[C:13]1([S:19]([O-:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1OCCOCCOCCOCCOCCOC1>CC#N>[C:13]1([S:19]([CH2:2][C:3]2[O:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S([O-])c1ccccc1
Reactant: BrCc1nc2ccccc2o1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: O=S(=O)(Cc1nc2ccccc2o1)c1ccccc1
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To 9.1 g (0.043 mol) of 2-bromomethyl-benzooxazole in CH3CN (300 mL) were added 7.39 g (0.045 mol, 1.05 eq) of benzenesulfinic acid sodium salt and 2.27 g (8.6 mmol, 0.2 eq) of 18-crown-6. Stirring was continued overnight, solvent evaporated and a column chromatography afforded 8.1 g (70%) of 2-benzenesulfonylmethyl-benzooxazole as a white solid, MS: 274 (H+). (Y. Nagao, S. Yamada, E. Fujita, Tet. Lett., 1983, 24, 2291)
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8](OCC)=[O:9].[NH2:24][CH2:25][C:26]([OH:28])=[O:27].[O-]CC.[Na+].Cl>CN(C=O)C.O>[OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:9]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(-c3ccc(OC)cc3)noc2c1O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2noc3c(O)c(C(=O)NCC(=O)O)ncc23)cc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
Ethyl 7-hydroxy-3-(4-methoxyphenyl)isoxazolo[4,5-c]pyridine-6-carboxylate (0.12 g, 0.38 mmol) was dissolved in 10 mL of DMF. Glycine (0.574 g, 7.64 mmol) and sodium ethoxide (0.391 g, 5.73 mmol) were added and the mixture was refluxed for 2 h. The mixture was cooled to room temperature and diluted with 70 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 3. The resulting suspension was filtered and the solid was dried under vacuum to give 94 mg of the title compound. MS: (+) m/z 344.37 (M+1).