Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C.[Cl-].[Na+]>C1COCC1>[CH:20]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1)=[O:21]
Reactant: CN(C)C=O
Reactant: COc1cc(Br)ccc1C#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1C#N
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 4-bromo-2-methoxybenzonitrile (1.0 g, 4.7 mmol) in 30 mL of anhydrous THF was added BuLi (1.6 M, 3.3 mL, 5.2 mmol) dropwise at −78° C. under nitrogen atmosphere. After the addition, the pale red solution was stirred for 5 min at −78° C. and dry DMF (0.6 mL) then added dropwise. After 20 min, the reaction mixture was poured onto a saturated solution of sodium chloride (50 mL). The organic phase was separated, extracted with diethyl ether (100 mL), dried over Na2SO4 and distilled off the solvent to afford 4-formyl-2-methoxybenzonitrile. MS m/z: 162 (M+1)+.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C@@H:14]3[CH3:19])=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:27]([O:31][C:32]([NH:34][C@H:35]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([F:47])[CH:41]=1)[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][C@@H:35]([NH:34][C:32](=[O:33])[O:31][C:27]([CH3:28])([CH3:29])[CH3:30])[C:36]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][CH2:6][C:7]=4[N:8]=[CH:9][N:10]=3)[C@@H:14]([CH3:19])[CH2:15]2)=[O:37])=[CH:41][C:42]=1[F:47]
Reactant: C[C@@H]1CCc2ncnc(N3CCNC[C@@H]3C)c21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)c(F)c1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)c(F)c4)NC(=O)OC(C)(C)C)C[C@@H]3C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a solution of (R)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (32 mg, 0.14 mmol) in DCM (5 mL) were added triethylamine (1 mL), (R)-2-(tert-butoxycarbonylamino)-3-(4-chloro-3-fluorophenyl)propanoic acid (44 mg, 0.14 mmol) and HBTU (52 mg, 0.14 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate to afford tert-butyl (R)-3-(4-chloro-3-fluorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (55 mg, 82%). 1H NMR (CDCl3, 400 MHz) δ 8.46 (s, 1H), 7.31-6.85 (m, 3H), 5.45-5.18 (m, 1H), 4.90-4.60 (m, 2H), 4.50-4.30 (m, 1H), 4.20-4.00 (m, 1H), 3.90-3.60 (m, 2H), 3.40 (m, 1H), 3.20-2.70 (m, 2H), 2.24 (m, 1H), 1.70 (m, 1H), 1.42 (s, 9H), 1.30-0.98 (m, 6H). MS (APCI+) [M+H] +532.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH3:28])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: Fc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Reactant: CNCCOC
Product: COCCN(C)CCCCOc1ccc2c(-c3ccc(F)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[d]isothiazole and N-(2-Methoxyethyl)methylamine were converted to yield {4-[3-(4-Fluoro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine which was transferred into its salt by treatment with formic acid, MS: 389 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][C:11]=2[O:20][CH3:21])=[C:4]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOC(C)=O.[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([CH2:14][OH:15])=[CH:12][C:11]=2[O:20][CH3:21])=[C:4]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(C(=O)OC)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CO)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 42.4 %

Procedure:
A solution of the product from step (iv) (2.4 g) in THF (50 mL) was added portionwise over 10 min to a stirred solution of lithium aluminum hydride (1M in THF; 12.89 mL) in THF (50 mL) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 10 min and then at rt for 1 h. EtOAc (20 mL) was added portionwise over 10 min and the resulting mixture stirred for a further 20 min. The mixture was added portionwise to 2M NaOH (300 mL) and stirred for 30 min. The resulting suspension was filtered through a pad of celite and the resulting biphasic filtrate separated. The aqueous phase was extracted with EtOAc (200 mL) and the combined organic phase was dried, filtered and evaporated. The crude product was purified by chromatography, eluting with 5 to 10% MeOH in DCM. to afford the subtitle compound as a colorless gum 0.94 g.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].CO>C(OCC)(=O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:30])([F:32])[F:31])[CH:23]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccc(Cl)c(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-(3-trifluoromethyl-4-chlorophenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 85% overall yield. FDMS m/e=469 (M+ of free base). α[D]589 =-11.53 c=0.54, methanol).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:27]=[C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:1]([C:3]2[N:8]=[C:7]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)NCCc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 64.4 %

Procedure:
tert-Butyl 2-(6-cyano-2-pyridyl)ethylcarbamate (2.0 g, 8.1 mmol) and methyl thiosalicylate (2.0 g, 12 mmol) were dissolved in toluene (10 ml), and triethylamine (5.0 ml, 36 mmol) was added thereto. The mixture was refluxed for 14 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (3:2, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (2.0 g, 64%) as white crystals.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:27])[C@@H:8]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][CH2:10][O:11][Si](C(C)(C)C)(C)C)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C>C(O)(=O)C.C1COCC1.O>[CH:1]1([O:6][C:7](=[O:27])[C@@H:8]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:9][CH2:10][OH:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO[Si](C)(C)C(C)(C)C)C(=O)OC1CCCC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OC1CCCC1
Temperature: 30 °C
Reaction time: 16 h

Procedure:
(S)-2-tert-Butoxycarbonylamino-4-(tert-butyl-dimethyl-silanyloxy)-butyric acid cyclopentyl ester (1.57 g, 3.9 mmol) was dissolved in acetic acid:THF:water (3:1:1, 100 ml). The reaction mixture was stirred at 30° C. for 16 hours for complete reaction. Ethyl acetate (200 ml) was added and washed with 1M Na2CO3, 1M HCl and brine. The ethyl acetate extracts were dried over magnesium sulphate and evaporated under reduced pressure to give the product as a clear oil which crystallised on standing (1.0 g, 95%). LCMS purity 100%, m/z 310.3 [M++Na], 1H NMR (300 MHz, CDCl3), δ: 5.40 (1 H, d, J=6.5 Hz), 5.20 (1 H, m), 4.40 (1H, m), 3.65 (2H, m), 2.15 (1H, m), 1.90-1.55 (9H, bm), 1.45 (9H, s).
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[F:9][C:10]([F:24])([F:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=O)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH2:1]([CH:4]1[CH2:7][O:8][CH:21]([CH2:20][CH2:19][CH2:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C:10]([F:9])([F:23])[F:24])=[CH:16][CH:15]=2)[O:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC(CO)CO
Reactant: O=CCCCCc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: CCCC1COC(CCCCc2ccc(C(F)(F)F)cc2)OC1
Yield: 51.2 %

Procedure:
2-Propyl-1,3-propanediol 5.90 g (49.9 mmol) and the above 5-(4-trifluoromethylphenyl)pentanal 7.50 g (32.6 mmol) were dissolved in toluene 70 ml, and PTS 1 g was added, and the mixture was refluxed with heating for 3 hours while removing water formed with Dien-Stark. The reactant was washed with a saturated sodium bicarbonate aqueous solution, and then with saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: toluene), and recrystallized twice from ethanol to obtain 5-propyl-2-(4-(4-trifluoromethylphenyl)butyl)-1,3-dioxane 5.55 g (16.7 mmol). The yield was 51.2% from 5-(4-trifluoromethylphenyl) pentanal.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C@@H:13]([C:15]1[CH:19]=[C:18]([C:20]([OH:22])=O)[O:17][N:16]=1)[CH3:14])=[O:11].CN(C([O:30][N:31]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O1CCCCC1ON>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C@@H:13]([C:15]1[CH:19]=[C:18]([C:20]([NH:31][OH:30])=[O:22])[O:17][N:16]=1)[CH3:14])=[O:11]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[C@@H](NC(=O)c1cc2ccccc2o1)c1cc(C(=O)O)on1
Agent: F[P-](F)(F)(F)(F)F
Agent: NOC1CCCCO1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cc2ccccc2o1)c1cc(C(=O)NO)on1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the crude (R)-3-(1-(benzofuran-2-carboxamido)ethyl)isoxazole-5-carboxylic acid in a microwave vial was added HATU (0.0544 g, 0.143 mmol), TEA (0.087 g, 0.858 mmol) in DMF (1.0 mL), followed by O-(tetrahydropyran-2-yl)hydroxylamine (0.0335 g, 0.286 mmol) in DMF (1.0 mL). The mixture was shaken at rt for 16 h, then the solvent was evaporated. To the residue was added THF (2.0 mL) and hydrochloric acid (0.0715 mL, 4.0 M in 1,4-dioxane). After shaking at rt for 1 h, the solvent was evaporated. To the residue was added DMSO (1.2 mL). After filtration, the solution was purified by prep-HPLC to give ((R)-3-(1-(benzofuran-2-carboxamido)ethyl)-N-hydroxyisoxazole-5-carboxamide. LC-MS: (FA) ES+ 347.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5]Br)[CH3:2].[OH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:10][C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:35])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:28])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(C(C)=O)C>[CH2:1]([O:3][CH2:4][CH2:5][O:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:10][C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:35])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:28])[CH:21]=1)[CH3:2]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCOCC)c1
Yield: 95.6 %

Procedure:
In a manner similar to that of Example (25a), by reaction of 230 mg (1 mmol, 1.5 eq) of 2-bromoethyl ethyl ether and 400 mg (1.0 mmol, 1 eq) of methyl 3-[2-hydroxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate (prepared as in Example 46d) in 10 ml of methyl ethyl ketone in the presence of 415 mg (3.0 mmol, 3 eq) of potassium carbonate and 60 mg (0.4 mmol, 0.4 eq) of sodium iodide at 90° C. for 48 hours, 450 mg of methyl 3-[2-(2-ethoxyethoxy)-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate are obtained in the form of a yellow oil. Yield=96%
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]1[N:24]([CH3:25])[N:23]=[C:22]([C:26](Cl)=[O:27])[CH:21]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26]([C:22]1[CH:21]=[C:20]([C:16]2[O:15][CH:19]=[CH:18][CH:17]=2)[N:24]([CH3:25])[N:23]=1)=[O:27]
Reactant: Cn1nc(C(=O)Cl)cc1-c1ccco1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1-c1ccco1
Yield: 75.9 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g, 0.432 mmol), 5-(furan-2-yl)-1-methyl-1H-pyrazole-3-carbonyl chloride (0.096 g; 0.454 mmol), and triethylamine (0.156 mL; 1.08 mmol) in dichloromethane (2.87 mL). Flash chromatography on silica gel eluting with 5% of ethyl acetate in dichloromethane gave 0.121 g (98%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(furan-2-yl)-1-methyl-1H-pyrazole-3-carboxamide as a solid.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I:12](O)(=O)(=O)=O.S(=O)(=O)(O)O.II>O.C(O)(=O)C>[I:12][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][C:1]([OH:11])=[O:10])=[CH:9][CH:8]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: O=C(O)CCc1ccccc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCc1ccc(I)cc1
Temperature: 105 °C
Yield: 460.8 %

Procedure:
Hydrocinnamic acid is iodinated to form 4-iodohydrocinnamic acid. The process is performed by mixing 201.2 g hydrocinnamic acid, 1 L acetic acid, 152 mL water, 52.8 g periodic acid, 76 mL sulfuric acid, and 144 g iodine. The mixture is heated at 105° C. for 6.5 hours. Next, 200 mL water is added, and the mixture is cooled to room temperature overnight. The solid product in the resultant mixture is filtered and washed with water, yielding 350 g unpurified 4-iodohydrocinnamic acid. Further purification is not necessary and is not conducted, and the product is used as is in the second step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([O-])(=O)C.[NH4+].C([O-])(=O)C.[Na+].C([BH3-])#[N:26].[Na+]>C(O)(=O)C.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH2:26])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(C)=O)cc1OC
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CC(C)N)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
To 2 g (10.29 mmol) of 3,4-dimethoxyphenyl acetone was added 10 mL of methanol, 7.9 g (102 mmol) of ammonium acetate, 844 mg (10.2 mmol) of sodium acetate and 970 mg (15.4 mmol) of sodium cyanoborohydride. The pH of the reaction was adjusted to between 6-7 by addition of glacial acetic acid. The reaction mixture was allowed to stir at room temperature 18 hours and concentrated under reduced pressure. To the residue 100 mL of water was added, and the pH of the reaction was adjusted to 14 using 6 N NaOH. The aqueous layer was extracted with 6×30 mL of chloroform. Organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure to give 2 g (10.24 mmol, 99%) of 3A as a light yellow gum (M+H, 196).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1.O.NN.[OH-].[K+]>C(O)COCCO>[CH3:23][O:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:1])[C:11]([CH2:12][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[CH:10]2
Reactant: COc1ccc2nc(N)c(C(=O)c3ccccc3OC)cc2c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: COc1ccc2nc(N)c(Cc3ccccc3OC)cc2c1
Temperature: 160 °C

Procedure:
(2-Amino-6-methoxyquinolin-3-yl)(2-methoxyphenyl)methanone (1.1 g, 3.6 mmol) was dissolved in diethylene glycol (15 mL), mixed with hydrazine hydrate (0.56 mL, 18 mmol) and pulverized potassium hydroxide (1.1 g, 19.8 mmol) and heated to 160° C. for 1.5 hours.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]#[N:32])[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:33]([CH2:35]N)[OH:34].CCN(C(C)C)C(C)C>CCO>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]5[O:34][CH2:33][CH2:35][N:32]=5)[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(C#N)c4)cc3C2)c1
Reactant: NCCO
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(C5=NCCO5)c4)cc3C2)c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of N-(3-tert-butylphenyl)-7-[(2-cyanopyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxamide (1.184 g, 2.78 mmol) in EtOH (30 mL) was added ethanolamine (1.00 mL, 16.6 mmol) and DIPEA (1.00 mL, 5.74 mmol). The reaction mixture was allowed to stir at 100° C. for 12 h. The mixture was concentrated and the residue was diluted with water and EtOAc. The solution was extracted with EtOAc and the organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-(3-tert-butylphenyl)-7-{[2-(4,5-dihydro-1,3-oxazol-2-yl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-305 (1.069 g, 82%) as a white solid. 1H NMR (400 MHz, d6-DMSO, HCl salt) δ: 9.97 (s, 1H), 9.02 (t, 1H), 8.52 (d, 1H), 7.66-7.62 (m, 1H), 7.52-7.47 (m, 1H), 7.40-7.36 (m, 1H), 7.26-7.17 (m, 3H), 7.08-6.94 (m, 3H), 3.72 (t, 2H), 3.59 (q, 2H), 2.97-2.71 (m, 5H), 2.15-2.06 (m, 1H), 1.85-1.74 (m, 1H), and 1.25 (s, 9H). LCMS: (FA) ES+470.4, ES−468.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][S:18][CH2:17]3)=[O:15])[O:11][C:10]=2[C:21]2[CH:22]=[C:23]([C:27]#[N:28])[CH:24]=[CH:25][CH:26]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:37])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][S:18](=[O:37])[CH2:17]3)=[O:15])[O:11][C:10]=2[C:21]2[CH:22]=[C:23]([C:27]#[N:28])[CH:24]=[CH:25][CH:26]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1cccc(-c2oc(C(=O)N3CCSC3)cc2-c2cc(F)cc(Cl)c2)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cccc(-c2oc(C(=O)N3CCS(=O)C3)cc2-c2cc(F)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
95.0 mg (0.23 mmol) of the compound from Example 1 are provided in 3 ml of dichloromethane, and 51.6 mg (0.23 mmol) of meta-chloroperbenzoic acid are added. The mixture is stirred at room temperature overnight, a saturated aqueous sodium thiosulfate solution is subsequently added and the reaction mixture is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water gradient). 63.0 mg (64% of theory) of the title compound are obtained.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:27]=[CH:26][C:11]([CH2:12][C:13]2[O:17][C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([OH:24])[CH:23]=3)=[N:15][N:14]=2)=[CH:10][CH:9]=1.[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43]Br)[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]>O1CCCC1.CN(C)C=O>[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43][O:24][C:22]3[CH:23]=[C:18]([C:16]4[O:17][C:13]([CH2:12][C:11]5[CH:26]=[CH:27][C:8]([Cl:7])=[CH:9][CH:10]=5)=[N:14][N:15]=4)[CH:19]=[CH:20][C:21]=3[CH3:25])[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]
Reactant: Cc1ccc(-c2nnc(Cc3ccc(Cl)cc3)o2)cc1O
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nnc(Cc5ccc(Cl)cc5)o4)ccc3C)csc12
Temperature: 68 °C
Reaction time: 2 h

Procedure:
A suspension of cesium carbonate (0.54 g, 1.66 mmol), 5-[5-(4-chloro-benzyl)-[1,3,4]-oxadiazol-2-yl]-2-methyl-phenol (0.36 g, 1.20 mmol) (from Example 40 supra) in tetrahydrofuran/N,N-dimethylformamide (5:2, 21 mL) was heated at 68° C. for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.36 g, 1.08 mmol) (from Example 1 supra) was added. Heating was continued for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phase washed with water and brine, dried (magnesium sulfate) and concentrated. The residue washed with ethyl acetate and dried to give 4-chloro-3-{5-[5-(4-chloro-benzyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.17 g, 26%).
Reaction SMILES: N1C=CC=CC=1.Cl.[OH:8][CH:9]([C:17]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]2[C:18]=1[CH2:19][CH2:20][C:21](=[O:28])[NH:22]2)[CH:10]([NH:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH3:12].[C:29]([Cl:34])(=[O:33])[CH:30]([CH3:32])[CH3:31].C(OCC)C>CC(C)=O>[ClH:34].[OH:8][CH:9]([C:17]1[CH:26]=[CH:25][C:24]([O:27][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])=[C:23]2[C:18]=1[CH2:19][CH2:20][C:21](=[O:28])[NH:22]2)[CH:10]([NH:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH3:12]
Reactant: CCC(NC(C)C)C(O)c1ccc(O)c2c1CCC(=O)N2
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCC(NC(C)C)C(O)c1ccc(OC(=O)C(C)C)c2c1CCC(=O)N2
Temperature: 0 °C

Procedure:
25 ml of pyridine was added to 1 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxy-3,4-dihydrocarbostyril hydrochloride, and 3 ml of isobutyryl chloride was added dropwise to the mixture while cooling with ice-water and stirring followed by stirring for 3 hours. After addition of about 200 ml of diethyl ether, acetone was added to the precipitate formed to obtain a crystalline product. The product thus obtained was recrystallized from acetone to obtain 0.8 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-isobutyryloxy-3,4-dihydrocarbostyril hydrochloride having a melting point of 239°-240° C. (with coloration and decomposition).