Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH2:15][N:16]3[C:20](=O)[CH2:19]O[CH-]3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(OC(C)C)(C)C.[BrH:29]>C(O)(=O)C>[BrH:29].[BrH:29].[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH2:15][NH:16][CH2:20][CH2:19]3)=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: O=C1CO[CH-]N1CCNc1ccc(N2CCOCC2)cc1
Agent: Br
Solvent: CC(C)OC(C)C
Solvent: CC(=O)O
Product: c1cc(N2CCOCC2)ccc1N1CCNCC1

Procedure:
A solution of 3-[2-(4-morpholinophenylamino)ethyl]-2-oxazolidone (5 g) in 30% hydrobromic acid in acetic acid (35 ml) was stirred for 24 hours at ambient temperature. The reaction mixture was pulverized with diisopropyl ether. The precipitate was collected by filtration and added to ethanol (35 ml). The solution was refluxed for 8 hours and pulverized with diisopropyl ether. The precipitate was collected by filtration to give 1-(4-morpholinophenyl)-piperazine dihydrobromide (7.42 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19]C)[CH:3]=1.[C:21]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])([CH3:23])[CH3:22]>>[Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:17][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:27])[CH3:26])=[CH:15][CH:16]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:27])[CH3:26])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(O[Si](C)(C)C(C)(C)C)cc(Br)c3o2)cc1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 24, Route a, Step a, from 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole, and tert-butyl(chloro)dimethylsilane. The desired product was obtained as a white solid, m.p. 90-91° C.; MS m/e 534 (M+H)+.
Reaction SMILES: CC([CH:5]1[C:14]2[C:9](=[C:10]([C:15]([NH:17][OH:18])=[NH:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][N:6]1[C:19]([O-:21])=[O:20])(C)C.[H-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH:36]([CH3:38])[CH3:37])[C:28](OC)=O>O1CCCC1>[Cl:24][C:25]1[CH:26]=[C:27]([C:28]2[O:18][N:17]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[C:14]4[C:9]=3[CH2:8][CH2:7][N:6]([C:19]([O:21][C:9]([CH3:14])([CH3:10])[CH3:8])=[O:20])[CH2:5]4)[N:16]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH:36]([CH3:38])[CH3:37]
Reactant: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Reactant: CC(C)(C)C1c2cccc(C(=N)NO)c2CCN1C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(C(=O)OC(C)(C)C)C4)no2)cc1Cl
Yield: 159.5 %

Procedure:
1,1-dimethylethyl5-[(hydroxyamino)(imino)methyl]-3,4-dihydro-2(1H)-isoquinoline carboxylate (Preparation 1) (2 g, 6.86 mmol) was dissolved in tetrahydrofuran (THF) (100 mL) and stirred with sodium hydride (60% dispersion, 0.302 g, 7.55 mmol) under argon at room temperature for 30 minutes. Then methyl 3-chloro-4-[(1-methylethyl)oxy]benzoate (Preparation 2, 2.355 g, 10.30 mmol) was added and the reaction heated at reflux temperature for 1.5 hours. The cooled reaction was evaporated and partitioned between DCM (100 mL) and water (100 mL). The water layer was washed with DCM (50 mL) and the combined DCM layers dried (hydrophobic frit) and evaporated. The crude product was purified by chromatography through a small silica pad, eluting with DCM to yield 1,1-dimethylethyl 5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2(1H)-isoquinoline carboxylate (2.57 g, 5.47 mmol, 80% yield). 1H NMR (400 MHz, CDCl3) δ 8.23 (1H, s), 8.05 (1H, d), 7.95 (1H, d), 7.34 (1H, t), 7.27 (1H, d), 7.06 (1H, d), 4.76-4.63 (1H, m), 4.66 (2H, br.s), 3.67 (2H, br.t), 3.25 (2H, br.t), 1.51 (9H, s), 1.45 (6H, d); m/z (API-ES) 414, 416 [M+H-56]+.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]([NH:15][C@@H:16]([C:20]([F:23])([F:22])[F:21])[CH:17]([CH3:19])[CH3:18])=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12](Cl)[N:11]=[CH:10][CH:9]=3.C1C[O:29]CC1>Cl.CCOC(C)=O>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]([NH:15][C@@H:16]([C:20]([F:23])([F:22])[F:21])[CH:17]([CH3:19])[CH3:18])=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:29])[C:13]=3[C:4]=2[CH:3]=1
Reactant: CC(C)[C@@H](Nc1nc2ccnc(Cl)c2c2cc(Br)ccc12)C(F)(F)F
Reactant: C1CCOC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)[C@@H](Nc1nc2cc[nH]c(=O)c2c2cc(Br)ccc12)C(F)(F)F

Procedure:
9-bromo-1-chloro-N-[(1R)-2-methyl-1-(trifluoromethyl)propyl]benzo[c]-1,6-naphthyridin-6-amine (1.0 g, 2.31 mmol) in 6 N HCl (4 mL) and THF (4 mL) was heated to 90° C. for 2 hr. The reaction was cooled and diluted with EtOAc and quenched with sat. NaHCO3. The mixture was extracted and the organic layers were separated, dried with MgSO4, filtered, and concentrated to give the crude product. Column chromatography on silica gel 100% Hex. to 100% EtOAc afforded 9-bromo-6-{[(1R)-2-methyl-1-(trifluoromethyl)propyl]amino}benzo[c]-1,6-naphthyridin-1(2H)-one. 1H NMR (600 MHz, CD3OD) δ 10.1 (d, 1H), 8.31 (d, 1H), 7.75 (d, 1H), 7.40 (d, 1H), 6.65, (d, 1H), 5.46 (m, 1H), 2.35 (m, 1H), 1.12 (d, 3H), 1.06 (d, 3H). LRMS (ESI) calc'd for (C17H16BrF3N3O) [M+H]+, 414.0; found 414.0.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13]C)=[O:12])[C:5]=2[CH:4]=[N:3][N:2]=1.[OH-].[Li+].C1COCC1>O>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH:4]=[N:3][N:2]=1
Reactant: COC(=O)c1cccc2cnncc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc2cnncc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 50 mL round bottom flask was added methyl phthalazine-5-carboxylate (1.0 g, 5 mmol), lithium hydroxide (0.3 g, 11 mmol), THF (4 mL) and water (4 mL). The resulting solution was stirred for 1 hour at room temperature. After removal of THF, the residue was acidified with 1N HCl until a precipitate was formed. The precipitate was filtered to provide phthalazine-5-carboxylic acid, used directly for next step. LCMS (M+H) 175.1 calc. for C9H7N2O2 175.0. 1H NMR (400 MHz, CDCl3): δ ppm 8.06 (d, J=8.41 Hz, 1H) 8.51-8.56 (d, 1H) 8.71 (d, 1H) 9.64 (s, 2H). Carboxylic acid H not detected.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([O:16]CC)=O)[N:11]=[CH:10][C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH2:25]([N:27]([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:28][CH3:29])[CH3:26]>>[CH2:25]([N:27]([CH2:28][CH3:29])[CH2:30][CH2:31][CH2:32][NH:33][C:14](=[O:16])[CH2:13][N:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=[N:11]1)[CH3:26]
Reactant: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccc(O)cc1
Reactant: CCN(CC)CCCN
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccccc2)c1-c1ccc(O)cc1

Procedure:
A solution of 10 g (0.031 mol) of ethyl 5-(4-hydroxyphenyl)-4-phenyl-1H-pyrazole-1-acetate of example 5 in 48 mL of diethylaminopropylamine was stirred on a steam bath under nitrogen for 14 hours. The excess amine was removed in vacuo at 80° C., the residue dissolved in ethyl acetate, washed twice with water, once with brine and dried over sodium sulfate. They ethyl acetate was stripped to yield 12 g of a dark oil which was triturated in hot cyclohexane several times. The insoluble residue was combined with a small amount of a mixture of oil and crystals, which had separated from the cyclohexane on cooling, and recrystallized from ethyl acetate to yield 6.6 g of product, mp 110°-113° C.
Reaction SMILES: [Br:1][C:2]1[C:9]2[S:8][CH:7]=[N:6][C:5]=2[NH:4][C:3]=1[CH3:10].CS(O[CH:16]([CH3:20])[CH2:17][O:18][CH3:19])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:9]2[S:8][CH:7]=[N:6][C:5]=2[N:4]([CH:16]([CH3:20])[CH2:17][O:18][CH3:19])[C:3]=1[CH3:10]
Reactant: Cc1[nH]c2ncsc2c1Br
Reactant: COCC(C)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCC(C)n1c(C)c(Br)c2scnc21
Temperature: 70 °C

Procedure:
To a solution of 6-bromo-5-methyl-4H-pyrrolo[2,3-d]thiazole (2.5 g, 11.52 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added 1-methoxypropan-2-yl methanesulfonate (3.87 g, 23.03 mmol), and potassium carbonate (3.18 g, 23.03 mmol) followed. The resulting reaction mixture was heated to 70° C. and allowed to stir over night at 70° C. The reaction mixture was washed with water and brine, extracted with acetic ester (30 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel eluted with (petrol ether/acetic ester 30:1→20:1→10:1) to the title compound (2.0 g, 60%) as orange oil. LCMS (M+H+) m/z: calc'd. 287.99. found 290.9.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][CH:16]([O:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27]O)[CH2:17][CH3:18]>>[CH3:15][CH:16]([O:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1)[CH2:17][CH3:18]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CCC(C)Oc1cc(Cl)ccc1CO
Product: CCC(C)Oc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-butan-2-yloxy-4-chlorophenyl)methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C20H19ClN4O2, 383; Found, 383.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Br.Br.Br.[CH2:14]([C:16]1[C:17]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([C:33]4[NH:42][C:36]5[CH2:37][CH2:38][NH:39][CH2:40][CH2:41][C:35]=5[N:34]=4)=[N:29][NH:30]3)=[CH:26][CH:25]=2)=[CH:18][C:19]([F:23])=[C:20]([OH:22])[CH:21]=1)[CH3:15]>>[CH2:14]([C:16]1[CH:21]=[C:20]([OH:22])[C:19]([F:23])=[CH:18][C:17]=1[C:24]1[CH:32]=[C:31]2[C:27]([C:28]([C:33]3[NH:42][C:36]4[CH2:37][CH2:38][N:39]([C:6]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=5)=[O:8])[CH2:40][CH2:41][C:35]=4[N:34]=3)=[N:29][NH:30]2)=[CH:26][CH:25]=1)[CH3:15]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNCC4)n[nH]c2c1
Reactant: O=C(O)c1ccc(F)cc1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3ccc(F)cc3)CC4)n[nH]c2c1
Yield: 35.3 %

Procedure:
The title compound was prepared from 4-fluoro-benzoic acid (12.5 mg, 85 μmol) and 5-ethyl-2-fluoro-4-[3-(1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 32, 50 mg, 80 μmol) using the method of Example 8. The crude material was purified by HPLC Method B to afford 14.5 mg of the title compound.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:5]=1[NH2:6])[CH3:3].[Br:14]Br>O>[Br:14][C:10]1[C:4]([CH2:2][CH3:3])=[C:5]([C:7]([CH2:12][CH3:13])=[CH:8][C:9]=1[CH3:11])[NH2:6]
Reactant: CCc1cc(C)cc(CC)c1N
Reactant: BrBr
Agent: Cl
Solvent: O
Product: CCc1cc(C)c(Br)c(CC)c1N
Reaction time: 3.75 h

Procedure:
Concentrated HCl (10 ml) is cooled to 5° C. in an ice-water bath and 1.63 g of 2,6-diethyl-4-methylaniline is added dropwise to give a slurry. Bromine (1.59 g) with 10 ml of concentrated HCl is added dropwise over 30 minutes. The reaction is allowed to stir for 3.75 hours and 25 ml of distilled water is added. After cooling for 1.0 hour, the reaction mixture is filtered and washed twice with 25 ml of cold distilled water. After drying under vacuum for about 16 hours, the crude solid (2.3 g) is dissolved in 100 ml of 10% NaOH and extracted with a 150 ml portion and with a 100 ml portion of methylene chloride. After drying over sodium sulfate, the methylene chloride solution is rotary evaporated to 1.9 g of crude product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][N+:10]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:13][CH3:14].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CCN)cc1F
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of 2-fluoro-1-methoxy-4-(2-nitro-vinyl)benzene (1.5 g, Intermediate (2)] in THF (50 mL) is treated dropwise with a solution of lithium aluminum hydride in ether (23 mL, 1M). The mixture is heated at 40° C. for 3 hours, cooled to room temperature, diluted with ether and quenched with Na2SO4.10H2O (104 g). After standing at room temperature overnight the reaction mixture is filtered and the filtrate is evaporated. The residue is subjected to chromatography on silica gel eluting with EtOAc to give 2-(3-fluoro-4-methoxy-phenyl)-ethylamine [0.81 g, Intermediate (3)] as an oil. MS: 170 (M+H); 1H NMR (CDCl3): 6.9-7 (3H, m); 3.85 (3H, s); 2.95 (2H, t); 2.7 (2H, t).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[O:34][N:33]=2)=[CH:28][CH:27]=1)=O.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.CC(O)=O>[NH:2]1[C:1]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:4][CH:3]1[CH2:24][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[O:34][N:33]=2)=[CH:30][CH:31]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: NC(=O)c1cc(-c2ccc(C=O)cc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: NC(=O)c1cc(-c2ccc(CC3Cc4ccccc4N3)cc2)no1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
To a solution of isoindoline (11 μL, 0.097 mmol) in dichloroethane (1 mL) was added Na(OAc)3BH (59 mg, 0.278 mmol). The mixture was stirred at room temperature under argon for 20 min. A slurry of 3-(4-formyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 20; 20 mg, 0.093 mmol) in dichloroethane (1 mL) was added, followed by AcOH (20 μL). The reaction mixture was stirred at room temperature overnight. 1 M Na2CO3 solution was added and the mixture was extracted with CHCl3 (3×25 mL). The organic layer was washed with brine, dried (Na2SO4), evaporated, and purified by chromatography (20-25% acetone/CH2Cl2) to give 3-[4-(1,3-dihydro-indol-2-ylmethyl)-phenyl]-isoxazole-5-carboxylic acid amide (10 mg, 32%) as an off-white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.36 (br. s., 1H), 7.99 (br. s., 1H), 7.88 (d, J=8.2 Hz, 2H), 7.48-7.61 (m, 3H), 7.09-7.26 (m, 4H), 5.74 (s, 2H), 4.07 (br. s., 1H), 3.92 (s, 1H), 3.30 (d, J=3.0 Hz, 2H), 3.15 (d, J=4.8 Hz, 2H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:13]([NH2:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>C(O)C>[CH2:11]([O:10][C:8]([CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[NH:18][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:9])[CH3:12]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: CC(C)CCN
Solvent: CCO
Product: CCOC(=O)C1CCCCC1NCCC(C)C
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-oxocyclohexanecarboxylate (3.0 mL, 17.8 mmol) in ethanol (30 mL) was added isoamylamine (2.1 mL, 17.9 mmol) at 25° C. The mixture was heated at reflux for 12 h. The reaction mixture was allowed to cool to 25° C. and concentrated in vacuo. The crude material was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-30% ethyl acetate in hexanes) to afford the desired product, (2-(3-methylbutylamino)-cyclohexanecarboxylic acid ethyl ester (3.23 g, 13.5 mmol, 76%), as a yellowish oil. LC-MS (ESI) calcd for C14H25NO2 239.19, found 240.3 [M+H+].
Reaction SMILES: [C:1]([C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:26])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:8][CH2:7][CH2:6][CH2:5]1)([OH:3])=[O:2].[OH-].[Na+].[BH4-].[Na+]>CC(O)C.O.[BH4-].[Na+]>[C:23]([C:18]1([CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([OH:26])[CH2:12][CH2:11][CH2:10][CH2:9][C:4]2([C:1]([OH:3])=[O:2])[CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:19][CH2:20][CH2:21][CH2:22]1)([OH:25])=[O:24]
Reactant: O=C(CCCCC1(C(=O)O)CCCC1)CCCCC1(C(=O)O)CCCC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)C1(CCCCC(O)CCCCC2(C(=O)O)CCCC2)CCCC1
Reaction time: 23 h
Yield: 105 %

Procedure:
To a mixture of 1-[9-(1-carboxycyclopentyl)-5-oxononyl]-1-cyclopentanecarboxylic acid (4.70 g, 11.5 mmol) in iPrOH (30 mL) and H2O (30 mL) was added NaOH (1.10 g, 27 mmol). To the resulting clear solution, NaBH4 (0.242 g, 6.4 mmol) was added. After 23 h, TLC analysis revealed the reaction to be incomplete, and an additional portion of NaBH4 (0.036 g, 0.95 mmol) was added. Stirring was continued for 17 h and then, the reaction mixture was concentrated in vacuo. The remaining residue was dissolved in H2O (80 mL) and washed with Et2O (20 mL). The aqueous layer was acidified with aqueous HCl (6M, 15 mL) and then extracted with Et2O (3×50 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4) and concentrated in vacuo to give 1-[9-(1-carboxycyclopentyl)-5-hydroxynonyl]-1-cyclo-pentanecarboxylic acid (4.45 g, 98%, contains 7% (w/w) Et2O) as a thick, slightly hazy, light yellow oil. 1H NMR (CDCl3): δ=3.56 (br s, 1H), 2.16-2.10 (m, 4H), 1.65-1.60 (m, 12H), 1.51-1.18 (m, 16H). 13C NMR (CDCl3): δ=184.1 (2×), 71.1, 54.2 (2×), 39.4 (2×), 37.1 (2×), 36.1 (2×), 35.7 (2×), 26.0 (2×), 25.8 (2×), 25.03 (2×), 25.00 (2×).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH:7]1([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[CH:27]=[N:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[O:17])[C:13]([NH:28][C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1>>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:21]([C:20]1[CH:24]=[CH:25][N:26]=[CH:27][C:19]=1[NH:18][C:16]([C:14]1[C:13]([NH:28][C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)=[CH:12][CH:11]=[C:10]([CH:7]2[CH2:9][CH2:8]2)[N:15]=1)=[O:17])=[O:22]
Reactant: NCC(O)CO
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: O=C(NCC(O)CO)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 33 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 3-amino-propan-1,2-diol with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (33%) as amorphous yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](O)=[O:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:32]4[N:31]([CH3:30])[CH:35]=[CH:34][CH:33]=4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: Cn1cccc1C(=O)O
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cccn2C)c1

Procedure:
Prepared as described in Example 105 using (1R,28)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 39 mg, 100 mmol) and 1-methyl-2-pyrrolecarboxylic acid (25 mg, 200 μmol). Yield 35 mg (70%).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].Br[CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[K+]>C(O)C>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: CCCCCc1ccc(-c2ccc(O)cn2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCc1ccc(-c2ccc(OCCCC)cn2)cc1

Procedure:
2.8g of the resulting 2-(p-pentylphenyl)-5-hydroxypyridine, 2g of 1-bromobutane and 0.8g of potassium hydroxide placed in 60ml of ethanol were heated under reflux for 4 hours. The potassium bromide precipitated during the reaction was removed by filtration. The ethanol was removed by distillation. The residue was extracted with diethylether and the ether layer was washed with water several times and then the ether was removed by distillation. The residue was distilled under reduced pressure. The collected fraction having a boiling point of 185° to 187° C./2mmHg was recrystallized from methanol to yield 1.7g of 2-(p-pentylphenyl)-5-butyloxypyridine.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(NC(C)C)(C)C.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: O=C(Nc1ccc(F)cc1[N+](=O)[O-])Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
To a solution of 4-fluoro-2-nitroaniline (1.56 g) and diisopropylamine (1.68 ml) in dichloromethane (20 ml) was added dropwise under ice-cooling phenyl chloroformate (1.51 g). After stirring the mixture at room temperature overnight, the reaction solution was washed with water, saturated saline, dried over anhydrous MgSO4 and the solvent was distilled off. Crystallization of the residue from diisopropyl ether afforded phenyl 4-fluoro-2-nitrophenylcarbamate (0.79 g, 29%) as crystals.
Reaction SMILES: C([Li])CCC.O1CCCC1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1.[Cl:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[CH:23][N:22]=1>O>[Cl:20][C:21]1[N:26]=[C:25]([O:17][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=2)[CH:24]=[CH:23][N:22]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OCc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(COc2ccnc(Cl)n2)cc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
n-Butyl lithium (2.6 M n-hexane solution, 10.1 mL) was added to tetrahydrofuran solution (12 mL) of 4-fluorobenzyl alcohol (3.08 mL) at −78° C., and stirred at the same temperature for 30 minutes. This reaction liquid was gradually added to tetrahydrofuran suspension (24 mL) of 2,4-dichloropyrimidine (4.0 g) and stirred at room temperature for 2 hours. After addition of water, the reaction liquid was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was crystallized from mixed solvent of chloroform and hexane to provide the title compound (4.36 g, 68%).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].Br[CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22]>>[C:17]([C:9]1[C:10]([C:13]([F:15])([F:16])[F:14])=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22])[C:4]([CH2:1][CH2:2][CH3:3])=[CH:12]2)#[N:18]
Reactant: COC(=O)C(C)Br
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)C(=O)OC

Procedure:
Synthesized in a manner similar to Example 1 using 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and methyl 2-bromopropanoate: MS (ESI): m/z 339 (MH+).