Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@@H:6]([CH3:13])[N:5]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)[C:4]=2[N:3]=1.[CH3:25][O:26][CH2:27][CH2:28][CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CO.C(Cl)Cl>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:29][CH2:28][CH2:27][O:26][CH3:25])[C:7](=[O:12])[C@@H:6]([CH3:13])[N:5]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)[C:4]=2[N:3]=1
Reactant: COCCCO
Reactant: COc1c(C)cnc(CN2c3nc(N)ncc3NC(=O)[C@H]2C)c1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCCCN1C(=O)[C@@H](C)N(Cc2ncc(C)c(OC)c2C)c2nc(N)ncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.7 %

Procedure:
(7R)-2-Amino-8-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7-methyl-7,8-dihydropteridin-6(5H)-one (Example 2[2])(60 mg, 0.18 mmol) was suspended in THF (10 mL) and the 3-methoxy-1-propanol (70 μL, 0.73 mmol) was added, followed by triphenylphosphine (192 mg, 0.73 mmol) and DIAD (144 μL, 0.73 mmol). The mixture was stirred at room temperature for 2 hours. A further quantity of triphenylphosphine (192 mg, 0.73 mmol) and DIAD (144 μL, 0.73 mmol) were added and stirring continued for 2 hours. A further quantity of triphenylphosphine (192 mg, 0.73 mmol) and DIAD (144 μL, 0.73 mmol) were added and stirring continued overnight. TLC and LCMS analysis showed complete reaction; the mixture was diluted with methanol (5 mL) and loaded onto an SCX-2 column which had been equilibrated with 30% methanol in DCM. The column was eluted with 30% methanol in DCM to remove impurities, then with 30% (3M NH3 in methanol) in DCM to elute the product. The appropriate fractions were concentrated in vacuo; the residue (about 40 mg) was found to be a mixture of N- and O-alkylated products. The sample was dissolved in methanol (5 mL) and 6N HCl (2 mL) was added. The mixture was stirred at room temperature for 2 hours. LCMS showed complete hydrolysis of the O-alkylated material; the desired N-alkylated material was unchanged. The mixture was concentrated in vacuo and the residue was purified by chromatography, eluting with 0 to 5% (10:1 methanol/concentrated NH3 (aqueous)) in DCM. The appropriate fractions were concentrated under reduced pressure to give the title compound as a pale yellow gum (20 mg, 27%); 1H NMR spectrum (400 MHz, CDCl3) δ 1.36 (3H, d), 1.89 (2H, ddt), 2.17 (3H, s), 2.25 (3H, s), 3.39 (2H, td), 3.75 (3H, s), 3.81 (1H, dd), 3.97 (1H, dd), 4.03 (1H, q), 4.09 (1H, d), 4.67 (2H, s), 5.70 (1H, d), 7.70 (1H, s), 8.18 (1H, s); Mass spectrum: (M+H) 401.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][CH2:4][O:3]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:18][S:19]([O:9][CH2:8][CH:6]1[CH2:5][CH2:4][O:3][C:2]([CH3:10])([CH3:1])[CH2:7]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CC(CO)CCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CC(COS(C)(=O)=O)CCO1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(2,2-Dimethyltetrahydro-2H-pyran-4-yl)methanol (2.54 g) was dissolved in dry DCM (40 mL) and triethylamine (4.9 mL) was added with stirring. The solution was cooled (ice bath) under nitrogen and methanesulphonyl chloride (1.77 mL) was added dropwise over 5 mins. The mixture was allowed to warm slowly to room temperature as the ice bath melted and was left for 16 h. The mixture was shaken with saturated sodium bicarbonate solution and the aqueous layer was extracted with DCM (×2). The combined organics were washed with brine, dried using a hydrophobic frit and evaporated to give the title compound (3.93 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>CN(C)C=O.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([Cl:23])=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCCCCCC=Cc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCCCCCCC=Cc1ccc(F)cc1

Procedure:
A solution of 10-(4-fluoro-phenyl)-dec-9-enoic acid (230 mg, 0.87 mmol), oxalyl chloride (0.11 mL, 1.3 mmol), and N,N-dimethylformamide (one drop) in dichloromethane (3 mL) was stirred at room temperature for 2 hours, then volatile material was removed by distillation to afford 10-(4-fluoro-phenyl)-dec-9-enoyl chloride. This was redissolved in dichloromethane, then N,N-diisopropylethylamine (140 mg, 1.04 mmol) was added dropwise, followed by (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride. The reaction mixture was stirred at room temperature for 16 h, then washed with water. The organic layer was evaporated and the residue purified by preparative HPLC to afford (R)-4-dimethylamino-3-[10-(4-fluoro-phenyl)-dec-9-enoylamino]-butyric acid benzyl ester (100 mg, 24%), m/e=483.4 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:19][CH:18]([O:20][C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH2:17]3)=[O:15])=[N:11][N:10]=2)=[CH:5][CH:4]=1.Cl.[CH3:30][C:31]1([CH2:37][OH:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC1(CO)CCNCC1>C(Cl)Cl.CO>[OH:38][CH2:37][C:31]1([CH3:30])[CH2:36][CH2:35][N:34]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH:18]3[CH2:17][N:16]([C:14]([C:12]4[O:13][C:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)=[N:10][N:11]=4)=[O:15])[CH2:19]3)=[CH:22][CH:23]=2)[CH2:33][CH2:32]1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Reactant: CC1(CO)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCC(C)(CO)CC5)cc4)C3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a solution of 55A (5.03 g, 13.3 mmol) in DCM (250 mL) was added (4-methylpiperidin-4-yl)methanol hydrochloride (2.4 g, 14.6 mmol) followed by DIPEA (2.5 mL, 14.6 mmol). The mixture was stirred at RT for 20 min before the addition of sodium triacetoxyborohydride (5.6 g, 26.5 mmol) and MeOH (5 mL). The reaction mixture was stirred at RT overnight. Further (4-methylpiperidin-4-yl)methanol (360 mg, 2.7 mmol), DIPEA (0.5 ml) and sodium triacetoxyborohydride (1.1 g, 5.2 mmol) were added and the mixture was stirred at RT for 3 days. Even more sodium triacetoxyborohydride (2 g, 9.5 mmol) was added and the mixture was stirred for another 2 h. Yet another portion of sodium triacetoxyborohydride (4 g, 19 mmol) was added and the mixture was left at RT overnight. The mixture was then washed with a saturated aqueous solution of Na2CO3. The organic layer was filtered through a phase separator and the solvent was removed by evaporation. The crude product was purified by flash chromatography starting with EtOAc and then eluting the product with 5% methanol in DCM where the methanol contained ammonia (2 M). The pure fractions were combined and evaporated. The residue was triturated with diethyl ether and there was obtained 3.55 g (54%) of the product as a crystalline solid, m. p. 102° C. and 146° C. 1H NMR (500 MHz, CDCl3): δ 0.94 (s, 3H), 1.33 (m, 2H), 1.55 (m, 2H), 2.28 (m, 2H), 2.53 (m, 2H), 3.37 (m, 2H), 3.47 (s, 2H), 3.88 (s, 3H), 4.33 (m, 1H), 4.62 (m, 1H), 4.72 (m, 1H), 5.06 (m, 1H), 5.11 (m, 1H), 6.71 (d, 2H), 7.00 (d, 2H), 7.26 (m, 2H), 8.08 (d, 2H), MS (APCI+) m/z 493 [M+H]+, LC purity: 97%.
Reaction SMILES: [NH2:1][C:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([C:26]([F:29])([F:28])[F:27])[CH2:22][CH2:21]3)[CH:15]=2)[CH:10]=1)([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(O)(C(F)(F)F)=O.[N+](C(C1C=CC2C(=CC=C(O[C@H]3CC[C@@H](C(F)(F)F)CC3)C=2)C=1)(C)CCC(O)=O)([O-])=O>>[NH2:1][C:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][C@H:20]3[CH2:25][CH2:24][C@@H:23]([C:26]([F:27])([F:28])[F:29])[CH2:22][CH2:21]3)[CH:15]=2)[CH:10]=1)([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CC(N)(CCC(=O)O)c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1
Agent: CC(CCC(=O)O)(c1ccc2cc(O[C@H]3CC[C@@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: CC(N)(CCC(=O)O)c1ccc2cc(O[C@H]3CC[C@@H](C(F)(F)F)CC3)ccc2c1
Yield: 21 %

Procedure:
4-Amino-4-[6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid was synthesized as per 4-amino-4-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid (Example 282) in 21% yield as TFA salt, using 4-nitro-4-[6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid as the starting material. MS: m/z=432.20 [M+Na]+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 7.64-7.75 (m, 3H), 7.35 (dd, J=8.8, 2.0 Hz, 1H), 7.14 (dd, J=8.9, 2.1 Hz, 1H), 7.08 (s, 1H), 4.67 (br. s., 1H), 2.22-2.41 (m, 2H), 1.98-2.20 (m, 5H), 1.63-1.80 (m, 7H), 1.48-1.61 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][N:4]=[C:5]([CH:9]([NH:11][C:12](=O)[CH2:13][CH2:14][CH3:15])[CH3:10])[C:6](=[O:8])[N:7]=1.[OH-].[Na+]>O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2=[C:9]([CH3:10])[N:11]=[C:12]([CH2:13][CH2:14][CH3:15])[N:4]2[N:3]=1
Reactant: CCCC(=O)NC(C)c1n[nH]c(N)nc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCc1nc(C)c2c(=O)[nH]c(N)nn12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
N-[1-(3-Amino-2,5-dihydro-5-oxo-1,2,4-triazin-6-yl)ethyl]butyramide (37.0 g) was added to stirred polyphosphoric acid (260 g) at 90° C. over 30 minutes and then the mixture was stirred at 150° C. for 2 h. The mixture was allowed to cool overnight, then warmed to 100° C. and poured into a mixture of ice (370 g) and water (370 g). The solution was adjusted to pH6 by adding 70% sodium hydroxide solution (ca. 230 ml). The precipitated solid was filtered off and was dissolved in 1 N hydrochloric acid (740 ml). The solution was clarrified and adjusted to pH8 by adding 2 N sodium hydroxide solution to give the imidazo[5,1-f]1,2,4-triazin-4(3H)-one as an off-white solid which was filtered off, washed with water, and dried in vacuo at 80° C. Yield=30.2 g; m.p. 266° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[Br:14]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.C(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:14][CH2:13][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(OC)ccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(OC)ccc1CBr
Temperature: 77 °C
Yield: 99.8 %

Procedure:
Step 1 A suspension of methyl 5-methoxy-2-methylbenzoate (1.00 g, 5.55 mmol), N-bromosuccinimide (1.037 g, 5.83 mmol) and benzoyl peroxide (81 mg, 0.333 mmol) in tetrachloromethane (10 mL) was heated at 77° C. for 3 h. The mixture was diluted with DCM, washed with NaHCO3 (aq), dried and concentrated to provide crude methyl 2-(bromomethyl)-5-methoxybenzoate as a light yellow solid (1.435 g), used without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.48 (1H, d, J=2.64 Hz), 7.37 (1H, d, J=8.36 Hz), 7.02 (1H, dd, J=8.58, 2.86 Hz), 4.93 (2H, s), 3.95 (3H, s), 3.85 (3H, s).
Reaction SMILES: CC(C)(OC([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=2)=[O:15])[N:12]=1)=O)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=2)=[O:15])[N:12]=1
Reactant: CCOC(=O)Cc1csc(NC(=O)Cc2csc(NC(=O)OC(C)(C)C)n2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(NC(=O)Cc2csc(N)n2)n1

Procedure:
The product from step (i) (0.8 g) in dry dichloromethane (15 ml) was treated with trifluoroacetic acid (5 ml). After 6 hours at room temperature the mixture was azeotroped with toluene. The residue was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate. The organic solution was dried (MgSO4) and evaporated under reduced pressure. The residue was triturated with ethyl acetate/isohexanes and filtered. Yield 0.53 g.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])=[O:5])[CH3:3].[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[BH4-].[Na+]>C(O)C>[CH2:21]([NH:1][C@H:2]([C:4]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])=[O:5])[CH3:3])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](NCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
A mixture of L-alanyl-L-prolyl-L-proline (12.83 g, 9.99 m mole), benzaldehyde (5.50 g, 51.8 m mole), zeolite "3A" (20 g), and ethanol (60 ml), was stirred overnight at room temperature. Sodium borohydride (1.609 g, 42.3 m mole) - ethanol (70 ml) suspending solution was added dropwise thereto, and after that, the mixture was stirred for 10 hours. The zeolite was removed by filtration and the filtrate was concentrated under reduced pressure. To the solution, ether was added to effect crystallization. The thus produced crystals were obtained by filtration, washed with three 50 ml portions of ether, then purified with the ion exchange resin "Dowex 50 W-X4", and then recrystallized with ethanol-ether to give N-benzyl-L-alanyl-L-prolyl-L-proline (2.10 g).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[N:12][O:13][CH3:14])[CH2:10][CH3:11])[C:4](OCC)=[O:5].[CH3:15][NH2:16]>>[CH3:15][NH:16][C:4](=[O:5])[C:3](=[N:2][OH:1])[C:9](=[N:12][O:13][CH3:14])[CH2:10][CH3:11]
Reactant: CCOC(=O)C(=NO)C(CC)=NOC
Reactant: CN
Product: CCC(=NOC)C(=NO)C(=O)NC
Reaction time: 0.08 h

Procedure:
a mixture of 7.6 parts ethyl 2-hydroxyimino-3-methoxyiminovalerate was mixed with 7 parts 40% aqueous methylamine solution at 25° C. and stirred till homogeneous (5 minutes). The mixture was allowed to stand 18 hours and then evaporated under reduced pressure (15 mm) at 50° C. water-bath temperature to dryness. Recrystallization of the residue from acetonitrile gave 4.3 parts of N-methyl-2-hydroxyimino-3-methoxyiminovaleramide, m.p. 168°-170° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]([C:15]([O:17]CC(Cl)(Cl)Cl)=O)C(OC(Cl)(Cl)Cl)=O)=[CH:5][CH:4]=[N:3]1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[N:31]=[C:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[S:33][CH:34]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[N:31]=[C:32]([N:35]2[CH2:36][CH2:37][N:38]([C:15]([NH:7][C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)=[O:17])[CH2:39][CH2:40]2)[S:33][CH:34]=1
Reactant: Cn1nccc1N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OC(Cl)(Cl)Cl
Reactant: Fc1ccccc1-c1csc(N2CCNCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cn1nccc1NC(=O)N1CCN(c2nc(-c3ccccc3F)cs2)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 18.8 %

Procedure:
A mixture of trichloromethyl 2,2,2-trichloroethyl (1-methyl-1H-pyrazol-5-yl)imidodicarbonate (255 mg, 0.570 mmol), 4-[4-(2-fluorophenyl)-1,3-thiazol-2-yl]piperazine (300 mg, 1.14 mmol) and diisopropylethylamine (0.198 ml, 1.14 mmol) in dimethyl sulfoxide (3.8 ml) was stirred at 70° C. for 16 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 41.4 mg (18.8%) of the desired product as a solid.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[ClH:17]>CO.[Pd]>[ClH:17].[NH2:2][CH2:1][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)CCCCc1cccnc1C#N
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)CCCCc1cccnc1CN

Procedure:
2-Cyano-3-(4-methoxycarbonylbutyl)pyridine (2.40 g) is dissolved in 92 ml of methanol containing 2.4 ml of conc. hydrochloric acid and hydrogenated at atmospheric pressure with 1.2 g of 10% palladium on charcoal for 3 hours. Filtration, evaporation and recrystallization from ether-methylene chloride yields 2-aminomethyl-3-(4-methoxycarbonylbutyl)pyridine hydrochloride, m.p. 79°-81°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:28])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:35][N:36](C)C(=O)C>O.[Cl-].[Na+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[K+].[Fe+6]>[C:35]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:28])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[CH2:15][CH2:14]1)#[N:36]
Reactant: O=C(N[C@H]1CC[C@H](Oc2ccnc3c(Br)cccc23)CC1)c1cccc(F)c1
Reactant: CC(=O)N(C)C
Agent: [Fe+6]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Product: N#Cc1cccc2c(O[C@H]3CC[C@H](NC(=O)c4cccc(F)c4)CC3)ccnc12
Temperature: 120 °C
Reaction time: 3 h

Procedure:
N-{trans-4-[(8-Bromoquinolin-4-yl)oxy]cyclohexyl}-3-fluorobenzamide (500 mg, 1.13 mmol) (see example 12), sodium carbonate (120 mg, 1.13 mmol) and palladium(II) acetate (13 mg, 0.06 mmol) were dissolved in N,N-dimethylacetamide (23 mL) and finely triturated potassium hexacyanoferrate (105 mg, 2.5 mmol) was added. The reaction mixture was stirred under a nitrogen atmosphere for 3 hours at 120° C. After cooling to room temperature, the reaction mixture was diluted with water and saturated sodium chloride solution and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, then the sodium sulphate and solvent residues were removed. After chromatography of the residue, the desired product was obtained at 43% yield (190 mg).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:26])=[N:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[N:11]=2)[C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2.[Si:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][C:46](Cl)=[O:47])=[CH:41][CH:40]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[S:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH:26][C:46](=[O:47])[CH2:45][C:42]3[CH:41]=[CH:40][C:39]([O:38][Si:31]([C:34]([CH3:36])([CH3:35])[CH3:37])([CH3:32])[CH3:33])=[CH:44][CH:43]=3)=[N:8][CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:16][CH:17]=3)[N:11]=2)[C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3csc4ccccc34)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2csc3ccccc23)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 63.5 %

Procedure:
Under an argon atmosphere, to a mixture of 3-(benzo[b]thiophen-3-yl)-5-[4-(tert-butyldimethylsilyloxy)phenyl]pyrazin-2-amine (7i) (505 mg, 1.16 mmol) and 4-(dimethylamino)pyridine (15.0 mg, 123 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyl dimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 15 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11i (505 mg, 740 μmol, 63.5%) as a yellow solid. Rf=0.19 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.15 (s, 6H), 0.20 (s, 6H), 0.91 (s, 9H), 0.93 (s, 9H), 3.41 (s, 2H), 6.65-6.71 (AA′BB′, 2H), 6.93-7.00 (2AA′BB′, 4H), 7.35-7.42 (m, 2H), 7.80 (s, 1H), 7.95-8.07 (m, 4H, includes AA′BB′), 9.01 (s, 1H), 10.49 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.5 (4C), 17.89, 17.93, 25.47 (3C), 25.54 (3C), 41.6, 119.5 (2C), 120.4 (2C), 122.6, 123.5, 124.4 (2C), 127.3, 127.9, 128.1 (2C), 128.9, 130.3 (2C), 132.3, 137.5, 137.5, 139.4, 143.7, 143.8, 147.6, 153.8, 156.7, 169.4; IR (KBr, cm−1) 683, 700, 735, 758, 781, 804, 839, 914, 1169, 1261, 1331, 1362, 1435, 1472, 1508, 1605, 1670, 2857, 2886, 2930, 2955; HRMS (ESI+) m/z 704.2781 ([M+Na]+, C38H47N3NaO3SSi2+ requires 704.2769).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([CH3:17])=[CH:12][C:13]=1[C:14]([OH:16])=[O:15])(=[O:8])=[O:7])(C)(C)C.ClC1C=CC=CC=1Cl.[OH-].[Na+]>CCOCC>[CH3:17][C:11]1[S:10][C:9]([S:6](=[O:8])(=[O:7])[NH2:5])=[C:13]([C:14]([OH:16])=[O:15])[CH:12]=1
Reactant: Cc1cc(C(=O)O)c(S(=O)(=O)NC(C)(C)C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Clc1ccccc1Cl
Product: Cc1cc(C(=O)O)c(S(N)(=O)=O)s1
Temperature: 140 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
A mixture of 5.0 gm (18 millimols) of 2-(N-tert. butyl)sulfamoyl-5-methyl-thiophene-3-carboxylic acid and 20 ml of o-dichloro-benzene was heated, while stirring, for 4 hours at 140° C. After cooling, the reaction mixture was taken up in a mixture of ether and the equivalent amount of dilute aqueous sodium hydroxide. After separation of the ether phase, the aqueous phase was acidified with hydrochloric acid, and the precipitated material was suction-filtered off. The filter cake was recrystallized from ethyl acetate/cyclohexane, yielding 3.3 gm (83% of theory) of 5-methyl-2-sulfamoylthiophene-3-carboxylic acid.
Reaction SMILES: [CH3:1][Si:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[N:15][CH:14]=2)=[N:8]1.O1CCCC1.CO.[OH-].[Na+]>C(OCC)(=O)C>[CH3:1][Si:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[N:15][CH:14]=2)=[N:8]1
Reactant: COC(=O)c1cncc(Nc2ccn(COCC[Si](C)(C)C)n2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc(Nc2cncc(C(=O)O)n2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of 52 mg of methyl 6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol -3-yl)amino)pyrazine-2-carboxylate, 0.5 ml of tetrahydrofuran and 1 ml of methanol was added an aqueous sodium hydroxide solution (1.0 M, 0.5 ml), followed by stirring at room temperature for 15 hours. The obtained reaction solution was diluted with ethyl acetate, and then washed with aqueous ammonium chloride and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and filtrate was concentrated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:29]=O)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[N:1][C:2]3[C:3]([C:12]=2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([F:11])([F:10])[F:9])=[CH:24][CH:23]=1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Reactant: O=CCc1ccc(F)cc1
Product: Oc1cccc(-c2c(-c3ccc(F)cc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (4-Fluoro-phenyl)-acetaldehyde following the procedure of Example 457: MS m/z 384; HRMS: calcd for C22H13F4NO+H+, 384.10060; found (ESI, [M+H]+), 384.0997.