Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].N1C=CC=CC=1.[Cl-].[F:29][C:30]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:31]=1[C:32]([O-])=[O:33].O>CN(C)C=O>[CH:19]([O:18][CH:12]([CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([CH2:2][NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:37]([C:39]([F:40])([F:41])[F:42])=[CH:38][C:30]=2[F:29])[CH:4]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:20])[CH3:21]
Reactant: O=C([O-])c1ccc(C(F)(F)F)cc1F
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OC)c(CNC(=O)c2ccc(C(F)(F)F)cc2F)c1)OC(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.1 %

Procedure:
0.15 g of ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate was dissolved in 5 ml N,N-dimethylformamide, and 0.2 ml pyridine and 0.24 g of 2-fluoro-4-(trifluoromethyl)benzoate chloride were added, followed by stirring at room temperature for 12 hours. Water was added to the reaction solution, followed by extracting with ethyl acetate The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, and from fractions eluted with ethyl acetate-hexane (1:2), 0.2 g of ethyl 2-isopropoxy-3-[4-methoxy-3-({[2-fluoro-4-(trifluoromethyl)benzoyl]amino}methyl)phenyl]propanoate was obtained as a pale yellow oil. This product was treated in the same manner as in Example 1d), to give 0.15 g of 2-isopropoxy-3-[4-methoxy-3-{[2-fluoro-4-(trifluoromethyl)benzoyl]amino}methyl)phenyl]propanoic acid as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:5]=2[N:6]=1>CC(O)=O.Br>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COc1ccc2nc(N)sc2c1
Agent: Br
Solvent: CC(=O)O
Product: Nc1nc2ccc(O)cc2s1
Temperature: 135 °C

Procedure:
To a vial equipped with a magnetic stir bar, was added 2-amino-6-methoxybenzthiazole (1.0 g, 5.55 mmol, 1.0 equiv). To the vial, was added 48% HBr in AcOH (1.5 mL) and 45% HBr aqueous solution (1.5 mL). The vial was sealed and heated to 135° C. for 3 h until LCMS indicated completion of the reaction. The mixture was allowed to rt. The solid precipitate was filtered, washed with water (2 mL), diethyl ether (2 mL×2) and dried in vacuo to afford an off white solid GC-4-49 (1.0 g, 73%). 1H-NMR (400 MHz, DMSO) δ: 9.42 (br, 2H), 7.31 (m, 2H), 6.87 (dd, J=8.8 Hz, 2.4 Hz, 1H); MS: 248.1 [M+H+—HBr].
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: COc1ccccc1CN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COc1ccccc1CNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of commercially available tert-butyl 4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2-methoxybenzylamine (0.130 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((2-methoxyphenyl)methyl)amino-piperidine carboxylate. Yield: 211 mg. To a solution of tert-butyl 4-((2-methoxyphenyl)methyl)amino-piperidine carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give N-((2-methoxyphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. N-((2-Methoxyphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2×15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 40 mg; 13C-NMR (CD3OD, rotamers): δ 26.1, 27.4, 40.0, 40.1, 43.5, 43.9, 51.5, 53.4, 54.5, 54.58, 54.63, 54.78, 54.83, 110.1, 110.5, 113.76, 113.78, 113.84, 114.0, 114.1, 120.1, 120.5, 125.4, 126.0, 126.5, 126.7, 127.1, 127.3, 127.7, 128.8, 129.8, 130.0, 130.08, 130.14, 156.5, 157.0, 159.0, 159.1, 173.2, 173.8.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: O=[N+]([O-])c1cc(F)ccc1NCCCO
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)ccc1NCCCO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 9.12 gm of 3-(2-nitro-4-fluoro-phenylamino)-propan-1-ol and 4.0 gm of 10% Pd on carbon is suspended in 300 ml methanol and shaken at ambient temperature under hydrogen (40 psi) for 12 hours. Thereafter, insoluble materials are removed by filtration and the reaction mixture is concentrated to a dark brown oil (5.25 gm of crude 3-(2-amino4-fluoro-phenylamino)-propan-1-ol).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[N:25](OCCCC)=O>C(#N)C>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[N:25]=[N:24][C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Reactant: CCCCON=O
Solvent: CC#N
Product: CCC(CC)Oc1cc(C)nc2c1nnn2-c1c(C)cc(C)cc1C
Temperature: 65 °C
Yield: 112 %

Procedure:
A mixture of 4-(1-Ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine (50 mg, 0.153 mmol) and butyl nitrite (24 mg, 0.229 mmol) in 4 ml acetonitrile was heated at 65° C. for 2 hours. An additional 0.13 ml of butyl nitrite was added and the resulting mixture was heated at 65° C. for 2 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 58 mg of brown oil. The oil was purified through silica gel column chromatography using 5% ethyl acetate in hexane as eluent to give 46 mg (88%) of the title compound as a light yellow oil. 1H NMR (CDCl3) ä 7.04(s, 2H), 6.60(s, 1H), 5.26(m, 1H), 2.57(s, 3H), 2.38(s, 3H), 1.94(s, 6H), 1.8-2.0(m, 4H), 1.07(t, 6H) ppm.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH3:13])[C:3]1=O.Cl.[NH:16]1[CH:20]=[C:19]([CH2:21][C:22]([NH2:24])=[S:23])[N:18]=[CH:17]1>>[NH:16]1[CH:20]=[C:19]([CH2:21][C:22]2[S:23][C:2]3[CH2:11][CH2:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[O:12][CH3:13])[C:3]=3[N:24]=2)[N:18]=[CH:17]1
Reactant: COc1cccc2c1CCC(Br)C2=O
Reactant: NC(=S)Cc1c[nH]cn1
Agent: Cl
Product: COc1cccc2c1CCc1sc(Cc3c[nH]cn3)nc1-2

Procedure:
Starting compounds: 2-bromo-5-methoxy-1-tetralone, 4-imidazolylthioacetamide hydrochloride
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][NH2:23])[CH:18]=[CH:19][CH:20]=1.[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(CCN)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(CCNCc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.22 ml of 2-(3-methoxy-phenyl)-ethylamine (1.5 mmol) were dissolved in 5 ml methanol at rt and then refluxed for 2 h. After cooling down to rt, 85 mg (2.25 mmol) of sodium borohydride were added in portions and the reaction mixture was then refluxed for 3 h. After cooling down to rt, the reaction mixture was treated with 0.15 ml 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (90 g silica gel; EtOAc/heptane 1:1) to give 520 mg light yellow oil (>100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9](Br)=[CH:10][C:11]3[C:12]4[C:20]([NH:21][C@H:22]([CH:27]5[CH2:29][CH2:28]5)[C:23]([F:26])([F:25])[F:24])=[N:19][CH:18]=[C:17]([C:30]([NH2:32])=[O:31])[C:13]=4[NH:14][C:15]=3[CH:16]=2)=[CH:4][N:3]=1.[CH3:34]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:34])=[CH:10][C:11]3[C:12]4[C:20]([NH:21][C@H:22]([CH:27]5[CH2:29][CH2:28]5)[C:23]([F:26])([F:25])[F:24])=[N:19][CH:18]=[C:17]([C:30]([NH2:32])=[O:31])[C:13]=4[NH:14][C:15]=3[CH:16]=2)=[CH:4][N:3]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: NC(=O)c1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(-c3cnc(N)nc3)c(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc2c(cc1-c1cnc(N)nc1)[nH]c1c(C(N)=O)cnc(N[C@H](C3CC3)C(F)(F)F)c12
Temperature: 100 °C

Procedure:
A mixture of 7-(2-aminopyrimidin-5-yl)-8-bromo-1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-5H-pyrido[4,3-b]indole-4-carboxamide (100 mg, 0.19 mmol), trimethylboroxin (48 mg, 0.38 mmol), Pd(PPh3)4 (11 mg, 0.0096 mmol), and sodium carbonate (61 mg, 0.58 mmol) in 1,4-dioxane (3 mL) was purged with nitrogen, heated to 100° C. overnight, and cooled to room temperature. The mixture was concentrated and purified by flash chromatography to afford the title compound. 1H NMR (500 MHz, CD3SOCD3) δ 11.55 (s, 1H); 8.47 (s, 1H), 8.36 (s, 1H); 8.27 (s, 2H); 7.95 (br s, 1H); 7.55 (s, 1H); 7.23 (br s, 1H); 6.91 (d, 1H); 6.73 (br s, 1H); 4.83 (m, 1H); 2.42 (s, 3H); 1.59 (m, 1H); 0.75 (m, 1H); 0.63 (m, 1H); 0.55 (m, 1H); 0.33 (m, 1H). LRMS (APCI) calc'd for (C22H20F3N7O) [M+H]+, 456.2. found 456.1.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C1COCC1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([NH:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NCc1ccccc1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)CC(NCc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 14 h

Procedure:
7-Nitro-3,4-dihydro-2(1H)-naphthaleneone (1.50 g, 7.85 mmol), benzylamine (4.30 ml, 39.3 mmol), acetic acid (8.0 ml), 4 Å molecular sieves (20 ml), THF (15 ml), and MeOH (15 ml) were introduced into a flask and cooled to 0° C. Sodium cyanoborohydride (0.99 g, 15.7 mmol) was then added portionwise over a 5-minute period. The mixture was stirred for 14 hr, filtered through celite, and concentrated to a syrup. The mixture was made basic with 2N NaOH and extracted with ether (3×50 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and chromatographed over silica gel (3% methanol/methylene chloride) to yield 7-nitro-2-((phenylmethyl)amino)1,2,3,4-tetrahydronaphthalene: (2.10 g, 95%); M.S. (M+H)+ =283.
Reaction SMILES: [NH2:1][C:2]1[C:7](C(O)=O)=[C:6]([CH3:11])[N:5]=[C:4]2[S:12][C:13]([CH3:16])=[C:14]([Br:15])[C:3]=12.C1(OC2C=CC=CC=2)C=CC=CC=1>>[Br:15][C:14]1[C:3]2[C:2]([NH2:1])=[CH:7][C:6]([CH3:11])=[N:5][C:4]=2[S:12][C:13]=1[CH3:16]
Reactant: Cc1nc2sc(C)c(Br)c2c(N)c1C(=O)O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(N)c2c(Br)c(C)sc2n1
Temperature: 200 °C
Yield: 109.4 %

Procedure:
To 4-amino-3-bromo-2,6-dimethylthieno[2,3-b]pyridine-5-carboxylic acid (1.95 g, 6.47 mmol) (Description 7) was added diphenyl ether (15 mL, 94 mmol) and the mixture heated at 200° C. for 4 h. This crude mixture was cooled and combined with material (1 g) from a similar reaction. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in cyclohexane afforded the title compound (1.82 g). LCMS (A) m/z: 257/259 [M+1]+, Rt 0.67 min (acidic).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([C:21](=[NH:22])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1ccc(C#N)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (3.57 g, 20.9 mmol) in toluene (150 mL), trimethylaluminum (15.6 ml, 2M solution in toluene, 31.4 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 4-methylbenzonitrile (5 ml, 41.8 mmol) in toluene (100 mL) was added over 10 minutes and the reaction mixture heated to 80-85° C. After 20 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates are concentrated in vacuo and the resulting yellowish solid was stirred with a mixture of hexane/ether (2/1, 600 mL). The intermediate was filtered and washed with more of hexane/ether (2/1). The pale yellow solid 4-methyl-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (5.3 g, 88%) was used in the next reaction without further purification: mp (DSC) 213° C. Anal. Calc'd for C15H16N2SO2: C, 62.48; H, 5.59; N, 9.71. Found: C, 62.00, H, 5.52; N, 9.60.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:24][C:25](=O)[NH:26][C:27]1[N:28]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)[N:29]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:31]=1>>[C:32]([C:30]1[CH:31]=[C:27]([NH:26][C:25]([NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C@H:5]([O:12][C:13]3[CH:18]=[N:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=3)[CH2:4][CH2:3]2)=[O:24])[N:28]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)[N:29]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: N#Cc1ccc(O[C@@H]2CC[C@H](N)c3ccccc32)cn1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc(C#N)nc3)c3ccccc32)cc1

Procedure:
The title compound was prepared starting from Intermediate 9a and [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety) using an analogous procedure to that described in Example 1 step d. LCMS (Method 5): Rt 5.25 mins, m/z 521 [MH+]. 1H NMR (400 MHz, CDCl3): 1.29 (9H, s), 1.76-1.88 (1H, m), 2.00-2.20 (3H, m), 2.36 (3H, s), 4.94-4.98 (1H, d, J 8.8), 5.00-5.08 (1H, m), 5.38-5.42 (1H, t, J 3.6), 6.03 (1H, s), 6.22 (1H, s), 7.16-7.20 (1H, m), 7.21-7.26 (3H, m), 7.26-7.32 (3H, m), 7.34-7.38 (2H, d, J 8.3), 7.63-7.66 (1H, d, J 8.8), 8.36-8.38 (1H, d, J 2.7).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](N)[C:5](=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=O)[C:6]([OH:8])=[O:7].C(Br)C1C=CC=CC=1.[NH2:24][C:25]1[CH:26]=[C:27]([CH:31]=C(S(C)=O)C=1Cl)C(O)=O.C1(CBr)CC1>>[CH:26]1([CH2:25][NH:24][C:3]2[CH:4]=[C:5]([CH:9]=[C:10]([S:11]([CH3:14])=[O:13])[C:2]=2[Cl:1])[C:6]([OH:8])=[O:7])[CH2:27][CH2:31]1
Reactant: CS(=O)c1cc(C(=O)O)cc(N)c1Cl
Reactant: CS(=O)(=O)c1cc(C(=O)O)c(N)cc1Cl
Agent: BrCC1CC1
Agent: BrCc1ccccc1
Product: CS(=O)c1cc(C(=O)O)cc(NCC2CC2)c1Cl

Procedure:
This product is prepared by replacing the 4-chloro-5-methylsulfonylanthranilic acid and the benzyl bromide employed in Example 4 by equivalent quantities of 3-amino-4-chloro-5-methylsulfinylbenzoic acid and cyclopropylmethyl bromide, respectively and following substantially the same procedure described in Example 4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Br:10]Br.[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:10])=[C:4]([CH3:9])[N:3]=1
Reactant: BrBr
Reactant: Cc1cc(C)nc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc(N)nc(C)c1Br
Reaction time: 3 h

Procedure:
6.1 g (50 mmol) of 2-amino-4,6-dimethylpyridine are dissolved in 50 ml of acetic acid. A solution of 8 g (50 mmol) of bromine in 50 ml of acetic acid is added dropwise using a dropping funnel. The reaction medium is allowed to return to room temperature and the stirring is continued for 3 hours. The mixture is cooled in an ice bath and 40% sodium hydroxide is then added until the pH is basic. The mixture is filtered and dried. The residue is taken up in a little isopropyl ether and then chromatographed on silica gel, eluting with this same solvent. The expected product is collected in the form of white crystals. It is recrystallized from absolute ethanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)\[CH3:7])[CH3:2].[Br:21]N1C(=O)CCC1=O.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N>ClCCl>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[CH:13][CH:14]=1)\[CH2:7][Br:21])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1ccc(CC(C)(C)O)cc1
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: ClCCl
Product: CCOC(=O)/C=C(\CBr)Oc1ccc(CC(C)(C)O)cc1

Procedure:
A solution of (E)-3-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester (0.500 g, 1.80 mmol) in dichloromethane (40 mL) was treated with N-bromosuccinimide (0.350 g, 1.97 mmol) and 2,2′-azobis(2,4′-dimethylvaleronitrile) (0.045 g, 0.18 mmol) under nitrogen. The mixture was then refluxed for 5 h, cooled and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0% to 30% ethyl acetate/hexanes) to afford the intermediate (E)-4-bromo-3-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester. A solution of (E)-4-bromo-3-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester in acetonitrile (20 mL) was immediately treated with (L)-leucine methyl ester hydrochloride (0.21 g, 2.17 mmol) and N,N-diisopropylethylamine (0.510 g, 3.95 mmol). The resulting mixture was sealed in a tube and heated at 90° C. overnight and then cooled and partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (approximately 5 mL) and heated at 160° C., for 6 h in a sealed tube. At this time, the reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 30% to 100% ethyl acetate/hexanes) to afford, (S)-2-{4-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid methyl ester (0.180 g, 27%) as a waxy off-white solid.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([C:25]([NH2:30])([CH2:28][CH3:29])[C:26]#[CH:27])[CH3:24]>>[CH2:1]([C:8]1[C:13]([C:24]#[C:23][C:25]([NH2:30])([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Reactant: C#CC(N)(CC)CC
Product: CCC(N)(C#Cc1ccc(N2C[C@@H](O)[C@H](OC)C2)nc1Cc1ccccc1)CC

Procedure:
This was synthesized in the same manner as in Example 6 except that 2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine (Production Example 1) and 1,1-diethyl-2-propynylamine were used.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([C:11]=1[CH:12]=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.B.[Na]>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([C:11]=1[CH2:12][OH:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=Cc1c(Cl)nc(-c2ccccc2)c2ccccc12
Agent: B
Agent: [Na]
Solvent: CO
Product: OCc1c(Cl)nc(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.2 %

Procedure:
To 8.1 g 3-Chloro-1-phenyl-isoquinoline-4-aldehyde in 150 ml methanol there are added portionwise 1.8 g sodium boron hydride at 0° C. The solution is stirred at room temperature for 4 hours and the solvent is removed in vacuo. The residue is stirred with water. Filtration of the resulting mixture gives 7.2 g 3-chloro-4-hydroxymethyl-1-phenyl-isoquinoline having a melting point from 175° to 182° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([SH:9])[N:3]=1.[CH2:10](I)[CH2:11][CH3:12]>[OH-].[K+]>[CH2:10]([S:9][C:4]1[N:5]=[C:6]([OH:8])[CH:7]=[C:2]([OH:1])[N:3]=1)[CH2:11][CH3:12]
Reactant: Oc1cc(O)nc(S)n1
Reactant: CCCI
Agent: [K+]
Agent: [OH-]
Product: CCCSc1nc(O)cc(O)n1
Reaction time: 96 h

Procedure:
To a solution of 4,6-dihydroxy-2-mercaptopyrimidine (100 g) in potassium hydroxide (2.5N, 571 ml) was added propyl iodide (76.8 ml) and the whole was stirred for 4 days. The solution was acidified to pH 2-3 and filtered to afford the sub-title compound (15 g).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:27]=1[C:28](O)=[O:29]>>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:27]=1[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: COc1ccc(OC)c(C(=O)O)c1
Product: COc1ccc(OC)c(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,5-Dimethoxy-benzoic acid.