Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:36]=[CH:35][C:30]4[O:31][CH2:32][CH2:33][O:34][C:29]=4[CH:28]=3)[C:25]2=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C=Nc1ccc2c(c1)OCCO2
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc4c(c3)OCCO4)c(=O)n(C3CCCC3)c12
Yield: 40.4 %

Procedure:
1-Cyclopentyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (18 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 6-isocyanato-2,3-dihydro-benzo[1,4]dioxine (0.5 mmol) following general procedure C. LCMS: m/z 446 [M+1]+.
Reaction SMILES: CN(C)CC[N:5]1[C:13]2[CH:12]=[CH:11][C:10](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:9]3[C:25](=[O:32])[C:26]4[CH:27]=[CH:28][N:29]=[CH:30][C:31]=4[C:7]([C:8]=23)=[N:6]1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38]>N1C=CC=CC=1>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH:38][C:10]1[CH:11]=[CH:12][C:13]2[NH:5][N:6]=[C:7]3[C:31]4[CH:30]=[N:29][CH:28]=[CH:27][C:26]=4[C:25](=[O:32])[C:9]=1[C:8]=23
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c4c(nn3CCN(C)C)-c3cnccc3C(=O)c24)cc1
Reactant: CN(C)CCN
Solvent: c1ccncc1
Product: CN(C)CCNc1ccc2[nH]nc3c2c1C(=O)c1ccncc1-3
Reaction time: 1 h

Procedure:
A solution of 2-[2-(dimethylamino)ethyl]-5-(p-toluenesulfonyloxy)isoquino[8,7,6-cd]indazole-6 (2H)-one of Example 2 (0.463 g) and 2-(dimethylamino)ethylamine (0.80 mL) in dry pyridine (4.63 mL) is heated at 80° C. for 1 h, 30' under a nitrogen blanket. The solution is then concentrated to dryness and the dark residue obtained is partitioned between brine (30 mL) and ethyl acetate (4×25 mL). The combined organic solutions are dried over Na2SO4 and concentrated to about 3 mL. After addition of n-hexane (12 mL) and stirring for one hour the precipitate is collected by suction and dried at 40° C. under vacuum to give 2-[2-(dimethylamino)ethyl)]5-[[2-(dimethylamino) ethyl]amino]isoquino[8,7,6-cd]indazole-6(2H)-one (0.23 g).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:8]([F:11])=[CH:9][CH:10]=1.[C:30](Cl)(=[O:32])[CH3:31]>>[C:30]([N:23]([CH2:22][C:13]1[CH:14]=[C:15]([C:18]([F:21])([F:19])[F:20])[CH:16]=[CH:17][C:12]=1[C:7]1[C:8]([F:11])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:29])[CH:6]=1)[CH2:24][C:25]([F:28])([F:27])[F:26])(=[O:32])[CH3:31]
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CNCC(F)(F)F)c1
Reactant: CC(=O)Cl
Product: CC(=O)N(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1F)CC(F)(F)F

Procedure:
Prepared according to the procedure described in Example 1, Step 6 and Step 7, using the following starting materials: {6-fluoro-2′-[(2,2,2-trifluoro-ethylamino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[CH3:29])[N:22]([CH3:30])[CH:21]=2)[C:11]1=[O:31])[CH2:6][CH2:7][CH3:8])C.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:30][N:22]1[C:23]2[C:28](=[C:27]([CH3:29])[CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][N:12]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:10]([CH2:9][CH:5]([CH2:6][CH2:7][CH3:8])[C:4]([OH:32])=[O:3])[C:11]2=[O:31])=[CH:21]1
Reactant: CCCC(Cn1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cccnc21)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(Cn1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cccnc21)C(=O)O
Reaction time: 8 h
Yield: 30.8 %

Procedure:
To a stirred solution of 2-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-ylmethyl]-pentanoic acid ethyl ester (85 mg, 0.20 mmol) in dioxane (5 ml) and water (1.5 ml) was added lithium hydroxide monohydrate (41 mg, 0.98 mmol) at room temperature. After stirring overnight the reaction appeared complete. The reaction was concentrated to low volume and diluted with water (˜20 ml). Acidified using HOAc and collected the resulting precipitate via filtration. The product was suspended in 2 ml of 1:1 MeOH/acetonitrile, filtered and washed with acetonitrile. The solid was dried on house vacuum to give 25 mg (31%) of the title compound. LCMS, M++1, m/z: 407.91.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9](OCC)=[O:10])=[C:4]([Cl:14])[CH:3]=1.[NH3:15]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([NH2:15])=[O:10])=[C:4]([Cl:14])[CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1[nH]c(=O)c(Br)cc1Cl
Solvent: CCO
Product: NC(=O)c1[nH]c(=O)c(Br)cc1Cl
Temperature: 45 °C
Reaction time: 2 h

Procedure:
In a round bottom flask containing ethyl 5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxylate (4, 75.0 g, 267.38 mmol) was added liquid ammonia (150.0 mL, 267.38 mmol) in ethanol (100 mL) at 0° C. The reaction mixture was stirred at 45° C. for 2 h. At this time the mixture was concentrated to remove the ethanolic ammonia. The crude solids were washed with diethyl ether (500 mL) and dissolved in refluxing methanol (1 L) and filtered hot. The filtrate was concentrated under reduced pressure until ⅓ of solvent volume remained. Diethyl ether was added until all solids precipitated. The solid was filtered and dried under vacuum to afford 5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide (5) as a light brown solid. Yield: 45 g, 69%; MS (ESI) m/z 248.9 [M−1]−; 1H NMR (400 MHz, DMSO-d6) δ 7.92-7.82 (m, 1H), 7.61-7.59 (m, 1H), 7.36 (s, 1H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH2:16]([O:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CC(C)=O>[CH2:16]([O:22][CH2:23][CH2:24][CH2:25][NH:26][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: CCCCCCOCCCN
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCOCCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 140 °C
Reaction time: 44 h
Yield: 33.8 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mole) and 3-hexyloxypropylamine (1.75 g, 0.011 mole) was heated at 140° C. for 6 hours. After standing at ambient temperature for 44 hours, the reaction mixture was dissolved in acetone (10 ml) and the solution poured into water (150 ml). The light brown oil which separated from solution solidified on standing for 1 hour. The solid was collected and dried on absorbent paper for 18 hours. The solid was then triturated in isooctane (soluble) and the solution chilled to obtain a solid which was collected, washed with cold isooctane, and dried under ambient conditions to obtain 1.20 g (34%) of the product, m.p. 67°-69° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)[CH3:3].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:3][CH:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)[CH3:1]
Reactant: CC(C)c1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1ccc2c(c1)CCN2
Reaction time: 4 h
Yield: 102.5 %

Procedure:
To a cooled solution of indole (D17, 0.60 g, 3.75 mmol) in glacial acetic acid (12 ml) was added sodium cyanoborohydride (1.20 g, 19.1 mmol) in portions. The mixture was stirred under argon for 4 h, then diluted with water and basified with 10% aqueous sodium hydroxide. The mixture was extracted with dichloromethane and the extract was dried and evaporated. After combining with material from a previous experiment (from 0.14 g indole) the crude product was chromatographed on silica gel eluted with diethyl ether to give the title compound (0.62 g, 84%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1)(=O)=O.[Cl:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: OB(O)c1cccc(F)c1Cl
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: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(F)c2Cl)CC1
Temperature: 80 °C
Yield: 52.2 %

Procedure:
A mixture of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (2, 1.18 g, 3.56 mmol), 2-chloro-3-fluorophenyl boronic acid (0.621 g, 3.56 mmol), Pd(PPh3)4 (0.411 g, 0.356 mmol) and 2 M Na2CO3 (20 mL) in DME (50 mL) was heated at 80° C. for 6 h. The mixture cooled to ambient temperature, and the resulting solids were removed by filtration through a Celite pad. The filtrate was washed brine solution (4×50 mL) and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 40 g Redisep column, 0% to 80% EtOAc in hexanes) to provide tert-butyl 4-(2-chloro-3-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (12) as a clear oil (0.579 g, 52%): 1H NMR (300 MHz, DMSO-d6) δ 7.43-7.31 (m, 2H), 7.16-7.10 (m, 1H), 5.81-5.72 (m, 1H), 4.03-3.93 (m, 2H), 3.53 (t, J=5.7 Hz, 2H), 2.41-2.31 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=[O:10])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8].[OH-].[Na+:14]>CO>[Na+:14].[NH2:1][C:2]1[C:3]([C:9]([O-:11])=[O:10])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1ncnc(C)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncnc(C(=O)[O-])c1N

Procedure:
2.0 g (12 mmol) of the material from Step E was dissolved in 24 mL of methanol. 12 mL of 1N solution of sodium hydroxide was added. After 1 hour the solvent was removed with a rotary evaporator. The residue was dried in a vacuum oven overnight to afford 2.39 g of the title compound as a tan solid.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@H:4]([C:12]([NH:14][C@H:15]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)[CH3:16])=[O:13])[NH:3]1.[F:27][C:28]1[CH:37]=[CH:36][C:31]([O:32][CH2:33][CH:34]=O)=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:27][C:28]1[CH:37]=[CH:36][C:31]([O:32][CH2:33][CH2:34][N:3]2[C@@H:4]([C:12]([NH:14][C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=3)[CH3:16])=[O:13])[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:2]2)=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2)cc1
Reactant: O=CCOc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2CCOc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a mixture of methyl 4-[(1S)-1-[[(3R)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl]amino]ethyl]benzoate hydrochloride (800 mg, 2.13 mmol) and 2-(4-fluorophenoxy)acetaldehyde (493 mg, 3.2 mmol) in 1,2-dichloroethane (10.7 mL), add sodium triacetoxyborohydride (633 mg, 2.99 mmol) and stir the mixture at room temperature overnight. Add saturated aqueous NaHCO3 (25 mL), and extract the aqueous layer with ethyl acetate (2×25 mL). Wash the combined organic layers with saturated aqueous NaCl (25 mL), dry the organic phase over MgSO4, filter, and concentrate the filtrate under reduced pressure. Subject the resulting crude material to flash chromatography on silica gel using a 0% to 60% EtOAc/hexanes gradient. Consolidate the fractions containing the product, and concentrate them under reduced pressure to furnish the title compound as a colorless foam (550 mg, 54% yield). Mass spectrum (m/z): 477 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[CH:12]=[C:11](I)[C:9](=[O:10])[NH:8][C:6]1=[O:7])[CH3:2].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14](/[CH:15]=[CH:16]/[C:11]1[C:9](=[O:10])[NH:8][C:6](=[O:7])[N:5]([CH2:4][O:3][CH2:1][CH3:2])[CH:12]=1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOCn1cc(I)c(=O)[nH]c1=O
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOCn1cc(/C=C/C(=O)OCC)c(=O)[nH]c1=O
Temperature: 70 °C
Reaction time: 5 h
Yield: 74.4 %

Procedure:
Then, 1.184 g (4 mmol) of 1-(ethoxymethyl)-5-iodouracil, 870 μg (8 mmol) of ethyl acrylate, 45 mg of palladium acetate and 0.6 ml of triethylamine were dissolved in 40 ml of dimethylformamide, heated and stirred for 5 hours at 70° C. After the solvent was evaporated under reduced pressure, the residue was adsorbed on a silica gel column, eluted with a solution of dichloromethan/ethyl acetate (1:1 v/v) to recover the desired fraction, from which the solvent was evaporated under reduced pressure to obtain 798 mg of 5-(2-(E)-carboethoxyvinyl) -1-(ethoxymethyl)uracil as crystals.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:30]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:31]=2[CH2:32][OH:33])=[CH:25][CH:24]=1>C(Cl)Cl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([S:29][C:30]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:31]=2[CH:32]=[O:33])=[CH:27][CH:28]=1
Reactant: OCc1c(F)cccc1Sc1ccc(F)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1c(F)cccc1Sc1ccc(F)cc1
Reaction time: 8 h

Procedure:
Pyridinium dichromate (8.34 g, 22.2 mmol) is suspended in 30 ml of methylene chloride. A solution of 2-(4-fluorophenylthio)-6-fluorobenzyl alcohol (3.73 g, 14.8 mmol) in 10 ml of methylene chloride is then added dropwise to the suspension. The reaction mixture is then stirred overnight. The reaction mixture is filtered through diatomaceous earth (Celite®) and then through silica gel to afford the subtitle compound. m.p. 94°-97° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1
Reactant: OB(O)c1ccccc1Cl
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2Cl)cn1
Yield: 10 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (68.2 mg, 0.3 mmol) was converted, using 2-chlorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (11 mg, 10%) which was obtained as an off-white solid. MS: m/e=336.5 [M+H]+.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=2)[C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:17]2[CH:18]=[CH:19][C:20]([N:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=2)[C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CN(C)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 50 °C
Yield: 53.1 %

Procedure:
A mixture of {4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-dimethyl-amine (45 mg, 0.13 mmol) and 10% palladium on activated carbon (15 mg) in methanol (200 mL) was heated at 50° C. under hydrogen (50 psi) for 5 h. The mixture was cooled to room temperature, the catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded {4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-phenyl}-dimethyl-amine (23 mg, 51%): LC/MS m/e calcd for C22H27N3 [M+H]+ 334.48, observed 334.2; 1H NMR (400 MHz, CDCl3) δ ppm 8.13 (br. s., 1H), 7.91 (br. s., 1H), 7.11-7.20 (m, 2H), 7.01-7.11 (m, 1H), 6.68-6.77 (m, 2H), 6.33-6.38 (m, 1H), 4.03-4.13 (m, 1H), 2.91-2.97 (m, 6H), 2.07-2.20 (m, 2H), 1.70-1.87 (m, 3H), 1.62 (br. s., 2H), 1.48 (br. s., 2H), 1.13-1.28 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:19]=[N:20][C:21]=3F)[N:10]=2)=[CH:5][CH:4]=1.[F:44][C:45]1[CH:46]=[C:47]([NH2:53])[CH:48]=[N:49][C:50]=1[O:51][CH3:52].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH:19]=[N:20][C:21]=3[NH:53][C:47]3[CH:48]=[N:49][C:50]([O:51][CH3:52])=[C:45]([F:44])[CH:46]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)C(=O)OC(C)(C)C)cnc3F)n2)cc1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)C(=O)OC(C)(C)C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
Tert-butyl 2-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)-2-methylpropanoate (185 mg, 0.315 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Aldrich; 67.1 mg, 0.472 mmol) were dissolved in tetrahydrofuran (3.1 mL) and the resulting mixture was cooled to −60° C. and sodium bis(trimethylsilyl)amide, 1 M in THF (Aldrich; 944 μL, 0.944 mmol) was added. The resulting mixture was stirred at −60° C. for 1 h, and the reaction mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated in vacuo. Chromatographic purification of the residue (silica gel) with 100% hexanes to 50% EtOAc/hexanes to give the title compound (11% yield) as a yellow oil. m/z (ESI, +ve) 709.8 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=2)[N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:1]([O:4][CH:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=2)[NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCN(C(=O)OC(C)(C)C)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC1CCNc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To rac-tert-Butyl 8-acetoxy-2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 3)(110 mg, 0.232 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (0.089 ml, 1.161 mmol). The solution was stirred at room temperature for 4 hrs. To the reaction mixture was added a saturated aqueous sodium carbonate (2 ml) and the mixture was vigorously stirred for 10 minutes. The organic layer was separated and concentrated in vacuo to afford the title compound;
Reaction SMILES: [OH:1][CH:2]([C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:3]([O:5]CC)=[O:4].[Li+].[OH-]>C1COCC1.O>[OH:1][CH:2]([C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)C(C)(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccccc1)(c1ccccc1)C(O)C(=O)O
Temperature: 40 °C
Reaction time: 4 h
Yield: 50.3 %

Procedure:
1.75 g (6.2 mmol) of ethyl 2-hydroxy-3,3-diphenylbutyrate were dissolved in 10 ml of THF, and a solution of 0.23 g (9.3 mmol) of LiOH in 6 ml of water was added. The mixture was stirred at room temperature for 16 hours and at 40° C. for 4 hours. The mixture was subsequently concentrated under reduced pressure, taken up in water and washed with ethyl acetate. This was followed by acidification with HCl and extraction three times with ethyl acetate. The combined ethyl acetate phases were dried with MgSO4, and the solvent was stripped off under reduced pressure. The residue was chromatographed on silica gel with CH2Cl2/MeOH (2:1). 0.80 g (50%) of 2-hydroxy-3,3-diphenylbutyric acid was obtained.
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([C@H:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[N:9]1[CH2:15][CH2:16][S:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=O)C>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][S:17][CH2:16][CH2:15][N:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH2:13][C@@H:8]1[CH2:6][OH:5]
Reactant: CCOC(=O)[C@H]1CCCC(=O)N1CCSCCCC(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Product: COC(=O)CCCSCCN1C(=O)CCC[C@@H]1CO
Reaction time: 4.5 h
Yield: 23.8 %

Procedure:
Lithium borohydride (2.0 M in THF, 0.25 mL, 0.50 mmol) was added slowly to a solution of (R)-1-[2-(3-methoxycarbonyl-propylsulfanyl)-ethyl]-6-oxo-piperidine-2-carboxylic acid ethyl ester (160 mg, 0.48 mmol) in CH2Cl2 (1.5 mL) at −40° C. After 4.5 h at −40° C., the reaction was quenched by addition of a few drops of aqueous HCl (6 N) until gas evolution ceased. Solid NaHCO3 was added and the reaction mixture was filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 33 mg (˜23%) of an inseparable mixture of desired product 4-[2-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-ethylsulfanyl]-butyric acid methyl ester and undesired product (R)-1-[2-(4-hydroxybutylsulfanyl)-ethyl]-6-oxo-piperidine-2-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH:18]([CH2:24][CH2:25][CH3:26])[C:19]([O:21]CC)=[O:20])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH:18]([CH2:24][CH2:25][CH3:26])[C:19]([OH:21])=[O:20])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCC(Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1)C(=O)O

Procedure:
A solution of 3.5 g of ethyl 2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}pentanoate, 30 ml 15% sodium hydroxide and 30 ml methanol is heated under reflux for 1.5 hr. The reaction mixture is poured into ice/dil hydrochloric acid with stirring. The precipitate is collected, washed with water and dried in vacuo. Recrystallization from toluene/acetonitrile affords 2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}pentanoic acid, mp 170° C.