Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(O)=CC=1O.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=1.CC([O-])=O.[Na+]>B(F)(F)F>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]=[O:20])=[CH:14][CH:13]=1
Reactant: COc1ccc(CC(=O)O)cc1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: Oc1ccc(Cl)c(O)c1
Product: COc1ccc(CC=O)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
4-Chlororesorcinol (1 eq) and para-methoxyphenylacetic acid (1 eq) were combined in boron trifluoride diethyletherate (5 eq) and heated to 90° C. under nitrogen for 3 hours. The reaction was allowed to cool to room temperature and was then added drop wise to 10% NaOAc (aq). The mixture was allowed to stand overnight, and the subsequent solid was collected by vacuum filtration. The solid was dried under vacuum to give 1-5-chloro-2,4-dihydroxy-phenyl)-2-(4-methoxy-phenyl)-ethanone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[F:19])=O.[CH3:20][S:21]([CH2:24][C:25](=O)[CH3:26])(=[O:23])=[O:22].[Na]>CC(O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:25]([CH3:26])[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[C:9]2[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[F:19]
Reactant: CC(=O)CS(C)(=O)=O
Reactant: Nc1ccc(Br)cc1C(=O)c1cc(F)c(F)cc1F
Agent: [Na]
Solvent: CC(C)O
Product: Cc1nc2ccc(Br)cc2c(-c2cc(F)c(F)cc2F)c1S(C)(=O)=O
Yield: 20.4 %

Procedure:
(2-Amino-5-bromo-phenyl)-(2,4,5-trifluoro-phenyl)-methanone (compound of example A.4) (1.9 g, 5.7 mmol), methanesulfonylacetone (1.18 g, 8.6 mmol) and sodium tetrachloroaureate(III) dihydrate (0.12 g, 0.28 mmol) were heated at reflux in 2-propanol (50 ml) for 4 days. The resulting mixture was evaporated to dryness and the residue extracted with dichloromethane (2×), NaOH (2×) and NaCl (1×). The crude product was purified by chromatography on silica gel with a heptane/ethyl acetate gradient from 100:0 to 90:10. One obtained a light yellow solid (0.5 g, 20%). MS: m/z=430 (M).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:25])=[CH2:24])=[CH:19][N:18]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:24][CH:23]([C:20]3[CH:19]=[N:18][C:17]([CH3:16])=[CH:22][CH:21]=3)[CH3:25])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=C(C)c1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)c2ccc(C)nc2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 2-methyl-5-(prop-1-en-2-yl)pyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: CN(CC)C.[CH2:6]([N:13]1[CH2:35][CH2:34][N:16]2[C:17]3[CH:33]=[CH:32][CH:31]=[CH:30][C:18]=3[N:19]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=O)[CH2:20][CH2:21][CH:15]2[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[CH2:6]([N:13]1[CH2:35][CH2:34][N:16]2[C:17]3[CH:33]=[CH:32][CH:31]=[CH:30][C:18]=3[N:19]([CH2:22][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[CH2:20][CH2:21][CH:15]2[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(c1ccncc1)N1CCC2CN(Cc3ccccc3)CCN2c2ccccc21
Agent: CCN(C)C
Solvent: C1CCOC1
Product: c1ccc(CN2CCN3c4ccccc4N(Cc4ccncc4)CCC3C2)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of alane-N,N-dimethylethylamine complex (Aldrich, 0.5 M in toluene, 3.1 mL, 1.55 mmol) was added dropwise with stirring to an ice-cooled solution of the product of Example 43 (123 mg, 0.309 mmol) in tetrahydrofuran (10 mL). The mixture was stirred under nitrogen as the ice bath was allowed to expire over 2.5 hours. The reaction was quenched by addition of methanol (2 mL) and concentrated under vacuum. The residue was purified by flash chromatography (SiO2, eluted with CH2Cl2-methanol-15 M NH4OH) and then by HPLC (30×100 mm, C18, Waters XBridge™ column eluting with aqueous 0.1 M (NH4)2CO3-methanol (80:20-0:100 over 15 minutes)) to provide the title compound: 1H NMR (300 MHz, CD3OD) δ ppm 1.60 (ddt, J=15.3, 2.4 Hz, 1H), 1.85-2.03 (m, 1H), 2.26 (t, J=10.7 Hz, 1H), 2.37 (td, J=11.1, 3.2 Hz, 1H), 2.70 (br d, J=10.7 Hz, 1H), 2.86-2.98 (m, 3H), 3.06 (dt, J=11.5, 2.8 Hz, 1H), 3.25-3.35 (m, 1H), 3.55 (td, J=11.4, 2.2 Hz, 1H), 3.61 (s, 2H), 4.32 (d, J=16.7 Hz, 1H), 4.61 (d, J=16.7 Hz, 1H), 6.75 (dd, J=6.8, 2.4 Hz, 1H), 6.78-6.92 (m, 2H), 6.94 (dd, J=7.1, 2.1 Hz, 1H), 7.24-7.39 (m, 5H), 7.42 (d, J=5.9 Hz, 2H), 8.40 (d, J=6.3 Hz, 2H); MS (ESI) m/z 385 (M+H)+.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[CH2:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C(OCC)C>[Br:1][CH:2]([CH3:6])[C:3]([O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: CC(Br)C(=O)Cl
Solvent: O
Solvent: CCOCC
Product: CC(Br)C(=O)OCc1ccccc1

Procedure:
2-Bromopropionyl chloride (213.4 g) was added dropwise to benzyl alcohol (145.8 g) with stirring under a stream of nitrogen, keeping the temperature of the reaction mixture below 30° C. by cooling with cold water. When all the acid chloride has been added, the mixture was stirred for another two hours at ambient temperature. The reaction mixture was then diluted with diethyl ether (200 ml) and washed with water until free of acid. The ethereal solution was dried and evaporated and the residue distilled to give benzyl 2-bromopropionate, b.p. 82°-85°/0.5 Torr.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:23][C:24]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32]([OH:34])=O)=[CH:28][CH:27]=1)=[O:25].Cl.Cl.[N:39]1([C:45]([O:47][C:48]2[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=2)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:23][C:24]([C:26]1[CH:27]=[CH:28][C:29]([O:30][CH2:31][C:32]([CH:42]2[CH2:43][CH2:44][N:39]([C:45]([O:47][C:48]3[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=3)=[O:46])[CH2:40][CH2:41]2)=[O:34])=[CH:35][CH:36]=1)=[O:25]
Reactant: NC(=O)c1ccc(OCC(=O)O)cc1
Reactant: O=C(Oc1cccnc1)N1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(OCC(=O)C2CCN(C(=O)Oc3cccnc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.2 %

Procedure:
TEA (0.251 ml), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (259 mg), 1-hydroxybenzotriazole (122 mg) and the above-produced compound [4-(aminocarbonyl)phenoxy]acetic acid (184 mg) were added to a DMF (5 ml) solution containing 3-pyridyl 1-piperidinecarboxylate dihydrochloride (252 mg) obtained in the method of Example 121, followed by stirring at room temperature for 5 hours. An aqueous saturated sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=95:5 (v/v)), and the resulting solid was recrystallized from EtOAc/acetonitrile to obtain pyridin-3-yl 4-{[4-(aminocarbonyl)phenoxy]acetyl}piperidine-1-carboxylate (274 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[CH:2]=1.[H][H]>CO.C(N(CC)CC)C.[Co]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:2]=1
Reactant: [H][H]
Reactant: N#CCCCCCc1cccnc1
Agent: [Co]
Solvent: CCN(CC)CC
Solvent: CO
Product: NCCCCCCc1cccnc1
Yield: 87.1 %

Procedure:
A solution of 52.15 g of 3-pyridinehexanenitrile in 600 ml of methanol and 13 ml of triethylamine was hydrogenated over 13 g of Raney cobalt at an initial hydrogen pressure of 1000 psi and 100° C. The cooled mixture was filtered and concentrated. The residue was distilled to give 46.5 g (87%) of 3-pyridinehexanamine, bp 102°-107° C./0.2 mm. This material was purified through its phthalimide which was formed by reaction with 39.53 g of phthalic anhydride in 300 ml of glacial acetic acid at reflux overnight. The residue obtained after evaporation of the solvent was dissolved in 300 ml of ethyl acetate, washed with dilute sodium hydroxide and sodium bicarbonate, dried over potassium carbonate and concentrated. The residue was crystallized from ethyl acetate-hexane to give 62.87 g (77%) of 2-[6-(3-pyridinyl)hexyl]-1H-isoindole-1,3(2H)-dione, mp 89°-92° C. A solution of this material in 880 ml of ethanol and 33 ml of hydrazine hydrate was heated to reflux for 3 hours. The cooled mixture was filtered and concentrated. The residue was taken up in 500 ml of dichloromethane and was washed with 10% sodium hydroxide and dried over potassium carbonate. The residue obtained after concentration was distilled to give 31.6 g (60% based on starting nitrile) of 3-pyridinehexanamine, bp 140°-150° C./0.3 mm which gave a single peak on gas chromatography.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12]CCC1CC2C(C)=C(OCC3C=CC=CC=3)C(C)=C(C)C=2O1>>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([OH:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC(CCO)O2
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 177.9 %

Procedure:
105 mg of p-toluenesulfonyl chloride is added to a solution of 156 mg of 2-(RS)-(2-hydroxyethyl)-2,3-dihydro-5-benzyloxy-4,6,7 -trimethylbenzofurane in 0.5 ml cooled to 0° C. The reaction mixture is stirred for 3 hours, then it is acidified and extracted. The organic extracts are dried and evaporated, thus giving 185 mg of raw product, which is then purified with chromatography (SiO2). 153 mg of p-toluenesulfonate of 2[2,3-dihydro-5-benzyloxy-4,6,7-trimethyl-2-(RS)benzofuranyl]ethyl are obtained. IR (KBr): 1359, 1177 cm-1 (νSO2). The product thus obtained is then solubilized in 2 ml of anhydrous tetrahydrofurane and added to a suspension of 45 mg of lithium and aluminum hydride in 5 ml of anhydrous tetrahydrofurane. The reaction mixture is stirred in an inert atmosphere for 30 minutes. The reaction process is carried out using the same procedure described in example 1. 82 mg of a white solid are obtained. m.p. 65°-67° C. IR (KBr): 1595 (νC--C), 1237 cm-1 (νC--O--C); 1H-NMR (CDCl3): δ 7.5-7.1 (5H,m), 4.8-4.4 (1H,m), 4.7 (2H,s), 3.3-2.5 (2H,m), 2.2 (6H,s), 2.1 (3H,s), 1.9-1.5 (2H,m), 1.0-(3H,t).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35]
Reactant: O=C(N[C@@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: O=C(N[C@@H]1CCN(C(=O)CO)C1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A142) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [S:1]1[CH:5]=[C:4]2[C:6]([O:8][C:9](=[O:10])[C:3]2=[CH:2]1)=[O:7].[CH2:11]([NH2:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1(C)C=CC=CC=1>[CH2:11]([NH:19][C:6]([C:4]1[C:3]([C:9]([OH:8])=[O:10])=[CH:2][S:1][CH:5]=1)=[O:7])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1OC(=O)c2cscc21
Reactant: CCCCCCCCN
Solvent: Cc1ccccc1
Product: CCCCCCCCNC(=O)c1cscc1C(=O)O

Procedure:
The anhydride was subsequently dissolved in toluene (320 mL) in a 500 mL flask, followed by the addition of n-octylamine (6.72 g, 52.02 mmol, 8.6 mL). The resulting reaction mixture was subsequently refluxed over a period of 24 h. The reaction mixture was allowed to cool and was subsequently concentrated affording 4-octylcarbamoylthiophene-3-carboxylic acid as a solid. The acid was dissolved in thionyl chloride (SOCl2) (270 mL) and refluxed over a period of 4 hours. The reaction mixture was cooled down and subsequently concentrated to dryness. The residue was purified by column chromatography using methylene dichloride:hexanes (2:1) as the eluant to afford the title compound as a pure white solid (5.2 g, yield 57%): mp: 120-122° C.; GC-Ms: 265; 1H NMR (400 MHz, CDCl3, ppm) δ:7.8(s, 2H), 3.62-3.59 (t, 2H), 1.64-1.62(m, 2H), 1.26(m, 10H), 0.87-0.85(m, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ: 162.4, 136.7, 125.2, 37.9, 31.7, 29.2 (2C), 28.4, 26.8, 22.4, 14.1.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:28])[C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:3]1=[O:29].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([C:14]([N:13]([CH3:28])[C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][CH:2]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:3]4=[O:29])=[CH:8][CH:9]=3)=[O:27])=[CH:16][CH:17]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(Br)C2=O)cc1
Reactant: C1CCNC1
Product: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(N3CCCC3)C2=O)cc1

Procedure:
N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with pyrrolidine by method L. This resulted in the product with the molecular weight of 445.61 (C28H35N3O2); MS (ESI): 446 (M+H+).
Reaction SMILES: Cl.[F:2][C@@H:3]1[C@H:7]([OH:8])[C@@H:6]([CH2:9][OH:10])[O:5][C@H:4]1[N:11]1[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]1=[O:13].N1C=CC=CC=1.C(#N)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C(N(CC)CC)C.CN(C=O)C>[C:28]([NH:16][C:15]1[CH:17]=[CH:18][N:11]([C@@H:4]2[O:5][C@H:6]([CH2:9][OH:10])[C@@H:7]([OH:8])[C@H:3]2[F:2])[C:12](=[O:13])[N:14]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)n1

Procedure:
1 g (about 4 mmol) of 2′-fluoro-2′-deoxycytidine hydrochloride is coevaporated with 20 ml of abs. pyridine twice and twice with 10 ml of abs. acetonitrile each time in a 100 ml Schlenk flask. The dried nucleosidic material is suspended in 40 ml of abs. DMF, and 0.6 ml (about 4.4 mmol) of acetic anhydride is added. Over the course of one day 0.5 ml (4.4 mmol) of abs. triethylamine is added dropwise to the mixture. The solvent is subsequently stripped off under oil pump vacuum. The crude product is washed with 50 ml of diethyl ether and subsequently dried. Purification was by column chromatography (silica gel 60 H, column 4×10 cm, mobile phase methylene chloride with 0.1% pyridine, gradient methanol); the product is eluted at 8% methanol.
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][C:12]([C@H:14]2[C@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[F:26])[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15]2)=[O:13])[CH:5]=1.[OH-].[Na+]>CO>[Cl:25][C:21]1[C:20]([F:26])=[C:19]([C@@H:18]2[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:41])([CH3:39])[CH3:40])[NH:15][C@H:14]2[C:12]([NH:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:42])=[O:2])=[O:13])[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCc2cccc(C(=O)O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 1.5 h

Procedure:
rac 3-({[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-benzoic acid methyl ester (40 mg) was dissolved in MeOH (10 mL) with help of slight heating. To the stirred solution was added NaOH (1N, 2 mL) and the mixture was stirred for 1.5 hrs. The solvent was removed and the residue was treated with 1 N HCl to make the mixture acidic. The white suspension was extracted with EtOAc (3×10 mL) and the extracts combined and dried with sodium sulfate. The solvent was removed and the residue was freeze dried to give a white powder. 38 mg.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([CH3:16])[C:10]=2[C:17]([O:19]CC2C=CC=CC=2)=[O:18])[CH:6]=[CH:7][CH:8]=1)#[N:2].[H][H]>C(O)C.O1CCCC1.[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([CH3:16])[C:10]=2[C:17]([OH:19])=[O:18])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: [H][H]
Reactant: Cc1cc(-c2cccc(C#N)c2)c(C(=O)OCc2ccccc2)c(C)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(-c2cccc(C#N)c2)c(C(=O)O)c(C)n1
Yield: 75.4 %

Procedure:
A solution of benzyl 4-(3-cyanophenyl)-2,6-dimethyl-3-pyridinecarboxylate (0.45 g) in a mixture of ethanol (9 ml) and tetrahydrofuran (9 ml) was hydrogenated under an atmospheric pressure of hydrogen over 10% palladium charcoal (90 mg) at 60° C. for 1.5 hours. After removal of the catalyst, the solvent was evaporated in vacuo. The residue was triturated with diethyl ether and dried to give 4-(3-cyanophenyl)-2,6-dimethyl-3-pyridinecarboxylic acid (0.25 g).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(O)c1c(F)cc(F)c(F)c1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1c(F)cc(F)c(F)c1F

Procedure:
38.8 g of 2,3,4,6-tetrafluorobenzoic acid, a known compound, was treated with thionyl chloride to give 36 g of 2,3,4,6-tetrafluorobenzoyl chloride as an oil. b.p. 87°-89° C. (36 mmHg).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[C:9]([N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:8]=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[N:6]=1)([CH3:3])[CH3:2]>CC(O)C.ClCCl.[Pd]>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:7]2[N:6]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[CH:10]=[C:9]([N:11]3[CH2:12][CH:13]4[O:18][CH:16]([CH2:15][CH2:14]4)[CH2:17]3)[N:8]=2)=[CH:24][CH:23]=1
Reactant: CC(C)Nc1cc(N2CC3CCC(C2)O3)nc(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)Nc1cc(N2CC3CCC(C2)O3)nc(-c2ccc(N)cc2)n1
Reaction time: 1 h

Procedure:
In a 250 mL round-bottomed flask was placed 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-isopropyl-2-(4-nitrophenyl)pyrimidin-4-amine (17, 74 mg, 0.200 mmol) in 2-propanol (7 mL) and dichloromethane (7 mL) to give a yellow solution. A catalytic amount of Pd on charcoal (wet) was added and the mixture was stirred under a hydrogen atmosphere for 1 hour. The mixture was filtered over Celite™, rinsed with dichloromethane and concentrated to give the title compound in quantitative yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH3:16])=[N:13]2)=[CH:8][CH:7]=1.[O:17]1CCOCC1>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH:16]=[O:17])=[N:13]2)=[CH:8][CH:7]=1
Reactant: C1COCCO1
Reactant: COCCOc1ccc2ccc(C)nc2c1
Solvent: O
Product: COCCOc1ccc2ccc(C=O)nc2c1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of 7-(2-methoxyethoxy)-2-methylquinoline (235 mg, 1.08 mmol) in dioxane (3 mL) and water (0.03 mL) was added SeO2 (132 mg, 1.19 mmol). The reaction mixture was heated at reflux for 2 hours. After cooling to ambient temperature, the solid was removed by filtration and washed with DCM. The filtrate was concentrated under reduced pressure and The residue was purified by flash chromatography on silica gel (4:1 hexanes/EtOAc) to give 7-(2-methoxyethoxy)quinoline-2-carbaldehyde (195 mg, 78%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[OH:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:13]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)=[O:14])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: OC(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a stirred solution of (2-(4-fluorophenyl)thiazol-5-yl)(pyridin-4-yl)methanol (0.55 g, 1.92 mol) in DCM (20 mL) was added Dess-Martin periodinane (1.6 g, 3.84 mol) at room temperature. The resulting solution was stirred for 1 h. To the reaction mixture was added NaHCO3 solution (20 mL) and ethyl acetate (50 mL). The organic layer was extracted with ethyl acetate (2×20 mL), washed with brine solution (2×20 mL), dried over anhydrous sodium sulfate and the solvent removed via distillation under reduced pressure. The crude was purified through silica gel (100-200 mesh) column chromatography using 10% methanol in DCM) to obtain (2-(4-fluorophenyl)thiazol-5-yl)(pyridin-4-yl)methanone as off-white solid (0.4 g, 67% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.86 (d, 2H), 8.51 (s, 1H), 8.19 (dd, 2H), 7.82 (d, 2H), 7.45 (t, 2H); LC-MS m/z calculated for [M+H]+ 285.04 found 284.98.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:31]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:16][S:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)OC)c2ccc(OCCN)cc2)cc1
Solvent: c1ccncc1
Product: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)OC)c2ccc(OCCNC(C)=O)cc2)cc1

Procedure:
A solution of 0.219 g (0.507 mmol) of methyl(2R)-[4-(2-aminoethoxy)phenyl]({[4-(2-butynyloxy)phenyl]sulfonyl}amino)ethanoate in 2.5 mL of acetic anhydride and 0.25 mL of pyridine was stirred at room temperature for 15 h and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:1) to provide 0.213 g of methyl (2R)-{4-[2-(acetylamino)ethoxy]phenyl}({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-ethanoate as a white foam. Electrospray Mass Spec 475.3 (M+H)+.