Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]#[N:18])[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH2:27][C:28](=[O:32])[N:29]([CH2:30][CH3:31])[C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]#[N:18])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:20][C:21]2[CH:34]=[CH:33][C:24]3[CH2:25][CH2:26][CH2:27][C:28](=[O:32])[N:29]([CH2:30][CH3:31])[C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CCN1C(=O)CCCc2ccc(N)cc21
Reactant: N#CCCc1cccc(Nc2nc(Cl)ncc2Cl)c1
Product: CCN1C(=O)CCCc2ccc(Nc3ncc(Cl)c(Nc4cccc(CCC#N)c4)n3)cc21

Procedure:
3-{3-[5-Chloro-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-pyrimidin-4-ylamino]-phenyl}-propionitrile was prepared from 3-[3-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-propionitrile and 8-Amino-1-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one) in an analogous manner to Example 1d. Title compound isolated as a white foam. Purity 99% (HPLC). LCMS: 462.50 (M+H). 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.96 (bs, 1H), 7.66 (bs, 1H), 7.62 (s, 1H), 7.28-7.26 (m, 2H), 7.25-7.23 (m, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.06 (s, 1H), 6.98 (d, J=7.3 Hz, 1H), 4.00-3.55 (m, 2H), 2.97 (t, J=6.6 Hz, 2H), 2.69 (t, J=6.0 Hz, 2H), 2.67-2.64 (m, 2H), 2.30-2.27 (m, 2H), 2.18-2.08 (m, 2H), 1.10 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12](O)[CH:11]([CH2:17][C:18]([OH:20])=[O:19])CC2.[CH2:21]([O:23][CH2:24][CH3:25])C>>[CH3:21][O:23][C:24]1[C:25]2[C:8](=[CH:7][C:6]([O:5][CH3:4])=[CH:15][CH:14]=2)[CH:13]=[CH:12][C:11]=1[CH2:17][C:18]([O:20][CH3:3])=[O:19]
Reactant: C=[N+]=[N-]
Reactant: CCOCC
Reactant: COc1ccc2c(c1)CCC(CC(=O)O)C2O
Product: COC(=O)Cc1ccc2cc(OC)ccc2c1OC
Temperature: 210 °C

Procedure:
A solution of 4.2 g. of diazomethane and 75 ml. of diethyl ether is added to a mixture of 23.6 g. of 6-methoxy-1-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetic acid and 150 ml. of diethyl ether. The reaction mixture is stirred until colorless; then it is evaporated. The residue, containing methyl 6-methoxy-1-methoxy-1,2,3,4-tetrahydro-2-naphthylacetate is esterified by treatment with 240 mg. of sodium hydride in 25 ml. of methanol followed by the addition of 2.4 g. of methyl iodide. The product, methyl 1,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthylacetate, is dehydrogenated by heating it with 2 g. of 10% palladium-on-charcoal catalyst; the resulting mixture is heated to 210° C for 12 hours. The cooled mixture is then diluted with 150 ml. of methylene chloride, filtered, and evaporated to yield methyl 1,6-dimethoxy-2-naphthylacetate. The product is refluxed in a mixture of 150 ml. of glacial acetic acid and 150 ml. of 48% hydrobromic acid for ten minutes. The product is extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered and evaporated to yield a mixture of methyl 1-hydroxy-6-methoxy-2-naphthylacetate and methyl 1-methoxy-6-hydroxy-2-naphthylacetate. The compounds are separated by distillation under reduced pressure and identified by nuclear magnetic spectroscopy.
Reaction SMILES: [C:1](=[O:3])=O.[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>ClCCl>[C:5]1([N:4]=[C:1]=[O:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C=O
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: O=C=Nc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Carbon dioxide was added subsurface to a dichloromethane (20 mL) solution containing aniline (Ph--NH2) (0.02 mol, 1.86 g) and triethylamine (0.06 mol, 6.0 g) at -10° C. (ice and salt bath) for 40 min at a pressure of 0 psig. The reaction mixture was transferred rapidly via cannula under carbon dioxide to the precooled solution of phosphorus oxychloride (0.02 mol, 3.2 g) in 20 mL dichloromethane. After stirring for ca. 30 min at -10° C. a white ppt. formed. The ppt. was filtered off and the filtrate concentrated in vacuo. The residue was extracted with 3×20 mL diethyl ether. The ether layers were concentrated and the residue was distilled under vacuum (ca. 0.1-0.3 torr) collecting product, phenyl isocyanate, at 71°-73° C. (1.45 g, 61%) of 99% purity as judged by GC. IR (neat) 2266 cm-1. 1H NMR (CDCl3) δ 7.30 (t, 2H, J=7.8), 7.17 (t, 1H, J=7.5), 7.07 (d, 2H, J=6.7) ppm.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9](=[O:11])[CH3:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5]>C1COCC1.[Ru](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:1][CH:2]([CH2:8][C:9](=[O:11])[CH3:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(=O)CC(C)=O
Agent: Cl[Ru]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CC(O)CC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
Methyl 3,5-dioxohexanoate (19.0 g) was dissolved in THF (380 mL) and tris(triphenylphosphine) ruthenium (II) dichloride (1.1 g) was added. The reaction mixture was hydrogenated at 5 bar, 50° C. for 16 h and then cooled to room temperature. The solvent was removed under vacuum and the oil was purified on silica gel (hexane/EtOAC 1:1) to give the final methyl 3-hydroxy-5-oxohexanoate (10 g).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]([OH:17])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15]O)[CH2:5][CH2:4]1)[CH3:2]>C(O)=O>[CH2:1]([N:3]1[CH2:4][CH2:5][C:6]2([C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:15][O:17]2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCC(O)(c2ccccc2CO)CC1
Solvent: O=CO
Product: CCN1CCC2(CC1)OCc1ccccc12

Procedure:
Treatment of 1-ethyl-4-hydroxy-4-(α-hydroxy-2-tolyl)piperidine with formic acid by the method described in Example 17c provides 1,3-dihydro-1'-ethylspiro[isobenzofuran-1,4'-piperidine] as an oil.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:10](Cl)=[O:11].CCN(C(C)C)C(C)C.O>CCOC(C)=O>[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:10]([N:3]([O:4][CH3:5])[CH3:2])=[O:11]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CNOC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 35 °C
Reaction time: 1 h
Yield: 107.3 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (1.48 kg, 14.9 mol) was suspended in EtOAc (16 L) and warmed to 35° C. A solution of 3,4-dichlorobenzoyl chloride (3.00 kg, 13.9 mol) in EtOAc (8 L) was added, followed by addition of DIPEA (5.45 ml, 31.2 mol) while maintaining the temperature below 40° C. The reaction suspension was stirred for 1 h. When TLC analysis confirmed reaction completion by the disappearance of starting material, the reaction mixture was cooled to rt and H2O (10 L) was added to achieve a clear, biphasic solution. After removing the aqueous layer, the organic layer was dried (Na2SO4) and concentrated to afford the title compound (3.49 kg, 100%) as an oil. Upon sitting at rt, the product crystallized. IR (KBr pellet): 3445, 3258, 3091.6, 2981.4, 2945.5, 1942.4, 1645.6, 1588.6, 1557.4, 1462.9, 1414.5, 1368, 1386.2, 1262, 1209, 1130, 1112.5, 1071.8, 1030.9, 100.9, 893.8. MS (ES+): mass calculated for C9H9Cl2NO2, 233.00; m/z found 234.0 [M+H]+. Mp: 39.5-43.2° C. 1H NMR (400 MHz, CDCl3): 7.80 (d, J=2 Hz, 1H), 7.54 (dd, J=8.4, 2.0 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 3.54 (s, 3H), 3.34 (s, 3H). 13C NMR (100 MHz, CDCl3): 167.2, 135.0, 133.9, 132.4, 130.7, 130.2, 127.9, 61.5, 33.7.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH2:3]1.CS[N:22]=[C:23]=[O:24].N1C=CC=C[CH:26]=1>>[CH3:26][NH:22][C:23]([NH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH2:3]1)=[O:24]
Reactant: c1ccncc1
Reactant: CSN=C=O
Reactant: CC(C)(CO)C1CC(N)c2cc([N+](=O)[O-])ccc2N1
Product: CNC(=O)NC1CC(C(C)(C)CO)Nc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 22 (50 mg) and 30 mg of methyl thioisocyanate were dissolved in 1 ml of pyridine. After 2 hours of stirring at room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=1:2) to obtain 42 mg of the title compound. Its physical properties are shown below.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].N[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15].N1C=CC=CC=1.Cl>C(#N)C>[CH2:5]([O:4][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15])=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1S(N)(=O)=O
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCOC(=O)c1ccccc1S(N)(=O)=O
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A solution of 3.5 g of ethyl chloroformate in 10 ml of anhydrous acetonitrile is dropwise added to a solution of 5.5 g of 2-aminobenzenesulfonamide and 2.5 g of pyridine in 80 ml of anhydrous acetonitrile at room temperature during 2 hours. After stirring at room temperature, the mixture is poured into ice water and acidified with 100 ml of 2N-hydrochloric acid solution. The mixture is extracted with ethyl acetate twice, washed with an aqueous saturated sodium hydrogen carbonate and then with a saturated brine, and dried over anhydrous sodium sulfate. Then the mixture is concentrated under reduced pressure. The residue is crystallized from chloroform to give 6.6 g of the title compound.
Reaction SMILES: CN(C)C=O.[CH2:6]([C:9]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][O:12][C:13]2([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])[CH2:7][CH3:8].[Br:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[K+].[K+]>O>[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][O:18][C:17]1[C:9]([CH2:6][CH2:7][CH3:8])=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:23]([F:26])([F:24])[F:25])([C:19]([F:20])([F:21])[F:22])[O:12][CH2:11]2
Reactant: BrCCCCBr
Reactant: CCCc1c(O)ccc2c1COC2(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCBr)ccc2c1COC2(C(F)(F)F)C(F)(F)F
Yield: 19.9 %

Procedure:
A N,N-Dimethylformamide (10 mL) solution of 4-propyl-1,1-bis(trifluoromethyl)-1,3-dihydroisobenzofuran-5-ol (800 mg, 2.55 mol), 1,4-dibromobutane (2.75 mL, 12.73 mmol) and potassium carbonate (528 mg, 3.82 mmol) was stirred at room temperature overnight. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated in vacuum. The obtained residue was purified by silica-gel column chromatography (hexane:ethyl acetate=50:1) and the title compound (1.136 g, 99%) was obtained as colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][C:30]3[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=3)[C:23]=1[F:39])=[O:19])=[CH:12]2.[N:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46](O)=[O:47])[CH:41]=1.CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([NH:8][C:46]([C:42]2[CH:41]=[N:40][CH:45]=[CH:44][CH:43]=2)=[O:47])=[CH:17][CH:16]=3)=[O:19])=[C:23]([F:39])[C:24]=1[O:29][C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Reactant: O=C(O)c1cccnc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(NC(=O)c5cccnc5)ccc4[nH]3)c2F)c1
Yield: 22.3 %

Procedure:
The title compound (0.011 g, 19%) was prepared from 5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.050 g, 0.086 mmol), 3-pyridinecarboxylic acid (0.011 g, 0.086 mmol), DIPEA (0.075 mL, 0.43 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.065 g, 0.257 mmol) in a similar manner as described in the general procedure. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.66 (s, 1H), 10.38 (s, 1H), 9.16 (s, 2H), 8.80 (s, 1H), 8.38 (s, 1H), 8.12 (s, 1H), 7.72-7.97 (m, 1H), 7.32-7.97 (m, 7H), 7.19 (s, 1H), 4.58 (d, 2H). MS: m/z 574 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.B(Cl)(Cl)Cl.ClCCl.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#N.[Al+3].[Cl-].[Cl-].[Cl-].[OH2:30]>ClC1C=CC=CC=1>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:21]([C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([F:17])[CH:19]=1)=[O:30]
Reactant: COc1ccc(N)cc1
Reactant: N#Cc1cccc(F)c1
Reactant: O
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: COc1ccc(N)c(C(=O)c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
To a 0° C. solution of para-anisidine (8.13 g, 66.0 mmol) in 25 mL of chlorobenzene was added dropwise a solution of BCl3 in dichloromethane (74.3 mL of 1 M, 74.3 mmol). The mixture was stirred at room temperature for one hour, then transferred slowly via syringe to solution of 3-fluorobenzonitrile (4.00 g, 33.0 mmol) and AlCl3 (5.06 g, 37.9 mmol) in 50 mL of chlorobenzene at 60° C. After the addition was complete, the reaction was stirred at 70° C. for 3 hours, then cooled to room temperature and stirred overnight. Water was added (125 mL), and the mixture stirred at 85 degrees for 6 hours. After cooling to room temperature, the mixture was poured into water, and the organic layer was extracted with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chomatography through SiO2 (50-100% CH2Cl2/hexane) to provide the titled product (1.83 g, 23% yield) as a red oil. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C14H13FNO2 (M+H+): 246.0929. Found 246.0925.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([B:10]2[O:18][C:15]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:13])[O:11]2)[CH:6]=[CH:7][C:8]=1F)#[N:2].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>CN1C(=O)CCC1>[N:19]1([C:8]2[CH:7]=[CH:6][C:5]([B:10]3[O:18][C:15]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:13])[O:11]3)=[CH:4][C:3]=2[C:1]#[N:2])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC1(C)OB(c2ccc(F)c(C#N)c2)OC1(C)C
Reactant: C1CCNC1
Solvent: CN1CCCC1=O
Product: CC1(C)OB(c2ccc(N3CCCC3)c(C#N)c2)OC1(C)C
Temperature: 140 °C
Yield: 943 %

Procedure:
3-Cyano-4-fluorophenyl-boronic acid pinacol ester (250 mg, 1.01 mmol) was dissolved in NMP (4 mL). Pyrrolidine (415 μL, 5.05 mmol) was added and the mixture heated at 140° C. in the microwave (300 W, stirring) for 5 minutes. The reaction was repeated 14 more times. The 15 reaction mixtures were combined and the solvent evaporated in vacuo (Genevac™). The residue was dissolved in EtOAc (200 mL) and the solution washed with saturated brine solution (2×75 mL). The organic phase was dried (MgSO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (40-63 mesh silica gel, 90% isohexane-EtOAc) to provide the title compound as an off-white solid (2.84 g, 63%); LC-MS, Rt=3.33 min (MeOH-FA method), m/z 298 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:16])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH3:15])[CH:9]=1)[CH3:6])[CH3:2].[CH:18]1([C:21]2[C:26]([CH2:27][C:28](O)=[O:29])=[CH:25][N:24]=[C:23]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)[N:22]=2)[CH2:20][CH2:19]1.ClCC1C(C2CC2)=NC(C2C=CC(C(F)(F)F)=CC=2)=NC=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([C:28](=[O:29])[CH2:27][C:26]2[C:21]([CH:18]3[CH2:19][CH2:20]3)=[N:22][C:23]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=3)=[N:24][CH:25]=2)[CH3:15])[CH:9]=1)([CH3:16])[CH3:6])[CH3:2]
Reactant: O=C(O)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(NC)c1
Agent: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)C(C)(C)Oc1cccc(N(C)C(=O)Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-(3-methylamino-phenoxy)-propionic acid ethyl ester (example 26 A]) was reacted with [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) in analogy to the sequences described in examples 26D] and 26E]) to give 2-[3-({2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetyl}-methyl-amino)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:9]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10]1>C(OCC)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C:9]2([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:4]=1
Reactant: O=C1CCCC1
Reactant: Clc1ccc(Br)cn1
Solvent: CCOCC
Product: OC1(c2ccc(Cl)nc2)CCCC1
Temperature: -20 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
5-Bromo-2-chloropyridine (3.0 g, 15.6 mmol) was dissolved in diethyl ether (100 mL) in an oven-dried, nitrogen-flushed 250 mL round bottom flask and cooled in a dry ice/acetone bath under nitrogen. n-BuLi (1.05 g, 16.4 mmol, 6.6 mL of a 2.5 M solution in hexanes) was added via syringe and the and the orange heterogenous mixture allowed to stir for 1 hour. Cyclopentanone (1.3 g, 15.6 mmol) was added via syringe and the mixture allowed to warm to −20° C. before being quenched with 1N HCl. The mixture was extracted with EtOAc and the organic extract washed with sat. NaHCO3. The NaHCO3 wash was used to neutralize the first aqueous layer and the combined aqueous layers were extracted with additional EtOAc and the combined organic layers dried (Na2SO4), filtered, concentrated, and purified by flash silica gel chromatography (hexanes:EtOAc; 2:1) to give 1-(6-chloropyridin-3-yl)cyclopentanol (2.33 g, 76%) as an off-white solid: mp 92-93° C., LC/MS (ESI) m/z 197, 1H NMR (300 MHz, CDCl3) δ 8.50 (d, 1H, J=2.4 Hz), 7.77 (dd, 1H, J=8.4, 2.4 Hz), 7.28 (d, 1H, J=8.4 Hz), 2.05-1.80 (m, 8H), 1.60 (s, 1H, OH).
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[C:7]([N+]([O-])=O)[C:6]([CH3:12])=[CH:5][N+:4]=1[O-:13].Cl.[CH3:15][OH:16]>C(OCC)(=O)C>[CH3:15][O:16][C:7]1[C:6]([CH3:12])=[CH:5][N+:4]([O-:13])=[C:3]([CH3:2])[CH:8]=1
Reactant: Cc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Reactant: CO
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Product: COc1cc(C)[n+]([O-])cc1C

Procedure:
12.2 g of sodium were dissolved in 2 l of methanol under argon, whereupon 60 g of 2,5-dimethyl-4-nitropyridine 1-oxide were added portionwise and the solution was left to boil under reflux overnight. The pH was adjusted to 7 with 5N hydrogen chloride in ethyl acetate while cooling and the mixture was evaporated in vacuo. The residue was taken up in 1 l of methylene chloride, the solution was filtered through silica gel, which was rinsed with 0.4 l of methylene chloride, and the combined filtrates were evaporated in vacuo. The residue crystallized from methylene chloride/petroleum ether and there was obtained 4-methoxy-2,5-dimethylpyridine 1-oxide of melting point 99°-101°.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15].C([O-])(O)=O.[Na+].[H][H]>CO.O1CCOCC1.[Pd]>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:2]2
Reactant: [H][H]
Reactant: COC(=O)c1cnc2ccc(OC)nc2c1Br
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cnc2ccc(OC)nc2c1
Yield: 96.7 %

Procedure:
To a mixture of methyl 4-bromo-6-(methyloxy)-1,5-naphthyridine-3-carboxylate (1.67 g, 5.64 mmol)) and NaHCO3 (0.84 g, 10 mmol) in MeOH (20 ml) and 1,4-dioxane (15 ml) was added 10% Pd/C (0.75 g) and the mixture was then stirred at rt under 1 atmosphere of hydrogen for 3 h. The reaction mixture was then filtered through a thin pad of Celite, washing through with EtOH. The filtrate was evaporated and stirred in 50 ml of water, the solid was then filtered off and dried in vacuo to give the desired product (1.19 g, 96%).
Reaction SMILES: [C-:1]#[N:2].[Na+].F[B-](F)(F)F.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+]#N)[CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[C:15]([O:32][CH3:33])[CH:14]=1)=[O:12].C(OCC)(=O)C.O>CN(C)C=O>[C:1]([C:27]1[CH:28]=[C:29]2[C:24]([CH:23]=[CH:22][CH:21]=[C:20]2[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:14][C:15]=2[O:32][CH3:33])=[CH:25][CH:26]=1)#[N:2]
Reactant: [C-]#N
Reactant: COC(=O)c1ccc(Cc2cccc3ccc([N+]#N)cc23)c(OC)c1
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cc2cccc3ccc(C#N)cc23)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
A mixture of cuprous cyanide (2.52 g), sodium cyanide (1.68 g), and dimethylformamide (50 ml, distilled over CaH2) was stirred for 1 h. The homogeneous solution was cooled to 0° C. and a solution of 1-(4-methoxycarbonyl-2-methoxyphenylmethyl)naphthalene-7-diazonium tetrafluoroborate (2.62 g), in dimethylformamide (12 ml, distilled over CaH2) was added. The reaction was stirred for 15 min at 0° C. and then at room temperature for 16 h. The mixture was added to ethyl acetate (200 ml) and water (300 ml) and filtered through diatomaceous earth with ethyl acetate washes. The organic layer was washed (water, brine), dried (MgSO4), and evaporated. Flash chromatography of the residue, eluting with methylene chloride, and trituration of the product with hot ether afforded methyl 4-(7-cyanonaphth-1-ylmethyl)-3-methoxybenzoate (1.04 g, 56%) as a pale yellow solid; mp 138.5°-139.5° C.; MS(CI), m/e=33Z(M+H).
Reaction SMILES: [SH:1][C:2]1[C:3]2[N:10]=[C:9]([CH2:11][OH:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.I[CH3:14]>[OH-].[Na+]>[CH3:14][S:1][C:2]1[C:3]2[N:10]=[C:9]([CH2:11][OH:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCc1nc2c(S)ncnc2s1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Product: CSc1ncnc2sc(CO)nc12
Yield: 53 %

Procedure:
A solution of (7-mercapto[1,3]thiazolo[5,4-d]pyrimidin-2-yl)methanol (Intermediate 75) (48.3 g) and iodomethane (16.6 mL) in 2M NaOH (450 mL) was stirred at ambient temperature for 5 hours. The crude product was collected by filtration, suspended in water and acidified by addition of 2N HCl. The flocculant solid was collected by filtration, washed with water (200 mL) and ether (200 mL) and dried under vacuum over phosphorus pentoxide to give the title compound as a pale brown solid (27.5 g, 53%);
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.Cl[CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:13])=[CH:3][C:2]=1[O:1][CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: COc1cc2c(cc1O)CCC2=O
Reactant: ClCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCCCOC1CCCCO1)CCC2=O

Procedure:
A mixture of 5-Hydroxy-6-methoxy-indan-1-one (Intermediate H, 2.98 g, 0.017 mole), 2-(3-chloro-propoxy)-tetrahydro-pyran (Compound 18a) (6.0 g, 0.034 mole), and potassium carbonate (10.0 g, 0.0725 mole) were stirred in 50 mL of DMF at 80° C. overnight under Argon. The reaction mixture was then diluted with 200 mL of ethyl acetate and washed 3 times with water. After drying over sodium sulfate, the solvent was removed in vacuo. The crude material solidified on standing to yield the title compound, 6-Methoxy-5-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-indan-1-one. MS m/z 309 (M+H)+.