Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1(OC)[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32](O)=[C:31]([F:36])[CH:30]=3)[N:21]=2)=[CH:16][CH:3]1[CH2:4][N:5]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[S:6]([CH3:9])(=[O:8])=[O:7].C(OC(N1CCC(N(CC2C=C(C3C=CN=C(Cl)N=3)C=CC=2F)S(C)(=O)=O)CC1)=O)(C)(C)C>>[F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:36])[CH:30]=3)[N:21]=2)=[CH:16][C:3]=1[CH2:4][N:5]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[S:6]([CH3:9])(=[O:7])=[O:8]
Reactant: COC1(F)C=CC(c2ccnc(NCCc3ccc(O)c(F)c3)n2)=CC1CN(C1CCNCC1)S(C)(=O)=O
Agent: CC(C)(C)OC(=O)N1CCC(N(Cc2cc(-c3ccnc(Cl)n3)ccc2F)S(C)(=O)=O)CC1
Product: CS(=O)(=O)N(Cc1cc(-c2ccnc(NCCc3cccc(F)c3)n2)ccc1F)C1CCNCC1

Procedure:
(N-(2-Fluoro-5-{2-[2-(3-Fluoro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-benzyl)-N-piperidin-4-yl-methanesulfonamide: Intermediate 91 was coupled with intermediate 83 following procedure F. The resulting product was deprotected following procedure G. The product was purified by HPLC. LC-MS showed the product had the expected M+H+ of 518. 1H NMR (Varian 300 MHz, DMSO, shifts relative to the solvent peak at 2.50 ppm) δ 8.0 (d, 1H), 7.3-7.2 (m, 2H), 7.0 (m, 2H), 6.8 (m, 3H), 4.4 (s, 2H), 3.5 (d, 2H), 3.0 (s, 3H), 2.8-2.6 (m, 7H), 1.7 (m, 4H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC[O:22]C(/N=N/C(OCC)=O)=O.C([O:34][C:35](=[O:52])[C@@H:36]([O:50][CH3:51])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]#[C:45][CH2:46][CH2:47][CH2:48][OH:49])=[CH:40][CH:39]=1)C.[C:53]([C:61]1[CH:66]=[CH:65][C:64](O)=[CH:63][CH:62]=1)(=[O:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C1COCC1>[C:53]([C:54]1[CH:55]=[CH:56][C:57]([O:49][CH2:48][CH2:47][CH2:46][CH2:45][C:44]([C:41]2[CH:40]=[CH:39][C:38]([CH2:37][C@H:36]([O:50][CH3:51])[C:35]([OH:34])=[O:52])=[CH:43][CH:42]=2)=[O:22])=[CH:58][CH:59]=1)(=[O:60])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCCO)cc1)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CO[C@@H](Cc1ccc(C(=O)CCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (0.915 mmol) in 5 mL of dry THF was treated at 0° C. with diethylazodicarboxylate (0.915 mmol) and stirred for 20 min. A solution of (2S)-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 21, Step A) (0.61 mmol) and 4-benzoylphenol (0.915 mmol) in 2 mL of dry THF was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum and purified by silica gel chromatography (silica gel, hexanes/ethyl acetate 10:1 to 3:1). Fractions with Rfs 0.48 and 0.45 (hexanes/ethyl acetate 2:1) corresponding to the coupled compound and starting phenol, respectively, were combined and concentrated. The mixture was dissolved in 5 mL of methanol and was treated with a mixture of 75 mg of mercury (II) oxide and 4% sulfuric acid in water. The solution was stirred at 55° C. for 3 hours, cooled to room temperature, diluted with saturated aqueous NaHCO3 (20 mL), and extracted with dichloromethane (4×20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated. The residue was dissolved in 6 mL of methanol and 2 mL of 1N NaOH and stirred for 2 hours. The methanol was evaporated under vacuum, and the aqueous solution was diluted with brine (6 mL) and washed with diethyl ether (3×15 mL). The aqueous layer was acidified with 1N HCl (pH 1–2) and extracted with ethyl acetate (3×15 mL) then concentrated to give the title compound. 1H-NMR (CDCl3, 200.15 MHz): 7.91–7.72 (m, 5H), 7.56–7.32 (m, 6H), 6.92 (d, 2H, J=8.9), 4.12–4.03 (m, 3H), 3.42 (s, 3H), 3.19–3.05 (m, 4H), 1.95–1.92 (m, 4H).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]([C:14]2[CH:36]=[CH:35][C:17]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]([C:29]([O:31]CC)=[O:30])[CH2:24][CH2:25][O:26]4)=[CH:21][C:20]=3[Cl:34])=[CH:16][CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]([C:14]2[CH:36]=[CH:35][C:17]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][O:26]4)=[CH:21][C:20]=3[Cl:34])=[CH:16][CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(C(C)(C)C)CC4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C1CCC(NC(=O)c2ccc(Oc3cc4c(cc3Cl)C(C(=O)O)CCO4)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.4 %

Procedure:
To a solution of ethyl 7-(4-(4-tert-butylcyclohexylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (0.037 g, 0.072 mmol) in 3:1 THF/methanol (1 ml) was added 1M sodium hydroxide (0.15 ml, 0.15 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was concentrated and the residue was diluted with dilute hydrochloric acid and extracted twice with EtOAc. The combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 32 mg of the title compound (91% yield). MS (apci) m/z=486.1 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.[OH2:6].[H][H]>[Re].O1CCCC1>[C:2]1(=[O:6])[O:1][CH2:5][CH2:4][CH2:3]1.[OH:1][CH2:5][CH2:4][CH2:3][CH:2]=[O:6]
Reactant: [H][H]
Reactant: C1=COCC1
Reactant: O
Agent: [Re]
Solvent: C1CCOC1
Product: O=C1CCCO1
Product: O=CCCCO

Procedure:
In a manner similar to that described in Example 1 10 mL/h of 2,3-dihydrofuran and 8 mL/h of water were passed at 220° C. in a stream of carrier gas comprising 13 L/h of hydrogen over 47 g of the rhenium-on-activated charcoal catalyst described in Example 5 (reactor volume: 100 mL). At a conversion of 99.5%, γ-butyrolactone was formed with a selectivity of 98% (tetrahydrofuran: 0.3%; 4-hydroxybutyraldehyde: 0.5%; remainder: small amounts of various non-analyzed low-boiling fractions).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH:10](Cl)[CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].CC(O)=O>C1COCC1>[C:1]([O:5][C:6]([C@H:7]1[C@H:10]([CH2:11][CH3:12])[CH2:9][N:8]1[CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(Cl)CN(CC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC[C@@H]1CN(C(c2ccccc2)c2ccccc2)[C@H]1C(=O)OC(C)(C)C
Yield: 86 %

Procedure:
To a stirred solution of [benzhydryl-(2-chlorobutyl)amino]acetic acid tert-butyl ester (7.7 g, 19.9 mmol, 1 eq.) in dry THF (120 mL) at −78° C. was added NaHMDS (49.7 mL, 49.6 mmol, 2.5 eq.) dropwise over 45 min. The reaction was then neutralized with AcOH (0.2 mL). The solid formed was filtered off and washed with EtOAc and the filtrate was concentrated in vacuo. The residue was redissolved in EtOAc, washed with brine, dried over MgSO4, filtered, concentrated in vacuo. The resulting product was chromatographed on silica gel using 50% DCM/hexanes/0.5% EtOAc mixture as eluent to afford (+)-trans-1-benzhydryl-3-ethylazetidine-2-carboxylic acid tert-butyl ester 86% yield. ESMS: m/z 352.3 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:21][C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:34][C:35]1[C:36]([O:43][CH3:44])=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:34][C:35]1[C:36]([O:43][CH3:44])=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)[C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CCl)c(OC)n1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)c(OC)n1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
5-Benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (2.03 g) was dissolved in dimethylformamide (27 mL), and sodium hydride (0.20 g) was added under ice-cooling. The mixture was stirred at the same temperature for 30 min. A solution of 3-chloromethyl-2,6-dimethoxypyridine (0.95 g) in dimethylformamide (6 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 5-benzyloxy-N-[(2,6-dimethoxypyridin-3-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.43 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[Cl:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:5]([OH:18])=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[Cs+].[Cs+].ClCI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH2:19][N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:16]([Cl:17])=[C:8]3[C:6]=2[N:7]=1
Reactant: Oc1ccc(Cl)nc1-c1[nH]c2ccccc2c1Cl
Reactant: O=C([O-])[O-]
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(n1)-c1c(Cl)c3ccccc3n1CO2
Yield: 74.7 %

Procedure:
A solution of 6-chloro-2-(3-chloro-1H-indol-2-yl)pyridin-3-ol (128 mg, 0.46 mmol) and Cs2CO3 (452 mg, 1.39 mmol) in DMF (6 mL) was stirred at 100° C. (internal temperature), then chloroiodomethane (173 mg, 0.92 mmol) in DMF (1 mL) was added dropwise. After the reaction was completed according to TLC, the mixture was filtered and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EtOAc=4:1) to provide 2,12-dichloro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (100 mg, yield: 75.2%). 1H-NMR (CDCl3, 400 MHz) δ 7.65 (d, J=8.0 Hz, 1H), 7.11˜7.31 (m, 5H), 5.82 (s, 2H). MS (M+H)+: 291/293.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]([OH:11])=O)=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH:15]([OH:27])[CH2:16][N:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][CH2:26][N:17]1[CH2:16][CH:15]([OH:27])[CH2:14][NH:13][C:9](=[O:11])[CH2:8][O:7][C:4]1[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=1
Reactant: Cc1ccc(OCC(=O)O)cc1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.1 %

Procedure:
A mixture of compound 2-(p-tolyloxy)acetic acid (100 mg, 0.60 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (124 mg, 0.60 mmol), BOP-Cl (183 mg, 0.72 mmol) and DIPEA (1 mL) in DCM (10 mL) was stirred at room temperature for 4 h. The solvent was removed by concentration and the crude product was purified by pre-HPLC to give the title compound (27.8 mg, yield 13.1%). 1H NMR (500 MHz, MeOD): δ 7.32-7.25 (m, 3H), 7.20 (d, J=7.2 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 4.65-4.52 (br.s, 1H), 4.52 (s, 2H), 4.46-4.30 (br.s, 1H), 4.30-4.24 (m, 1H), 3.85-3.70 (br.s, 1H), 3.43 (d, J=5.6 Hz, 1H), 3.26-3.17 (m, 4H), 2.26 (s, 3H) ppm; ESI-MS (m/z): 355.2 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]([CH3:26])[NH:21][CH2:20][CH2:19]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][CH:25]=[C:16]([O:15][CH3:14])[CH:17]=4)[CH:22]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ccc2c(c1)CCNC2C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: COc1ccc2c(c1)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:20])=[C:16]([O:18][CH3:19])[S:17][C:11]=2[NH:10][C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[N:40]=[C:39](C(Cl)(Cl)Cl)[O:38][N:37]=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-:46].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:20])=[C:16]([O:18][CH3:19])[S:17][C:11]=2[N:10]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][C:39](=[O:46])[O:38][N:37]=3)=[CH:26][CH:25]=2)[C:9]1=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: O=C([O-])[O-]
Reactant: COc1sc2[nH]c(=O)n(Cc3ccccc3)c(=O)c2c1C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1sc2c(c1C)c(=O)n(Cc1ccccc1)c(=O)n2Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A mixture of 3-benzyl-6-methoxy-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.50 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.82 g), potassium carbonate (0.46 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (4 mL) and methanol (4 mL). 1N Aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.90 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:23][S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35])[CH3:32]>CN1CCCC1=O.O>[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][N:39]([C:17]2[CH:16]=[C:15]([C:9]([OH:14])([C:10]([F:12])([F:11])[F:13])[CH:8]([C:7]3[CH:6]=[CH:5][C:4]([O:23][S:24]([C:27]([F:28])([F:29])[F:30])(=[O:25])=[O:26])=[CH:3][C:2]=3[Cl:1])[CH3:22])[CH:20]=[CH:19][N:18]=2)[CH2:38][CH2:37]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCN(c2cc(C(O)(C(C)c3ccc(OS(=O)(=O)C(F)(F)F)cc3Cl)C(F)(F)F)ccn2)CC1

Procedure:
Trifluoro-methanesulfonic acid 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester (Example 135-Step 1, 1.0 g) and piperidine-4-carboxylic acid ethyl ester (0.773 mL) in 1-methyl-2-pyrrolidon (10 mL) were heated at 220° C. in a microwave oven for 30 minutes. The reaction mixture was then diluted with water (100 mL), extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (70 g silica gel, heptane/acetic acid isopropylester 80/20 to 70/30) to give the title compound as light yellow viscous oil (119 mg). MS (m/e)=619.2 (MH+).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br.C1(C)C=CC=CC=1.O>CO>[CH3:1][O:2][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[Br:4]
Reactant: C[O-]
Reactant: BrCc1ccccc1Br
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: COCc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A temperature of 59.8 g of a 28% solution of sodium methoxide in methanol was raised to 60° C., a mixture solution of 70.4 g of o-bromobenzyl bromide and 70.4 g of methanol was added dropwise, and this was retained at 60° C. for 2 hours. After the mixture was cooled to room temperature, 211 g of toluene and 211 g of water were added thereto, the mixture was stirred, and layers were separated, and an organic layer was recovered. An aqueous layer was extracted with 211 g of toluene three times, the recovered organic layer and 211 g of water were added, and this was washed, and concentrated to obtain 55.3 g of 1-methoxymethyl-2-bromobenzene.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:17]=[CH:16][C:8]([CH2:9][NH:10][C:11]([CH:13]2[CH2:15][CH2:14]2)=[O:12])=[CH:7][CH:6]=1.[CH2:18](Br)[C:19]#[CH:20].C1(C)C=CC=CC=1>CCOCC.C1COCC1>[CH3:3][O:4][C:5]1[CH:17]=[CH:16][C:8]([CH2:9][N:10]([CH2:20][C:19]#[CH:18])[C:11]([CH:13]2[CH2:14][CH2:15]2)=[O:12])=[CH:7][CH:6]=1
Reactant: C#CCBr
Reactant: COc1ccc(CNC(=O)C2CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C#CCN(Cc1ccc(OC)cc1)C(=O)C1CC1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 62 %

Procedure:
Sodium hydride (60% in mineral oil, 709 mg, 17.72 mmol) was washed with dry ether (2×20 mL) and then suspended in dry THF (30 mL) and cooled with ice-water. Crude N-(4-methoxybenzyl)cyclopropanecarboxamide from last step in THF (5 mL) was added dropwise at 5° C. to the sodium hydride suspension. The reaction mixture was stirred at 5° C. for 20 min. A solution of propargyl bromide in toluene (80% wt., 2.69 mL, 24.17 mmol) was added dropwise with a syringe. The ice bath was removed and the mixture was stirred at room temperature overnight. The mixture was poured into ice-water (100 mL) and extracted with DCM (3×100 mL). The organic phases were combined and washed with brine (2×50mL), dried with anhydrous MgSO4, filtered and evaporated to dryness, then purified by silica gel column chromatography, eluting with MeOH/DCM (0-2%) to give the product (2.43 g, 62.0% yield), LRMS ESI (M+H+) 244.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH3:15])=[O:13])=[CH:6]2.[CH3:16][S:17]([CH3:19])=O.[ClH:20]>CO>[Cl-:20].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH3:15])=[O:13])=[C:6]2[S+:17]([CH3:19])[CH3:16]
Reactant: COC(=O)c1cc2cc(OC)ccc2[nH]1
Reactant: Cl
Reactant: CS(C)=O
Solvent: CO
Product: COC(=O)c1[nH]c2ccc(OC)cc2c1[S+](C)C
Product: [Cl-]
Yield: 52 %

Procedure:
A mixture of methyl 5-methoxy-1H-indole-2-carboxylate (8.3 g, 40 mmol; Blaikie KG, Perkin WH Jr, J. Chem. Soc. 1924;125:296) and dimethyl sulfoxide (4.0 mL, 4.4 g, 56 mmol) in 75 mL of methanol is cooled in ice and treated with gaseous HCl. The temperature of the reaction mixture increases to 45° C. as the HCl is added. Additional HCl is added intermittently and the rate of cooling is adjusted so that a reaction temperature of 40°-50° C. is maintained for 3 hours. The mixture is cooled and the precipitated solid filtered and washed with ether to yield 6.3 g (52%) of [5-methoxy-2-(methoxycarbonyl)-1H-indol-3-yl] dimethylsulfonium chloride suitable for further synthesis; mp 130° C.-dec.
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18].CN1C(=O)CCC1.O.[OH-].[Li+]>O>[C:16]([C:17]1[S:18][C:4]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=2[C:6]=1[NH2:7])([O:20][CH3:21])=[O:19]
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: COC(=O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1N
Temperature: 2 °C
Reaction time: 0.67 h
Yield: 84.8 %

Procedure:
Equip a 22-L, 3-necked, round-bottom flask with a mechanical stirrer, nitrogen bubbler, and a thermocouple probe, charge with 1.20 kg (5.55 mole) of 2-nitro-4-trifluoromethylbenzonitrile, 589.3 g (496 mL, 5.55 mole) of methyl thioglycolate, and 4.3 L of NMP. Cool the resulting yellow solution to 2° C., and add slowly, over a period of 78 min a solution prepared from 466.0 g (11.11 mole, 2.0 eq) of lithium hydroxide monohydrate in 3.36 L of water while maintaining the temperature between 2–20° C. Allow the brown slurry to warm to 21° C. over a 2 h period, and then dilute with 8.0 L of water (observe exotherm->27° C.). Stir for 40 min and cool to 18° C., collect the product by filtration, rinsing with 10 L of water, then air-drying at ambient temperature to give 1.295 kg (84.7% yield) of 2-carbomethoxy-3-amino-6-trifluoromethylbenzo[b]thiophene, as a light-yellow solid, 99.8% pure by HPLC assay.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:12]OS(OC)(=O)=O>>[CH3:12][O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc(O)c(C=O)c1
Product: COc1ccc(OC)c(C=O)c1

Procedure:
Accordingly, the present invention provides a process for preparing 2,5-dimethoxy benzaldehyde comprising the steps of: (a) reacting a crude 2-hydroxy-5-methoxy benzaldehyde with a metal hydroxide to produce a reaction mixture comprising a metal salt of 2-hydroxy-5-methoxy benzaldehyde; (b) separating the metal salt of 2-hydroxy-5-methoxy benzaldehyde from the reaction mixture of step (a) to obtain an at least substantially pure metal salt of 2-hydroxy-5-methoxy benzaldehyde; and (c) alkylating the metal salt of 2-hydroxy-5-methoxy benzaldehyde of step (b) with dimethylsulfate to produce 2,5-dimethoxy benzaldehyde.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]1([CH2:11][N:12]2[CH2:17][CH2:16][C:15](=O)[CH:14]([O:19][CH3:20])[CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>CO>[C:5]1([CH2:11][N:12]2[CH2:17][CH2:16][C@H:15]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:14]([O:19][CH3:20])[CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1ccccc1
Reactant: COC1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CO[C@@H]1CN(Cc2ccccc2)CC[C@@H]1Nc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 3.7 %

Procedure:
Sodium cyanoborohydride (0.17g, 27 mmol) and 5.2g of 3A molecular sieves were slowly added at room temperature to a stirred solution of 1-phenylmethyl-3-methoxy-4-piperidone (5b, Ig, 4.56 mmol) from Example 3 in 40ml of methanol, 2.55g (27 mmol) of aniline and 3.57ml of 2.55N hydrochloric acid in methanol. The reaction mixture was stirred at room temperature for 3 days, after which time the molecular sieves were filtered off and the solution was made acidic with 10ml of 10% hydrochloric acid. The methanol was evaporated under vacuum and the residue was diluted with 20ml of water, then extracted with ether (50ml). The aqueous layer was then made alkaline with 10% sodium hydroxide solution and extracted with 3×100ml of ether. The combined organic layers were dried, then concentrated under vacuum and purified by column chromatography (silica gel; ethyl acetate/hexane; 1:1) to yield the intermediates cis-1-phenylmethyl-3-methoxy-4phenylaminopiperidine (7b, 0.52g, 38.23%) and trans-1-phenylmethyl-3-methoxy-4-phenylaminopiperidine (7b, 0.05g, 3.7%).