Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:28]=[C:11]3[N:12]=[C:13]([CH3:27])[C:14]([C@H:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[C:15](I)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][C:34]2[CH:38]=[C:39]([F:51])[C:40](B3OC(C)(C)C(C)(C)O3)=[CH:41][C:33]1=2)[CH:30]=[CH2:31].C([O-])([O-])=O.[Na+].[Na+].N#N>CN(C=O)C.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>[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][C:34]2[CH:38]=[C:39]([F:51])[C:40]([C:15]3[N:10]4[N:9]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=5)[CH:28]=[C:11]4[N:12]=[C:13]([CH3:27])[C:14]=3[C@H:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[CH:41][C:33]1=2)[CH:30]=[CH2:31]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
Reactant: C=CCN1CCOc2cc(F)c(B3OC(C)(C)C(C)(C)O3)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: C=CCN1CCOc2cc(F)c(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(Br)c5)nn34)cc21
Temperature: 90 °C
Yield: 29.6 %

Procedure:
A solution of (S)-methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.100 g, 0.179 mmol), 4-allyl-7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.060 g, 0.188 mmol) and 2.0 M aq. Na2CO3 (0.179 mL, 0.358 mmol) in DMF (4 mL) was sparged with N2 for 5 min, treated with Pd(Ph3P)4 (0.014 g, 0.013 mmol), sparged for 2 minutes, then sealed and heated (90° C.) for 6 h. The reaction was filtered (0.45 μm syringe tip filter), and purified by prep-HPLC, affording the desired product (0.033 g, 0.053 mmol, 29.5% yield), as a yellow oily film. 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.45-7.50 (m, 1H), 7.28-7.33 (m, 1H), 6.97 (br. s., 1H), 6.83 (d, J=6.3 Hz, 1H), 6.74-6.81 (m, 1H), 5.73-5.84 (m, 1H), 5.14-5.30 (m, 3H), 4.35-4.46 (m, 2H), 3.95 (m, 1H), 3.79 (s, 3H), 3.69-3.76 (m, 1H), 3.41-3.50 (m, 1H), 3.36 (m, 1H), 2.67-2.76 (m, 3H), 1.00-1.05 (m, 9H). LCMS (M+H)=625.3.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([C@H:13]([C:16]1[O:17][CH:18]=[C:19]([C:21]([O:23]C)=[O:22])[N:20]=1)[CH2:14][CH3:15])[CH3:12])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1>[C:3]([O:7][C:8]([NH:10][C@@H:11]([C@H:13]([C:16]1[O:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=1)[CH2:14][CH3:15])[CH3:12])=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: CC[C@@H](c1nc(C(=O)OC)co1)[C@@H](C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@@H](c1nc(C(=O)O)co1)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100 %

Procedure:
1N aqueous sodium hydroxide (5.69 ml, 5.69 mmol) was added in one portion to a solution of methyl 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylate (100 mg, 0.32 mmol) in anhydrous THF (1.11 ml). The reaction mixture was allowed to stir at room temperature for 3.5 hours before evaporating the organic in vacuo. The remaining aqueous portion was cooled to 0° C. and acidified to pH 4 using 1N HCl. The aqueous phase was then extracted with ethyl acetate (3×3 mL). The aqueous pH was re-checked and judged to be ˜pH 6-7. A small amount of 1N HCl was added to re-acidify the aqueous layer which was once again extracted with an additional portion of ethyl acetate (1×3 mL). The combined organics were dried (MgSO4) and evaporated in vacuo to give crude 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylic acid (95 mg, 0.32 mmol, 100% yield) as a white solid which was used immediately in the next reaction. EDC (86 mg, 0.45 mmol) was added in one portion to a mixture of 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylic acid (95 mg, 0.32 mmol) and HOBT (69 mg, 0.45 mmol) in anhydrous dichloromethane (5.0 ml) and the reaction allowed to stir at room temperature under a nitrogen atmosphere for 30 minutes. Ammonia was then bubbled through for approximately 5 minutes and the resulting white suspension allowed to stir at room temperature overnight. The reaction was then evaporated in vacuo and the residue partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was then dried (MgSO4) and evaporated in vacuo to give tert-butyl((2R,3R)-3-(4-carbamoyloxazol-2-yl)pentan-2-yl)carbamate (95 mg, 0.32 mmol, 100% yield) which was used immediately in the next step. LC/MS: M+H+436.11, ret. time=1.89 min. Column: Phenomenex, 2.0×30 mm, 2.5-μm particles; Mobile Phase A: 10:90 methanol:water with 0.05% TFA; Mobile Phase B: 90:10 methanol:water with 0.05% TFA; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min. HPLC: ret. time=2.73 min. Column: YMC CombiScreen ODS-A, 4.6×50 mm; Mobile Phase A: 10:90 methanol:water with 0.2% H3PO4; Mobile Phase B: 90:10 methanol:water with 0.2% H3PO4; Temperature: 50° C.; Gradient: 0-100% B over 4 minutes, then a 0.75-minute hold at 100% B; Flow: 4 mL/min.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[C:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)#[CH:19]>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]#[C:19][C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)[CH:21]=1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: C#Cc1cccnc1
Product: C(#Cc1cccc2c3c([nH]c12)C1CCN(CC1)C3)c1cccnc1

Procedure:
The product of Example 1B (130 mg, 0.45 mmol) and 3-ethynylpyridine (74 mg, 0.72 mmol; Aldrich) were processed according to the method described in Example 3 and purified by reverse-phase HPLC (Waters XBridge™ C18 5 μm OBD 30×100 mm column, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in 0.1% trifluoroacetic acid over 15 minutes) to afford the title compound as the bis trifluoroacetate: 1H NMR (500 MHz, methanol-d4) δ ppm 2.26-2.35 (m, 2 H), 2.36-2.45 (m, 2 H), 3.44-3.48 (m, 1 H), 3.48-3.56 (m, 2 H), 3.69 (ddd, J=13.8, 8.9, 5.3 Hz, 2 H), 4.77 (s, 2 H), 7.12 (t, J=7.6 Hz, 1 H), 7.39 (d, J=7.0 Hz, 1 H), 7.51 (d, J=7.9 Hz, 1 H), 7.74 (dd, J=8.1, 5.3 Hz, 1 H), 8.37 (dt, J=8.0, 1.6 Hz, 1 H), 8.65 (d, J=4.6 Hz, 1 H), 8.96 (s, 1 H); MS (APCI) m/z 314 (M+H)+. Anal. Calcd. for C21H19N3.2.85 TFA: C, 50.24; H, 3.45; N, 6.58. Found: C, 49.97; H, 3.54; N, 6.80.
Reaction SMILES: C([Mg]Cl)(C)C.[C:6]([O:10][C:11](=[O:32])[NH:12][C:13]([C:15]1[S:16][C:17]([S:30][CH3:31])=[C:18]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](Br)[CH:24]=2)(=[O:22])=[O:21])[CH:19]=1)=[NH:14])([CH3:9])([CH3:8])[CH3:7].[Li]CCCC.C[O:39][B:40](OC)[O:41]C>C1COCC1>[C:6]([O:10][C:11](=[O:32])[NH:12][C:13]([C:15]1[S:16][C:17]([S:30][CH3:31])=[C:18]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([B:40]([OH:41])[OH:39])[CH:24]=2)(=[O:22])=[O:21])[CH:19]=1)=[NH:14])([CH3:9])([CH3:8])[CH3:7]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(B(O)O)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 98.6 %

Procedure:
A solution of 2M i-PrMgCl in THF (1.1 mL, 2.2 mmol) was added dropwise at 0° C. to {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.5 g, 1.0 mmol) (Example 27c) in 5.0 mL THF. The solution was stirred for 20 mins at 0° C., then cooled to −78° C. and a solution of 2.5 M n-BuLi in hexanes (0.6 mL, 1.5 mmol) was added. The mixture was stirred for 5 mins then trimethylborate (0.35 mL, 3.3 mmol) was added at −78° C. and the mixture allowed to attain RT. The reaction was quenched with sat. NH4Cl (10 mL) and extracted with EtOAc (3×20 mL), dried over Na2SO4 and evaporated. The crude solid was purified by elution from a 5 g SPE with 10% MeOH/DCM to give 0.45 g (95%) of the title compound as a yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.28 (m, 1H), 8.05 (m, 1H), 7.95 (m, 1H), 7.60 (m, 2H), 2.66 (s, 3H), 1.51 (s, 9H). Mass spectrum (ESI, m/z) calcd. for C17H21BN2O6S3 456.1, found 456.7 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:10]([OH:11])=[C:9]([CH3:12])[CH:8]=[CH:7][N:6]=1)[CH3:3].[NH:13]1C=CN=[CH:14]1>C1(C)C(C)=CC=CC=1>[N:2]1([CH2:4][C:5]2[C:10]([OH:11])=[C:9]([CH3:12])[CH:8]=[CH:7][N:6]=2)[CH:1]=[CH:14][N:13]=[CH:3]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccnc(CN(C)C)c1O
Solvent: Cc1ccccc1C
Product: Cc1ccnc(Cn2ccnc2)c1O
Yield: 71.2 %

Procedure:
The procedure described in Example 1 was then repeated except that 2-dimethylaminomethyl-3-hydroxy-4-methylpyridine (4.44 g.) and imidazole (1.82 g.) were reacted in xylene (15 ml.) to afford 2-(imidazol-1-ylmethyl)-3-hydroxy-4-methylpyridine (yield, 3.60 g.), m.p. 170°-172° C. after recrystallization from toluene.
Reaction SMILES: [OH:1][C:2]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:7][CH2:6][CH2:5][N:4]([CH3:8])[CH2:3]1.[BH4-].[Na+]>CO>[OH:7][CH2:6][CH2:5][N:4]([CH2:3][CH:2]([OH:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:8]
Reactant: CCCCCCCCCCCCCCCCC1(O)CN(C)CCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCC(O)CN(C)CCO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To suspension of 2-Hydroxy-4-methyl-2-hexadecylmorpholine (5 g, 14.66 mmol) in methanol (150 mL) at 0° C. was added NaBH4 (1.1 g, 29 mmol over a period of 10 min. The reaction mixture was brought to room temperature slowly and stirred at room temperature for 12 hours. Additional NnBH4 (200 mg, 5.2 mmol) was added at room temperature and stirred for 2 hours at room temperature. Methanol was removed by rotavop and the residue was treated with water (100 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic phase was washed with water, brine and dried over Na2SO4. Evaporation of the solvent gave a product which was used without further purification in the next step. Yield 4.92g, 98%. NMR 1H (CDCl3, 200 MHz) 0.88 (3H, t, CH3), 1.26 (28H, s, CH2), 1.40 (2H, m, CH2), 2.32 (3H, s, N--CH3), 2.3-2.7 (4H, m, CH2), 3.66 (3H, m, CH2OH, CHOH). NMR 13C (CDCl3, 50 MHz) 67.6, 64.2, 59.7, 59.3, 42.5, 34.9, 31.9, 29.6, 29.3, 25.6, 22.6, 14.0. IR (KBr) cm-1 3436, 2918, 2850, 1469, 1087, 880, 722.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[C:7]=2[C:13](=[O:15])[CH3:14])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[C:7]=2[C:13](=[O:15])[CH3:14])[CH2:2][CH2:3]1
Reactant: CC(=O)c1c(O)cccc1OCC1CC1
Reactant: COc1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: COc1ccc(COc2cccc(OCC3CC3)c2C(C)=O)cc1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a stirred solution of 1-{2-[(cyclopropylmethyl)oxy]-6-hydroxyphenyl}ethanone (56.3 g, 272 mmol) in acetone (1000 mL) was added potassium carbonate (188 g, 1364 mmol), 4-methoxybenzyl chloride (40.9 mL, 300 mmol) and tetrabutylammonium iodide (20.2 g, 54.6 mmol). The mixture was stirred at reflux overnight. The reaction mixture was allowed to cool to room temperature, filtered on Celite®, and then the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The separated organic phase was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Then the resulting white solid was recrystallized from ethanol, collected by filtration, washed with ethanol, and dried under reduced pressure to give 1-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}ethanone as a white solid (79.2 g, yield; 89%). [Starting Compound 1H]
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:11])=[CH:8]/[CH2:9][OH:10].C(N(CC)CC)C.Cl.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[C:31]([OH:38])(=[O:1])[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.[C:31]([OH:38])(=[O:1])[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.[OH:1][CH2:2]/[C:3](/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:11])=[CH:8]/[CH2:9][OH:10]
Reactant: O=C(Cl)c1ccncc1
Agent: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccncc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 1.0 g of (E,Z,E) and (E,E,E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol in 30 ml of anhydrous chloroform was added 3.0 ml of triethylamine and then 2.0 g of isonicotinoyl chloride hydrochloride dropwise at room temperature. Stirring was continued for 3 hours. The reaction mixture was poured into ice-water, extracted with chloroform, washed with aqueous sodium hydrogencarbonate and water and dried over anhydrous sodium sulfate. The solvent was distilled off to give an oily substance, which was then purified by a column chromatography with silica gel (20 g) to afford 1.4 g of the end product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C1C=CC(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:34]=[N+:35]=[N-:36])=[O:12])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)/C=C/c1ccc(F)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)/C=C/c1ccc(F)cc1
Reaction time: 18 h
Yield: 90.7 %

Procedure:
To a solution of (E)-3-(4-fluorophenyl)acrylic acid (25 g, 150 mmol) in benzene (120 mL) was added triethylamine (30.5 g, 301 mmol) followed by DPPA (41.4 g, 150 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by conventional column chromatography (Silica gel, 60-120 mesh) using 10% ethyl acetate in pet ether as mobile phase to get the desired compound as a white solid (26 g, 90%). 1H NMR (400 MHz, CDCl3): δ ppm 7.73-7.69 (d, J=16 Hz, 1H), 7.55-7.51 (m, 2H), 7.11-7.07 (m, 2H), 6.36-6.32 (d, J=16 Hz, 1H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:11]2[C:6](=[CH:7][C:8]([C:25]3[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:9][CH:10]=2)[N:5]=1.[O:35]([CH:37]([CH3:39])[CH3:38])[Na]>C(O)(C)C>[CH:37]([O:35][CH2:3][C:4]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:11]2[C:6](=[CH:7][C:8]([C:25]3[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:9][CH:10]=2)[N:5]=1)([CH3:39])[CH3:38]
Reactant: FC(F)(F)c1ccc(Nc2nc(CCl)nc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1
Reactant: CC(C)O[Na]
Agent: Cl
Solvent: CC(C)O
Product: CC(C)OCc1nc(Nc2ccc(C(F)(F)F)cc2)c2ccc(-c3ncccc3C(F)(F)F)cc2n1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a suspension of [2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine hydrochloride (1.9 g, 0.0037 mol) in dry isopropanol (100 mL), add 20 equivalents of NaO-iPr (prepared from Na and isopropanol). Stir the pale yellow mixture at 60° C. for 5 hours, cool and evaporate the solvent under reduced pressure. Partition the residue between ethyl acetate and water and wash the organic layer with water (1×). Dry the organic layer (Na2SO4) and concentrate to give [2-isopropoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine as a foam. IC50 in standard assay of capsaicin receptor activity is less than 10 nanomolar.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[C:37]1([CH2:43]O)([CH2:41][OH:42])[CH2:40][CH2:39][CH2:38]1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:38]1[C:37]2([CH2:41][O:42][C:24]3([CH2:23][CH2:22][CH:21]([N:11]4[C:10](=[O:28])[C:9]([CH2:8][C:7]5[CH:6]=[CH:5][C:4]([C:29]6[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=6)=[CH:3][C:2]=5[F:1])=[C:14]([CH2:15][CH2:16][CH3:17])[N:13]5[N:18]=[CH:19][N:20]=[C:12]45)[CH2:26][CH2:25]3)[O:27][CH2:43]2)[CH2:40][CH2:39]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: OCC1(CO)CCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCC2(CCC2)CO3)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
A mixture of 3′-fluoro-4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (3.5 g), cyclobutane-1,1-diyldimethanol (1 g), p-toluenesulfonic acid monohydrate (0.014 g) and toluene (60 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 16 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (3.6 g, 86%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>CO.C(Cl)Cl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH2:1][C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][CH:11]=3)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]4[S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1[nH]c2ccc(CN3CCN(c4ccc(F)cc4)CC3)cc2c1Sc1ccccc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) with 1-(4-fluorophenyl)piperazine (90 mg, 0.50 mmol) as described in General Procedure X to afford Iaa (69.0 mg, 55.6%) as an ivory colored solid, tlc Rf=0.4 (10% MeOH/CH2Cl2-0.20% Et3N), m/z obs=461 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][CH:8]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH2:7]1)=[O:5])[CH3:2].[H][H]>[Pd].C(O)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(C=CC(=O)O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)N1CCC(CCC(=O)O)C1
Yield: 100 %

Procedure:
A mixture of 13 parts of 3-[1-(ethoxycarbonyl)-3-pyrrolidinyl]-2-propenoic acid and 100 parts of acetic acid was hydrogenated at normal pressure and at 20° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in methylbenzene and the latter was evaporated again, yielding 13 parts (100%) of 1-(ethoxycarbonyl)-3-pyrrolidinepropanoic acid as a residue (int. 28).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH2:9][C:10]([OH:12])=[O:11])[C:4](=[O:13])[CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH2:9][C:10]([OH:12])=[O:11])[C:4](=[O:13])[C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(O)cc(=O)n1CC(=O)O
Solvent: CC(=O)O
Product: Cc1cc(O)c([N+](=O)[O-])c(=O)n1CC(=O)O
Temperature: 80 °C
Yield: 70 %

Procedure:
31.2 g (0.17 mol) of 4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-1-acetic acid are suspended in 255 ml of acetic acid, 24 ml of a 68% aqueous nitric acid solution are added at room temperature and the mixture is heated to 80° C. on an oil bath. The reaction medium is cooled, the solvent is evaporated off and the residue is taken up in twice 100 ml of water. The mixture is evaporated to dryness and the residue is taken up with twice 100 ml of toluene. The product is recrystallized from isopropanol and dried in an oven. 27.2 g of product are obtained in the form of yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:16]=1.Cl[C:18]1[N:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1.C(N(CC)C(C)C)(C)C.CCOC(C)=O.O>C(O)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:11][CH2:12][N:13]([C:18]4[N:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=4)[CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:16]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: Brc1ccc2oc(C3CCNCC3)nc2c1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1cnc(N2CCC(c3nc4cc(Br)ccc4o3)CC2)nc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
Intermediate 5 (1 g, 3.4 mmol) and 2-Chloro-5-fluoropyrimidine was dissolved in isopropanol (20 ml) and added N,N-diisopropylethyl amine (2.4 ml). This mixture was stirred at 90° C. for 90 mins. Isopropanol was removed on rotavapour to obtain a residue. Work up (EtOAc/H2O) followed by purification on combiflash using a gradient mixture of EtOAc and Petether (7:93) as eluent afforded the titled compound as a pink solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:13]([C:7]1[C:6]([CH3:8])=[CH:5][C:4]([NH:9][C:10](=[O:12])[CH3:11])=[CH:3][C:2]=1[F:1])(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1cc(C)cc(F)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)Nc1cc(C)c(C(C)=O)c(F)c1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A dry CS2 solution (42 mL) containing N-(3-fluoro-5-methylphenyl)acetamide (30-1, 5.00 g, 29.9 mmol) and acetyl chloride (3.2 mL, 45 mmol) was slowly added with aluminum chloride (10 g, 74.8 mmol). The reaction mixture was heated at reflux for 2.0 h. The solution was cooled to room temperature and CS2 was decanted. The remaining syrup was poured into icy HCl, and the resultant solids were collected, re-dissolved in EtOH, and decolorized by charcoal. The solution was filtered and the filtrate was concentrated under vacuum to give N-(4-acetyl-3-fluoro-5-methyl-phenyl)acetamide (30-2, 6.10 g, 29.2 mmol) as light yellow solids in 97% yield: 1H NMR (500 MHz, CDCl3) δ 7.46 (d, J=12.4 Hz, 1 H), 6.93 (s, 1 H), 2.53 (d, J=3.8 Hz, 3 H), 2.31 (s, 3 H), 2.18 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:10]([CH2:11][CH2:12][OH:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].CS(OCC[C@H]1C2C=CC(C(N)=O)=CC=2CCO1)(=O)=O>>[CH3:15][S:16]([O:13][CH2:12][CH2:11][C@H:10]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:6]=2[CH2:7][CH2:8][O:9]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCC[C@@H]1OCCc2cc(Br)ccc21
Agent: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Product: CS(=O)(=O)OCC[C@@H]1OCCc2cc(Br)ccc21

Procedure:
The title compound was prepared from 2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol and methanesulfonyl chloride, as described for the preparation of 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate.